Gastrointestinal Infections and Enterotoxigenic Poisonings

6 Gastrointestinal Infections and typeof a Enterotoxigenic Poisonings Ecoli cause thatcan idea PHAR 837 | Infectious Diseases I Marc Salvatus, Pharm.D., BCPS West Coast University, School of Pharmacy October 6, 2024 Introduction • Gastrointestinal (GI) infections and enterotoxigenic poisonings - medical conditions characterized by inflammation of the GI tract • Gastroenteritis – inflammation of the GI tract • • Diarrhea, nausea, vomiting, fever, and abdominal pain may be present Diarrhea = increase in frequency of stools to >3/day • Inflammation-induced vomiting and diarrhea  morbidity and mortality • Etiology: wide variety of viral, bacterial, and parasitic pathogens Roecker AM, Bates BN. Gastrointestinal Infections and Enterotoxigenic Poisonings. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: A Pathophysiologic Approach, 11e. McGraw-Hill. 4 Gut Microflora • Intestinal microflora contains over 400 bacterial species • Flora is sparse in the stomach and upper intestine - more prevalent in the lower bowel • Role of flora • • é Digestion Prevent overgrowth of potentially pathogenic organisms (i.e. Clostridium difficile) 5 Epidemiology Globally • Dehydration secondary to acute infectious diarrhea  2nd leading cause of mortality in children younger than 5 years • 1.7 billion cases of infectious diarrhea occur annually  >1.39 million deaths • Incidence of childhood diarrhea is declining; however, diarrhea remains a major health problem in children (especially in those younger than 1 year) United States • 179 million episodes of acute gastroenteritis occur annually  500,000 hospitalizations and >5,000 deaths • Highest mortality risk among elderly (age >60 years) • Other groups at risk for GI infections: travelers and campers, patients in chronic care facilities, military personnel stationed abroad, immunocompromised patients Roecker AM, Bates BN. Gastrointestinal Infections and Enterotoxigenic Poisonings. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: A Pathophysiologic Approach, 11e. McGraw-Hill. 6 Etiology • Wide variety of viruses, bacteria, and parasites • Incidence of each is difficult to quantify Pathogens Enterotoxigenic (Watery) Dysentery (Bloody) Vibrio cholerae Enterotoxigenic Escherichia coli (ETEC) Rotaviruses Noroviruses Shigella spp. Salmonella spp. Campylobacter spp. Yersinia spp. Enterohemorrhagic E. coli (EHEC) Roecker AM, Bates BN. Gastrointestinal Infections and Enterotoxigenic Poisonings. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: A Pathophysiologic Approach, 11e. McGraw-Hill. 7 Etiology: Viral Gastroenteritis • Viruses – leading global cause of infectious diarrhea Rotavirus Norovirus Peak Age of Onset 6 months to 2 years All age groups Time of Year October to April Peak in winter Duration 3-7 days 2-3 days Mode of Transmission Fecal-oral, water, food Fecal-oral, water, food, environment Common Symptoms N/V/D, fever, abdominal pain, lactose intolerance N/V/D, abdominal cramps, myalgia Roecker AM, Bates BN. Gastrointestinal Infections and Enterotoxigenic Poisonings. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: A Pathophysiologic Approach, 11e. McGraw-Hill. Mor 8 i W Bacterial Gastroenteritis: Vibrio Cholerae • Gram-negative bacillus • Rare in the United States due to advanced water and sanitation systems • Endemic in developing countries with poor sanitation (e.g. Indian subcontinent, sub-Saharan Africa) • Mode of transmission: contaminated food or water with human feces • Cholera toxin • Most fluid loss occurs in the duodenum • Increased chloride secretion, decreased sodium absorption  fluid secretion • Causes severe and voluminous diarrhea  dehydration Ebb Roecker AM, Bates BN. Gastrointestinal Infections and Enterotoxigenic Poisonings. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: A Pathophysiologic Approach, 11e. McGraw-Hill. 9 Bacterial Gastroenteritis: E. coli • Gram-negative bacillus • Commonly found in the GI tract • Categories of E. coli-associated diarrhea • Enteroaggregative (EAEC) Bloody • Enterohemorrhagic (EHEC)no • Enteroinvasive (EIEC) • Enteropathogenic (EPEC) • Enterotoxigenic (ETEC)a Watry • Mode of transmission: contaminated food or water with animal or human feces Roecker AM, Bates BN. Gastrointestinal Infections and Enterotoxigenic Poisonings. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: A Pathophysiologic Approach, 11e. McGraw-Hill. 10 Bacterial Gastroenteritis: ETEC • Accounts for about half of all cases of E. coli diarrhea • Most common cause of traveler’s diarrhea • Produce enterotoxins: heat-labile and heat-stabile toxins • Heat-labile • Two subunits (A and B) • Similar action as cholera toxin  secretory diarrhea • Heat-stabile • Acts on the small intestine • Symptoms: watery diarrhea, abdominal cramping Roecker AM, Bates BN. Gastrointestinal Infections and Enterotoxigenic Poisonings. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: A Pathophysiologic Approach, 11e. McGraw-Hill. 11 Bacterial Gastroenteritis: EHEC • Enterohemorrhagic E. coli, also known as Shiga toxin-producing E. coli (STEC, or E. coli O157:H7) • Disrupts the mucosal integrity of the large intestine • Toxin can reach the endothelial cells in small blood vessels that supply the gut and kidney • Causes watery diarrhea • In 80% of patients, watery diarrhea becomes bloody in 1 to 5 days • May cause hemorrhagic colitis and hemolytic uremic syndrome (HUS) • Antibiotics may increase risk of HUS (increases production of Shiga-like toxin) Roecker AM, Bates BN. Gastrointestinal Infections and Enterotoxigenic Poisonings. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: A Pathophysiologic Approach, 11e. McGraw-Hill. 12 Bacterial Gastroenteritis: EHEC or 305 countsare platelet toolot 13 Bacterial Gastroenteritis: Campylobacter • Gram-negative bacillus – flagellated and curved • 14 different species • Campylobacter jejuni responsible for >99% of Campylobacter-associated gastroenteritis • 2.4 million persons affected each year in the U.S. • Mode of transmission: Contaminated food (particularly poultry), water, or contact with infected animals • Increasing resistance to fluoroquinolones Roecker AM, Bates BN. Gastrointestinal Infections and Enterotoxigenic Poisonings. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: A Pathophysiologic Approach, 11e. McGraw-Hill. 14 Bacterial Gastroenteritis: Salmonella enterica • Gram-negative bacillus • • • Facultative anaerobe Enterobacteriaceae family Typhoid and non-typhoid Salmonella cause distinct infections • • Typhoid: Enteric fevers Non-typhoid: Gastroenteritis (diarrhea, abdominal cramping, fever) • Mode of transmission: contaminated food, water, or contact with infected animals • Increasing multidrug resistance worldwide Roecker AM, Bates BN. Gastrointestinal Infections and Enterotoxigenic Poisonings. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: A Pathophysiologic Approach, 11e. McGraw-Hill. 15 Bacterial Gastroenteritis: Salmonella enterica Typhoidal salmonella allergic • Salmonella enterica serotype Typhi or Paratyphi • Causes enteric fever (blanket term for both typhoid and paratyphoid fever) • Severe systemic illness with fever and abdominal pain • Diarrhea uncommon • Signs/Symptoms • Erythematous rash on abdomen at • Hepatomegaly and/or splenomegaly • Elevation of LFTs, WBCs reaction enlarge liver • ye enlargraitof pealiver Bacteremia can persist for several weeks Onwuezobe IA, Oshun PO, Odigwe CC. Antimicrobials for treating symptomatic non-typhoidal salmonella infection. Cochrane Database Syst Rev. 2012;2012(11). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532567/. Accessed Oct 4, 2022. doi: 10.1002/14651858.CD001167.pub2. 16 Bacterial Gastroenteritis: Salmonella enterica Nontyphoidal salmonella • Salmonella serotypes other than Typhi/Paratyphi • Causes gastroenteritis (usually self-limited) • Risk factors: • <1 year old or >50 years old • 2 HIV-infected • 3 Immunocompromised (including organ transplant recipients, cancer patients receiving chemotherapy, patients with sickle cell disease) • Treatment  fluid and electrolyte replacement • Antimicrobial therapy usually not indicated in healthy adults • No effect on duration of fever or diarrhea • Potential to increase resistance • Indications for antimicrobial therapy: • a Risk factors present • 2 Severe diarrhea (>9 stools/day) • 3 High or persistent fever • a Need for hospitalization Onwuezobe IA, Oshun PO, Odigwe CC. Antimicrobials for treating symptomatic non-typhoidal salmonella infection. Cochrane Database Syst Rev. 2012;2012(11). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532567/. Accessed Oct 4, 2022. doi: 10.1002/14651858.CD001167.pub2. 17 Bacterial Gastroenteritis: Shigella • Gram-negative bacillus • • Enterobacteriaceae family Four species often associated with disease • • • Gastroenteritis in the U.S.: Shigella sonnei, S. flexneri Developing countries: S. dysenteriae type 1, S. boydii S. dysenteriae produce Shiga toxin  Hemolytic Uremic Syndrome • Mode of transmission: Fecal-oral, contaminated food or water with infected human feces • Ingestion of 10-200 viable organisms causes disease in healthy adults • Symptoms: watery/bloody diarrhea, severe abdominal pain, fever, malaise sings Roecker AM, Bates BN. Gastrointestinal Infections and Enterotoxigenic Poisonings. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: A Pathophysiologic Approach, 11e. McGraw-Hill. 18 Bacterial Pathogens: Yersinia • Gram-negative coccobacilli • Non-lactose-fermenting • Six species known to cause disease in humans • Mode of transmission: Contaminated food or water • Children more likely to experience illness • Symptoms: fever, abdominal pain, diarrhea (often bloody) Roecker AM, Bates BN. Gastrointestinal Infections and Enterotoxigenic Poisonings. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: A Pathophysiologic Approach, 11e. McGraw-Hill. 19 Clinical Presentation IE Enterotoxigenic (Watery) Dysentery (Bloody) % of patients 90-95 5-10 Number of stools per day <10 >10 Fecal occult blood test (FOBT) Negative Positive Fecal polymorpho-nuclear cells Absent or few Many Mechanisms Toxins Reduced absorption Toxins Mucosal invasion Complications Potential severe dehydration Acidosis Shock Electrolyte imbalance Mild dehydration constant fed Tenesmus so Rectal prolapse ofneedingtog Seizures tobathroom Roecker AM, Bates BN. Gastrointestinal Infections and Enterotoxigenic Poisonings. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: A Pathophysiologic Approach, 11e. McGraw-Hill. 20 comet Evaluation and Initial Management Initial evaluation Bloody diarrhea • Assess duration, frequency, characteristics of symptoms • Assess volume status • Evaluate for exposures or comorbidities Rule out C. difficile infection Initial management Non-bloody diarrhea Initial management • Empiric antibiotic therapy for severe illness or high-risk patients • Fluid repletion/maintenance • Antimotility agents if indicated • Assess for severe illness* and high-risk patients^ • Submit stool for bacterial culture and additional testing as appropriate • Empiric antibiotic therapy (if STEC is ruled out) • Fluid repletion/maintenance • Antimotility agents if indicated (e.g. loperamide, BSS) • More details in C. difficile lecture • Submit stool for bacterial culture • E. coli O157:H7 and Shiga toxin testing • Additional testing (e.g. parasites) * Severe illness includes: fever, signs or symptoms of hypovolemia, >6 unformed stools/24 hours, severe abdominal pain, need for hospitalization ^ High-risk patients include age >70 years, serious comorbidities (e.g. cardiac/renal disease, immunocompromised, advanced HIV infection) 21 Treatment General approach • Prevent dehydration  correct fluid and electrolyte imbalances • Mild gastroenteritis: oral fluids and easily digestible foods • Severe dehydrating diarrhea: IV rehydration therapy, antibiotics, and/or antimotility agents • Signs of dehydration include reduced blood pressure, increased heart rate (bradycardia in severe cases), increased respiratory rate, decreased urine output Roecker AM, Bates BN. Gastrointestinal Infections and Enterotoxigenic Poisonings. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: A Pathophysiologic Approach, 11e. McGraw-Hill. 22 Oral Rehydration Therapy • Cornerstone of therapy for dehydration due to diarrhea • Oral rehydration therapy (ORT) – Pedialyte, Infalyte, Oralyte, Rehydralyte • Necessary components of oral rehydration solution (ORS) – carbohydrates (glucose), sodium, potassium, chloride, water • Enhances sodium and water transport across intestinal walls • Avoid hyperosmolar solutions (>310 mOsm/L) – may cause osmotic diarrhea • Soft drinks, sweetened fruit drinks, chicken broth, and sports drinks • Severe dehydration (>10% loss of body weight) is an indication for IV fluid replacement • Rapid restoration of fluid losses • Correction of metabolic acidosis (Lactated Ringer solution preferred initially over normal saline) • Replacement of potassium deficiency • Other indications for IV fluid replacement: uncontrolled vomiting, paralytic ileus, stool output >10 mL/kg/hr, shock, loss of consciousness we causemorediarrheal Roecker AM, Bates BN. Gastrointestinal Infections and Enterotoxigenic Poisonings. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: A Pathophysiologic Approach, 11e. McGraw-Hill. 23 Antimicrobial Therapy • Roles of antibiotics: shorten diarrhea duration, decrease fluid loss, decrease shedding of viable bacteria into the environment • Risks of antibiotic use: • Increases in antimicrobial resistance • Side effects of antimicrobial agents • Eradication of normal flora  superinfections destiny • Antibiotic therapy recommended in: • Severe cases of diarrhea (fever, >6 stools/day, severe abdominal pain, or hospitalization), with the exception of dysentery diarrhea caused by EHEC • z High-risk individuals (age >70 years or comorbidities such as cardiac/renal disease, immunocompromising condition) • 3 Culture-proven bacterial diarrhea Dryden MS, Gabb RJ, Wright SK. Empirical treatment of severe acute community-acquired gastroenteritis with ciprofloxacin. Clin Infect Dis. 1996 Jun;22(6):1019-25. doi: 10.1093/clinids/22.6.1019. PMID: 8783703. 24 ABoldedorforstline is meanoftemconosetproy Pathogen Ciprofloxacin Fas Azithromycin macrolide Bactrim Ceftriaxone sulfonamide Doxycycline Tetracyline ETEC 750 mg PO daily x1-3 days 1 g PO x1 day or 500 mg PO daily x3 days Vibrio cholerae 750 mg PO daily x3 days 500 mg PO daily x3 days Campylobacter 750 mg PO daily x7 days 500 mg PO daily x3 days Salmonella (non-typhoidal) 750 mg PO daily x7-10 days 500 mg PO daily x7 days 800/160 mg PO BID x7 days 2 g IV/IM x1 Shigella 750 mg PO daily x3 days 500 mg PO daily x3 days 800/160 mg PO BID x7 days 2 g IV/IM x1 Yersinia 750 mg PO daily x7 days 300 mg PO x1 day 800/160 mg PO BID x7 days Shane AL, Mody RK, Crump JA, et al. 2017 Infectious Diseases Society of America Clinical Practice Guidelines for the Diagnosis and Management of Infectious Diarrhea. Clin Infect Dis 2017; 65:e45. 29 Adjunctive Therapy Drug Class Antimotility Agents WIN Probiotics Examples Recommendation Comments Lomotil® (diphenoxylate/ atropine), loperamide Not recommended in toxin-mediated dysenteric diarrhea (e.g. EHEC, pseudomembranous colitis, shigellosis) • • Lactobacilli, bifidobacteria Not recommended • • • Zinc supplements Various May shorten duration of diarrhea by 27 hours • • • These agents slow passage of stool Extended exposure to toxins and decreased clearance of organism May increase risk of HUS Variable efficacy for treatment/prophylaxis Potential for fungemia or bacterial sepsis Inadequate dietary intake 20 mg/day for 1-2 weeks AEs: metallic taste, vomiting, epigastric pain, lethargy, fatigue Roecker AM, Bates BN. Gastrointestinal Infections and Enterotoxigenic Poisonings. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: A Pathophysiologic Approach, 11e. McGraw-Hill. 30 Prevention • Public health measures – improved water supply and sanitation facilities • Personal hygiene including hand washing with soap and running water to prevent spread • Safe food handling and preparation practices • Vaccines - few available for GI infections • • • i Typhoid fever – Ty21a (Vivotif®), ViCPS (Typhim Vi®) Rotavirus – RotaTeq®, Rotarix® ETEC, Shigella – in development Roecker AM, Bates BN. Gastrointestinal Infections and Enterotoxigenic Poisonings. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: A Pathophysiologic Approach, 11e. McGraw-Hill. 31 Traveler’s Diarrhea • Malaise, anorexia, abdominal cramps  sudden onset of diarrhea • Increased risk when traveling to Latin America, southern Europe, Africa, Asia • Caused by contaminated food or water • Common pathogens include ETEC, Campylobacter, Shigella, Salmonella • Other pathogens include rotavirus, norovirus, and Giardia • Prophylactic antibiotics recommended only in highrisk individuals • Severe IBD, severe vascular/cardiac/renal disease that would be compromised by dehydration, immunocompromised Roecker AM, Bates BN. Gastrointestinal Infections and Enterotoxigenic Poisonings. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: A Pathophysiologic Approach, 11e. McGraw-Hill. 32 Traveler’s Diarrhea Drug Bismuth subsalicylate Rifaximin Prevention Treatment Comments 524 mg PO QID for up to 3 weeks for the duration of travel 524 mg every 30 minutes for up to 8 doses • AEs: Black discoloration of tongue/stools, tinnitus 200 mg PO 1-3 times daily for the duration of travel 200 mg 3 times daily for 3 days • Effective against noninvasive strains of E. coli (ETEC) May induce resistance when used monotherapy Max doses Ciprofloxacin - 500 mg PO BID x3 days, or 750 mg PO x1 Levofloxacin - 500 mg PO daily for up to 3 days Azithromycin - 1 g PO x1, or 500 mg PO daily for 3 days • • If symptoms persist after single-dose therapy, continue for 2 more days Roecker AM, Bates BN. Gastrointestinal Infections and Enterotoxigenic Poisonings. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: A Pathophysiologic Approach, 11e. McGraw-Hill. 33 Food Poisoning • Ingestion of food containing pathogenic microorganisms or preformed toxins produced by microorganisms that cause enterotoxigenic poisonings • Microorganisms include those previously mentioned, as well as Bacillus cereus (fried rice syndrome), Clostridium (botulinum and perfringens), Staphylococcus aureus • Most cases are short in duration with recovery within 1-2 days • Treatment  supportive care • • • Symptomatic relief with antiemetics and antimotility agents • • ORT preferred for fluid and electrolyte balance IV therapy for severely ill/unable to tolerate oral therapy Avoid antimotility agents in patients with high fever, bloody diarrhea, or fecal leukocytes Prevention: proper food selection, preparation, storage; sanitation and clean water supply Roecker AM, Bates BN. Gastrointestinal Infections and Enterotoxigenic Poisonings. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: A Pathophysiologic Approach, 11e. McGraw-Hill. 34 Summary • Enterotoxigenic vs dysentery infectious diarrhea • • Clinical presentation, pathogens, indications for antimicrobial therapy Preferred and alternative antimicrobial therapy • Oral rehydration therapy • Adjunctive therapy • Prevention • Traveler’s diarrhea • Food poisoning 35