11/12/2020 Promoting Gut Commensalism in the Intensive Care Unit Leslie A. Hamilton, PharmD, FCCP, FCCM, BCPS, BCCCP Associate Professor University of Tennessee Health Science Center College of Pharmacy [email protected] 1 Objectives To describe the effects of selected medications on the gut microbiome To compare and contrast the effects of parenteral and enteral nutrition on the microbiome To critique the use of oral decontamination and the subsequent effects on gut bacteria To determine the best practices for stress ulcer prophylaxis with regard to the microbiome To assess the role of antibiotics in microbiome changes 2 1 11/12/2020 Disclosures Nothing to disclose 3 What is the microbiome? Important for overall defense Viruses, yeasts, protists, archaea, and bacteria Physical mass of several kilograms Bacteria provide ~10 trillion organisms from 10 major groups Firmicutes, Bacteriodetes, and Actinobacteria Am J Physiol Gastrointest Liver Physiol 2017;312:G246-56. 4 2 11/12/2020 Microbiome The majority of the gut’s microorganisms are housed in the colon Bacteria in the gastrointestinal (GI) tract assist in: Metabolism Synthesis of certain enzymes and vitamins Energy production Drug metabolism Nutr Clin Pract 2018;33:614-24. 5 Image from: https://phys.org/news/2016-03-gut-microbiome-remarkably-stable.html (accessed 8/27/20) 6 3 11/12/2020 Medication Class Clinical Changes Effect on Microbiome Dysmotility, decreased Delayed gastric emptying, microbiome diversity, Opioids dysmotility propagation of some pathogenic organisms Decreased microbiome diversity, decreased elimination Stress Ulcer Prophylaxis Changes in pH of gastric bacteria, overgrowth of acid-intolerant bacteria Changes in bile salts and Enteral Nutrition Changes in nutrition elimination through translocation Impaired mucosal immunity, Parenteral Nutrition Changes in nutrition changes in elimination through translocation Elimination and suppression of Bacterial growth suppression, Antibiotics bacteria development of resistance 7 Opioids Used frequently in intensive care unit (ICU) setting Alterations in microbiome may explain some mechanisms of tolerance and addiction Common side effects relating to GI tract: Nausea, vomiting, constipation Changes in gastric motility and emptying Curr Opin Pharmacol 2017;37:126-30. 8 4 11/12/2020 Opioids Mechanism of changes: Relaxation of smooth muscle fibers Reduced gastric tone Stimulation of retrograde duodenal contractions Mu receptors Found on neurons, myenteric, and submucosal plexus Curr Opin Pharmacol 2017;37:126-30. Curr Opin Crit Care 2018;24:118-23. 9 Opioids Mu receptors: Reduced motility and secretion Found on B and T-cells and macrophages Animal studies have shown morphine can reduce T-cell maturation and change cytokine secretion May reduce antibody production and major histocompatibility complex Toxicol Pathol 2017;45:150-6. 10 5 11/12/2020 Morphine Morphine Metabolized by liver and hydrolyzed by beta- glucuronidase Bacteroides and bifidobacteria are major sources of beta-glucuronidase Affects how morphine is metabolized Toxicol Pathol 2017;45:150-6. 11 Opioids Lead to less diversity in microorganisms May lead to greater resistance and increase virulence factors May lead to increased risk of Clostridioides difficile and Citrobacter rodentium Curr Opin Crit Care 2018;24:118-23. Toxicol Pathol 2017;45:150-6. 12 6 11/12/2020 Stress Ulcer Prophylaxis Used in the treatment of gastroesophageal reflux, in GI bleeding, can prevent stress ulcers in ICU patients Most often proton pump inhibitors (PPI) or histamine-2 receptor blockers (H2B) Decreased gastric acidity, may lead to colonization of microorganisms Aliment Pharmacol Ther 2018;47:332-45. Clin Lab Med 2014;34:771-85. 13 PPIs PPIs are associated with pH changes in the stomach and proximal duodenum Fewer changes in the small bowel Also associated with: Hypergastrinemia Changes in luminal contents that affect absorption Binding to non-gastric H+/K+-ATPases May increase incidence of C. difficile infection (CDI) Aliment Pharmacol Ther 2018;47:332-45. Digestion 2018;97:195-204. Clin Lab Med 2014;34:771-85. 14 7 11/12/2020 PPIs Variable literature on PPI effects on microbiome One study obtained saliva, gastric fluid, and fecal samples from patients Compared samples in patients taking PPIs vs. not Bacterial overgrowth in stomachs of PPI users caused by lack of organism killing due to ↑ pH instead of bacterial overgrowth Clin Transl Gastroenterol 2015;6:e89. 15 PPIs May cause decreases in: May cause increases in: Faecalibacterium Streptococcus Clostridium Actinomyces Erysipelotrichales Enterococcus Staphylococcus Escherichia coli Aliment Pharmacol Ther 2018;47:332-45. Clin Lab Med 2014;34:771-85. 16 8 11/12/2020 PPIs Positive effects: Shown to have bacteriostatic activity in treatment of Helicobacter pylori Omeprazole may inhibit in vitro growth of gram-positive and negative bacteria More recent studies show that patients receiving enteral nutrition (EN) may not need stress ulcer prophylaxis Aliment Pharmacol Ther 2018;47:332-45. J Crit Care 2018;43:108-13. 17 Antibiotics Importance of antimicrobial stewardship Inappropriate use can lead to multidrug- resistant strains of: Methicillin-resistant Staphylococcus aureus Vancomycin-resistant Enterococcus Gram-negative rods Especially associated with broad-spectrum agents Antimicrob Agents Chemother 2009;53:4264-9. 18 9 11/12/2020 Antibiotics Antibiotic Organism Affected Actinobacteria Azoles Firmicutes Beta-lactams Fusobacteria Clindamycin Fusobacteria Firmicutes (Fusobacteria) Fluoroquinolones Proteobacteria phyla Actinobacteria Nitrofurantoin Firmicutes Bacteriodetes Sulfonamides Firmicutes PLoS One 2014;(4):1-7. ISME J 2016;10:707-20. Br J Nutr 2014;112:536-46. Genome Biol 2012;13:1-18. J Microbiol Methods 2013;92:387-97. J Antimicrob Chemother 2013;68:214-21. 19 Antibiotic-Induced Diarrhea Clindamycin, cephalosporins, and broad- spectrum penicillins show increased risk or antibiotic-associated diarrhea A significant increase in risk has been associated with treatment for greater than three days (RR 2.28; 95% CI 1.23-4.21) Antimicrob Agents Chemother 2009;53:4264-9. 20 10 11/12/2020 Antibiotic-Induced Diarrhea Meta-analysis of over 2 million adverse events submitted to FDA show clindamycin most association with CDI Odds ratio 46.95 (95% CI 39.49 – 55.82) Some antibiotics may have protective properties: Doxycycline Piperacillin-tazobactam Int J Med Sci 2019;16:630-5. Antimicrob Agents Chemother 2013;57:2326-32. Infect Control Hosp Epidemiol 2008;29:44-50. BMC Infect Dis 2016;16:159. 21 Chlorhexidine Gluconate Used for topical oral decontamination Antibacterial and antifungal properties with activity against: Staphylococcus aureus Enterococcus faecalis Some Actinomyces species Candida albicans Relatively safe with mild adverse effects Iran Endod J 2008;2:113-25. 22 11 11/12/2020 Chlorhexidine Gluconate Historically, a standard of care in the ICU for the prevention of ventilator-associated pneumonia (VAP) Most recent evidence shows: Inconsistencies with decreased VAP and nosocomial pneumonia incidence No significant effect on morbidity or other patient-centered outcomes in mechanically ventilated patients J Hosp Infect 2013;84:283-93. JAMA Internal Med 2014;174:751-61. Cochrane Database Syst Rev 2016;10:CD008367. 23 Use in Cardiac Surgery Evidence supports a significant reduction in nosocomial infection incidence in mechanically ventilated cardiac surgery patients with the use of chlorhexidine 0.12% oral rinse Recommended standard practice by the 2003 CDC guidelines for ICU care of patients undergoing cardiac surgery, but not in other patient populations Lancet Infect Dis 2011:11:845-54. Intensive Care Med 2018;44:1017-26. MMWF Recomm Rep 2004;53:1-36. 24 12 11/12/2020 Enteral Nutrition Enteral nutrition (EN) should be initiated with 24-48 hours The GI tract forms a network that includes Autonomic nervous system Enteric nervous system Help to innervate the majority of the body’s immune cells J Parenter Enteral Nutr 2016;40:159-211. Am J Physiol Gastrointest Liver Physiol 2017;312:G246-56. 25 Levels of Defense Network has multiple levels of defense: Allows for digestion Prevents the development of infection Releases appropriate antibodies The GI tract mucosa prevents intraluminal bacteria and toxins from migrating from inside the GI tract Lancet Gastroenterol Hepatol 2018;3:281-7. 26 13 11/12/2020 Mucosal Barrier The GI mucosal barrier consists of three layers: Biochemical layer Physical barrier Immunological layer In the absence of EN, these layers degrade and the mucosa becomes leaky, allowing bacteria to migrate to the submucosal tissue Lancet Gastroenterol Hepatol 2018;3:281-7. 27 Image from: https://courses.lumenlearning.com/suny-ap2/chapter/overview-of-the-digestive-system/ (accessed 8/31/20) 28 14 11/12/2020 Mucosal Barrier The GI mucosa also experiences rapid cell turnover The entire mucosa is replaced every 3 – 6 days For this cell turnover to occur, however, the mucosa must receive enough nutrients through an oral or enteral route Lancet Gastroenterol Hepatol 2018;3:281-7. 29 Organism Functions Organisms in the microbiota: Protect against harmful pathogens Synthesize certain vitamins Assist with metabolism and excretion Gut-associated lymphoid tissues (GALT) are also found in the GI tract Release immunoglobulins to protect mucosal surfaces Am J Physiol Gastrointest Liver Physiol 2017;312:G246-56.