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]
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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
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Disclosures
Nothing to disclose
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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.
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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.
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Image from: https://phys.org/news/2016-03-gut-microbiome-remarkably-stable.html (accessed 8/27/20)
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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
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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.
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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.
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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.
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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
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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
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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.
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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
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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.
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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.
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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.
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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
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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.
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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.
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Image from: https://courses.lumenlearning.com/suny-ap2/chapter/overview-of-the-digestive-system/ (accessed 8/31/20)
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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.
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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.
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Enteral Nutrition
To minimize the changes on the microbiome, enteral nutrition should remain the mainstay of nutrition support, with parenteral nutrition only used when necessary
Nutrients 2017;9:987.
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Parenteral Nutrition
Parenteral nutrition (PN) should be restricted to those with restrictions to EN with the need for prolonged alternate forms of nutrition With PN, gut atrophy occurs and GALT levels ↓ Leads to changes in T lymphocytes and neutrophils and ↓ in memory B cells
J Parenter Enteral Nutr 2016;40:159-211.
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Effects of PN
Lower amounts of cytokines and immunoglobulin A are produced in the intestines and lungs With epithelial layer interruption, decreased production of antimicrobial defense mechanisms, and translocation of microbes and toxins Overproduction of certain bacteria can activate toll-like receptors, which modulates GI tract inflammation Am J Physiol Gastrointest Liver Physiol 2017;312:G246-56. Curr Opin Clin Nutr Metab Care 2015;18:496-500. 33
Effects of PN
Use of nutrition solely from a parenteral source can increase tumor necrosis factor, which regulates cell growth and death, and shift to more cell destruction
Curr Opin Clin Nutr Metab Care 2015;18:496-500.
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Change in Bacteria with PN
Decreases Increases Bacteroides fragilis Actinobacteria Firmicutes Bacteroidetes Enterobacteriaceae Proteobacteria
Am J Physiol Gastrointest Liver Physiol 2017;312:G246-56.
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Intestinal Failure
Multiple factors affecting microbiome in patients with intestinal failure: Amount of remaining portions of the GI anatomy Bowel resection can change pH, oxygen concentrations, and bile acid circulation, in addition to changes in bacterial flora Use of EN + PN Other medications
J Parenter Enteral Nutr 2019;43:194-205.
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Intestinal Failure
Review of patients in intestinal failure found: Decreased diversity of microorganisms Increase in Lactobacillus and Proteobacteria Especially Enterobacteriaceae and Gammaproteobacteria Reduced amounts of Bacteroidetes and Firmicutes
J Parenter Enteral Nutr 2019;43:194-205.
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Intestinal Failure
Other complications include: D-lactic acidosis Intestinal failure-associated liver disease Both may be contributed to by bacterial overgrowth of certain microorganisms In patients with parenteral nutrition- associated liver disease (PNALD), bile acid composition is altered due to the change in the gut microbiota
Nutrients 2017;9:987.
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Intestinal Failure
In patients with a normal microbiome: Bacteria conjugate bile acids to other forms Regulate metabolism Assist with absorption of fat and vitamins In patients with intestinal failure, there has been some association with microbiome changes and development of PNALD
Nutrients 2017;9:987.
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Intestinal Failure
Patients with intestinal failure have changes in their bile acid composition and excretion This may lead to: Inflammation Changes in microorganisms PNALD
Nutrients 2017;9:987.
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Conclusions
Practitioners often underestimate the critical role of the microbiome Institution of policies and protocols for appropriate use of opioids and PPIs Antibiotics should be used judiciously Focus on those with the narrowest spectrum De-escalate appropriately Prevent development of multi-drug resistant organisms
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Conclusions
Utilizing EN is vital in maintaining native gut flora If PN is required, limit its use to the shortest duration necessary These strategies can preserve the microbiome and contribute to gut commensalism
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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]
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24 MSPEN Annual Fall Conference and Chapter Meeting 2020 Promoting Gut Commensalism in the Intensive Care Unit Leslie A. Hamilton, PharmD, FCCP, FCCM, BCPS, BCCCP
Learning Objectives:
1. To describe the effects of selected medications on the gut microbiome 2. To compare and contrast the effects of parenteral and enteral nutrition on the microbiome 3. To critique the use of oral decontamination and the subsequent effects on gut bacteria 4. To determine the best practices for stress ulcer prophylaxis with regard to the microbiome 5. To assess the role of antibiotics in microbiome changes
Assessment Questions:
1. In ICU patients, which is the most protective of the gut’s microbiome? a. Enteral Nutrition b. Parenteral Nutrition c. Famotidine d. Pantoprazole 2. In which patient population has chlorhexidine gluconate 0.12% mouth rinse consistently shown a decrease in nosocomial infections a. All ICU patients who are mechanically ventilated b. Only non-mechanically ventilate trauma and burn ICU patients c. Cardiothoracic surgery patients receiving mechanical ventilation d. ICU patients who have antibiotic exposure within the previous 90 days 3. Which of the following is the primary mechanism for changes in the microbiome with opiates? a. Bacterial growth suppression b. Impaired mucosal immunity c. Dysmotility d. Changes in bile salts 4. Which scenario presents a greater risk for developing antibiotic-associated diarrhea or Clostridioides difficile infection in the ICU setting? a. A ten-day course of clindamycin 900 mg every 6 hours b. A pre-op and post-op dose of vancomycin IV 1500 mg c. A three-day course of amoxicillin 500 mg PO three times daily d. A seven-day course of doxycycline 100 mg PO twice daily