PROBIOTICS: HEALTHY BACTERIA USED IN HEART SURGERY PATIENTS. Crista Lynn Lickteig. A Thesis Submitted to the Faculty of the

1 PROBIOTICS: HEALTHY BACTERIA USED IN HEART SURGERY PATIENTS By Crista Lynn Lickteig A Thesis Submitted to the Faculty of the DEPARTMENT OF MEDICAL PHARMACOLOGY In Partial Fulfillment of the Requirements For the Degree of MASTERS OF SCIENCE In the Graduate College THE UNIVERSITY OF ARIZONA 2011

2 STATEMENT BY AUTHOR This thesis has been submitted in partial fulfillment of requirements for an advanced degree at The University of Arizona and is deposited in the University Library to be made available to borrowers under rules of the Library. Brief quotations from this thesis are allowable without special permission, provided that accurate acknowledgment of source is made. Requests for permission for extended quotation from or reproduction of this manuscript in whole or in part may be granted by the head of the major department or the Dean of the Graduate College when in his or her judgment the proposed use of the material is in the interests of scholarship. In all other instances, however, permission must be obtained from the author. SIGNED: (student signs their name here) APPROVAL BY THESIS DIRECTOR This thesis has been approved on the date shown below: Edward D. French Professor of Medical Pharmacology Date )

3 ACKNOWLEDGEMENTS I would like to acknowledge my committee members Edward D. French Ph.D., M. Cristy Smith M.D., and Thomas P. Davis Ph.D. for their support, enthusiasm, and knowledge. I would also like to thank Apameh Bashar R.D. for providing me with articles on nutrition and probiotics. Furthermore, I would like to also acknowledge Aleem Siddique for his guidance and constructive criticism.

4 DEDICATION I would like to dedicate this document to my classmates, family, friends, boyfriend, instructors, surgeons, and professors. They have supported and encouraged me throughout this huge journey. The laughter, kind words, and constructive criticism they have provided will forever be appreciated.

5 TABLE OF CONTENTS ABBREVIATIONS...6 LIST OF FIGURES...7 LIST OF TABLES...8 ABSTRACT...9 INTRODUCTION...11 History...11 Common Infections...13 Defining Probiotics...15 Target Audience...17 CURRENT LITERATURE...18 Use In Liver Transplants...18 Reduction In Disease Severity...20 Treatment Of Diarrhea...23 Safety Of Probiotics...25 CURRENT PROBLEM...30 Common Infections In Post-Cardiac Surgery Patients...30 Cost Effectiveness...34 RECOMMENDATIONS...38 REFERENCES...41

6 ABBREVIATIONS CABG- Coronary Artery Bypass Grafting CFU- Colony Forming Units FAO- Food and Agriculture organization FDA- U.S. Food and Drug Administration HAI- Hospital Acquired Infection LAB- Lactic Acid Bacteria WHO- World Health Organization OTC- Over The Counter

7 LIST OF FIGURES FIGURE 1. Actions of Probiotics. Extracted from Cresci..16 FIGURE 2. B. Infantis reduces S. typhimurium disease severity and systemic translocation. Extracted from Mahony...21

8 LIST OF TABLES TABLE 1. TABLE 2. TABLE 3. TABLE 4. TABLE 5. Classification of Major Probiotics. Extracted from Levitsky...28 Desirable Properties of a Probiotic Strain...29 Diagnosis of Mediastinitis and Antibiotic Therapy. Extracted from Stolf...31 Hospital Costs Due to HAI. Extracted from Graves...35 Hospital Costs Due to HAI Continued. Extracted from Graves...36

9 ABSTRACT Post-operative infections are of high concern and are a great risk to patients who have just had an open-heart surgical procedure. Exposing the human body to elements it s clearly not used to, by opening the chest to perform heart surgery, greatly increases a patients risk of infection. Surgery is usually the last line of defense used by physicians. This is not only because the invasiveness of the procedure, but because of the heightened risk of infection for the patient. In the treatment of surgical patients, the possibility of infection and protocol for treatment must be taken into account. Patients who undergo open-heart procedures, such as CABG s, Valve Repair/Replacement, Aneurysms, and Aortic Root Repair/Replacement, often have compromised immune systems. A compromised immune system, exposure of the chest cavity during surgery, and length of hospital stay are all contributing factors to hospital acquired

10 infections (HAI). Infections vary depending on the nature of the surgery, the institution, surgical technique, and also varies by patient. Pneumonia, sepsis, bacterial endocarditis, and mediastinitis are all potential concerns in patients who have undergone recent open-heart surgery. The recent societal push for a more holistic approach to medicine and an effort for treatments with fewer side effects have lead to increased research in the realm of probiotics. Probiotics are good bacteria that are thought to aid in the intestinal microbial balance. They also have been shown to improve gastrointestinal problems. By integrating the use of probiotics into the treatment of post cardiac surgery patients, we expect to see a decrease in gastrointestinal problems and infections. We also believe that this will improve patients overall health. This preventative treatment will save the hospital millions of dollars in revenue that is spent on treating infections and will also increase hospital bed turnover.

11 INTRODUCTION History Post-operative infections are of high concern and great risk to patients who have just had open-heart surgery. These patients often have compromised immune systems and are at a greater risk for hospital acquired infections (HAI). Pneumonia, sepsis, bacterial endocarditis, and mediastinitis are all potential concerns in patients who have undergone recent open-heart surgery. The integration of a more holistic approach to medicine and a push for treatments with fewer side effects has lead to increased research in the realm of probiotics. Probiotics are good bacteria that are thought to aid in the intestinal microbial balance and have shown to improve gastrointestinal problems. By integrating the use of probiotics into the treatment of post cardiac surgery patients, we expect to see a decrease in gastrointestinal problems and infections. We also believe that this will improve patients overall health and will save the hospital

12 millions of dollars in revenue that is spent on treating infections and will also increase hospital bed turnover. There is a vast array of information available on probiotics, such as manufacturer s websites to studies revealing the health benefits of a probiotic regimen in the average healthy individual. However, there is no literature available on the use of probiotics in postcardiac surgery patients. Therefore, we decided to review the current literature available and develop recommendations for the use of probiotics as a form of preventative medicine used after cardiac patients have undergone an open-heart procedure.

13 Commom Infections Patients who have undergone open-heart surgery are at risk for developing numerous infections, including, but not limited to: bacterial endocarditis, pneumonia, sepsis, and mediastinitis. These patients often have gastrointestinal complications post surgery. With the case of mediastinitis, determining the origin of the infection is often difficult and can lead to late diagnosis, making treatment even more difficult. Below in Table III, from Stolf s research on Mediastinitis After Cardiac Transplantation, the types of infection associated with mediastinitis and the antibiotic therapy used is neatly represented. This is an excellent representation of the large number of antibiotics used to treat infection in post-cardiac surgery patients. It is also important to note the number of infections that the multi-drug resistant antibiotic vancomycin is used.

14 Due to the vast array of antibiotics used, it seems more advantageous to give one form of therapy that reduces the risk of infection and thereby reducing the usage of antibiotics. The integration of a probiotic regimen, such as used in the Levitsky study would decrease the number of infections, decrease the number of antibiotics used to treat those infections, and would have the potential to lower the risk of antibiotic resistance. Fighting infection is a current battle for physicians who are treating patients with infections, where often the origin of the infection is unknown. By preventing the infection, patients are able to heal quicker and resume to a healthier state of being.

15 Defining Probiotics Probiotics as defined by the WHO are live microorganisms which when administered in adequate amounts confer a health benefit on the host, (FAO 2001). The use of probiotics have been documented for over 5,000 years. There use was even documented is as far back as Ancient Egyptians who used yeast. They are naturally occurring microorganisms that can be found in fermented dairy products, sauerkraut, and in recent years have been isolated and manufactured as OTC supplements.

16 Figure 1. Extracted from Cresci. Actions of Probiotics. PROBIOTICS Strengthen host defenses Produce short- fatty acids; chain Modify bile acids; Decrease intestinal ph Enhance secretory antibody Tighten mucosal barrier Balance T-helper cell response Competetitvelybind pathogen receptor sites Produce antimicrobial and antibiotic molecules

17 Target Audience The recommendations are intended for all individuals involved in the care and treatment of individuals who have had recent cardiac surgery. This includes, but is not limited to physicians, nurses, nutritionists, dieticians, pharmacologists, and at home caregivers.

18 Use In Liver Transplants CURRENT LITERATURE There currently is very little literature available about the use of probiotics in post-surgery patients. In fact, there is absolutely no literature on probiotics used in cardiac patients. The most applicable published study to date was a study performed in 2006, by Josh Levitsky, M.D. at Northwestern University Feinberg School of Medicine. In this study, liver transplant patients were divided into two groups: those who received four fibers and probiotics and those who received only the four fibers. Both groups received enteral nutrition. All study participants were placed on the regimen 1 day prior to surgery and continued the therapy for the 14 days following the surgery. The incidence of post-operative bacterial infections was significantly reduced; being 48% with only fibers and 3% with LAB (lactic acid bacteria) and fibers. In addition, the duration of antibiotic therapy was significantly shorter in the latter group, (Rayes 507).

19 Their findings indicate that it is advantageous for liver transplant patients to be on a probiotic regimen in order decrease the risk of infection and decrease the use of antibiotics.

20 Reduction In Disease Severity Another study performed at University College Cork in Cork, Ireland suggests that the consumption of gut microbiota can increase the response of the immune system. There mouse model study, which fed mice with the bacteria B. infantis, showed that mice who were fed Bifidobacterium infantis had an increase in Treg numbers and a reduction in the disease severity after infection with S. typhimurium (Figure 1). The deliberate consumption of one commensal organism, Bifiobacterium infantis 35624, resulted in the induction of Treg cells which protected the host from excessive inflammation during the course of infection as evidenced by reduced pro-inflammatory cytokine production, reduced T cell proliferation, reduced dendritic cell costimulatory molecule expression and attenuation of NF- κb activation, (Mahoney).

21 Figure 2- Mahoney nfantis reduces S. typhimurium disease severity and systemic translocation. Macroscopic clinical scoring of

22 mice infected with S. typhimurium reveals a significant reduction in B. infantis pre-fed mice disease symptoms 8 days following initial infection (n = 10/group); (B) S. typhimurium numbers were reduced in the spleens and livers of B. infantis fed mice 6 days following infection (n = 18/group). *p<0.05 versus placebo. (Mahoney)

23 Treatment Of Diarrhea Henry Tissier, a French pediatrician, observed that children with diarrhea had in their stools a low number of bacteria characterized by a peculiar, Y shaped morphology. These bifid bacteria were, on the contrary, abundant in healthy children (Tissier, 1906). He suggested that these bacteria could be administered to patients with diarrhea to help restore a healthy gut flora, (FAO). The use of probiotics has also been seen in the prevention and treatment of diarrhea associated with the use of antibiotics. It has also been used in acute infantile diarrhea and is thought to be a possible treatment of the infection Helicobacter Pylori. The use of antibiotics in infants is thought to destroy the good bacteria that naturally inhabit the gastrointestinal microflora, leaving these children more susceptible to certain strains of sepsis such as those caused by staphylococci, Enterobacteriaceae, and Enterococci,

24 (DeLorenzo). It is advocated by many nutritionists and dieticians that these pre-disposed infants would benefit from a probiotic regimen that would lessen the likelihood of them falling ill to acute infantile diarrhea or antibiotic-associated diarrhea.

25 Safety Of Probiotics The most commonly accepted definition of probiotics defined by the World Health Organization is: Live microorganisms which when administered in adequate amounts confer a health benefit on the host. Probiotics are naturally occurring microorganisms that have proven to be safe for over thousands of years. For example, yeast was used by the Egyptians over 5,000 years ago and is associated with the probiotic Saccharomyces Cerevisiae. Table 1 below, taken from the Levitsky study, shows that the byproducts of the listed probiotics are naturally occurring in the human body. Lactic acid bacteria (LAB) has been used for a long time with safe outcomes. However, some strains of probiotics are sensitive to some antibiotics that currently used clinically. With antibiotic resistance being of increasing concern to physicians and pharmacologists, it is

26 important to consider the probiotics resistance to certain antibiotics. Vancomycin is one of the last resort antibiotics used to treat multi-drug resistant pathogens and this could be detrimental to a patient who has built up a resistance to Vancomycin. (Salminen) Probiotics are naturally found in yeast, fermented cabage (sauerkraut), yogurt, buttermilk, some sour creams, and some cottage cheeses. These forms of probiotics have been the most widely used and tested by humans since the creation of each food item. They have all proven over time that they are safe to use in the average healthy individual. There are also probiotic supplements on the market, as well as beverages, sachets, chocolate, and yogurts with probiotic supplements added. The U.S. Food and Drug Administration (FDA) has not approved of a specific health benefit to the use of probiotics. More studies need to be done to have the data to prove that there is indeed a benefit to using probiotics. There are not an adequate

27 number of studies to entice the FDA to give there stamp of approval, although the studies that have been done are quite promising.

28 Table 1. Extracted from Levitsky- Classification of Major Probiotics Class Species Fermentation Products Lactic Acid Bacteria Lactococci Lactococcus lactis Lactic acid Lactococcus raffinolactis Lactobacilli Lactobacillus acidophilus Lactobacillus salivarius Lactobacillus casei Lactic acid + small amounts of CO2 Lactobacillus rhamnosus Lactobacillus plantarum Lactobacillus bifermentans Lactic acid, ethanol, CO2 Lactobacillus fermentum Bifidobacteria Bifidobacterium breve Lactic acid, acetic acid Bifidobacterium bifidum Bifidobacterium infantis Bifidobacterium logtis Bifidobacterium longum Other Lactic Acid Bacteria Enterococcus faecium SF68 Lactic acid Pediococcus pentosaceus Leuconostoc mesenteroides Lactic acid, ethanol, CO2 Other bacteria (Gram-positive) Streptococcus thermophilus Lactic acid Clostridium butyricum Lactic acid, acetic acid, butyric acid Other bacteria (Gram-negative) Escherichia coli Nissle 1917 Lactic acid, acetic acid, formic acid, ethanol, CO2 Yeast Saccharomyces (cerevisiae subsp.) boulardii Ethanol, CO2

29 Table 2. Cresci-Desirable Properties of a Probiotic Strain. Characteristic Functional and Technological Properties Human Origin Species-dependent health effects and maintenance of viability, applicability to fermented food Resistant to Survival into the intestine, maintenance acid and bile of adhesiveness Attachment to Immune modulation, competitive exclusion human of pathogens, maintenance of mild acidity epithelial throughout storage time, food acidity cells profile Colonization of the human intestine Production of antimicrobial substances Antagonism against pathogenic bacteria (not the normal flora) Safety in food and clinical use Clinically validated and documented beneficial effects on human health Survives fecal bacteria, multiplication in the intestinal tract at least temporarily, immune modulation Pathogen inactivation in the intestine, normalization of gut flora, good storage stability and shelf-life in functional food products Prevention of dental decay and pathogen exclusion, prevention of pathogen adhesion, normalization of gut flora, ability to keep properties after freeze drying, drying, and other processing methods Accurate strain identification (genus, species), documented safety Dose-response data for minimum effective dosage in different products

30 CURRENT PROBLEM Common Infection In Post-Cardiac Surgery Patients Patients who have undergone open heart surgery are at risk for developing numerous infections, including, but not limited to: bacterial endocarditis, pneumonia, sepsis, and mediastinitis. These patients often have gastrointestinal complications post surgery. With the case of mediastinitis, determining the origin of the infection is often difficult and can lead to late diagnosis, making treatment even more difficult. Below in Table III, from Stolf s research on Mediastinitis After Cardiac Transplantation, the types of infection associated with mediastinitis and the antibiotic therapy used is neatly represented. This is an excellent representation of the large number of antibiotics used to treat infection in post-cardiac surgery patients. It is also important to note the number of infections that the multi-drug resistant antibiotic vancomycin is used.

31 Table 3- Extracted From Stolf- DIAGNOSIS OF MEDIASTINITIS AND ANTIBIOTIC THERAPY

32 Due to the vast array of antibiotics used and the increasing resistance of bacteria to antibiotics, it would be more advantageous to give one form of therapy that reduces the risk of infection. This essentially would lead to the reduction in the necessity of antibiotics except for severe cases. With the ever increasing resistance of bacterial infection to antibiotics, a new approach to treatment is not only practical, but undeniably necessary. The integration of a probiotic regimen, such as used in the Levitsky study would decrease the number of infections, decrease the number of antibiotics used to treat those infections, and would have the potential to lower the risk of antibiotic resistance. Fighting infection is a current battle for physicians who are treating patients with infections, where often the origin of the infection is unknown. By preventing the infection, patients are able to heal quicker and resume to a healthier state of being. Preventative medicine has been practiced throughout human civilization. To prevent

33 hypothermia, humans have developed clothing and housing to protect them from environmental elements. In order to prevent the spread of bacteria, hand washing has become standard of care. It seems only rational to incorporate naturally occurring probiotics into the everyday life of everyone, in particular cardiac patients, to help prevent infection.

34 Cost Effectiveness With the increasing costs of health care, hospitals are forced to be more diligent in how resources are used and how the cost of treating a patient can be minimized without compromising patient care. Chronic diseases, including cardiovascular and neurodegenerative conditions, diabetes, stroke, cancers, and respiratory diseases, constitute 46% of the global disease financial burden and 59% if global diseases, (Cresi 20). A recent study in Brisbane, Australia looked in depth at how much infections actually cost hospitals. They took into account the length of stay, beds utilized, extra cases that could have been done had there been zero incidence of infection, the gross cost to the hospital, and the revenue made by the hospital per cases. Below shows the outcome of there study:

35 TABLE 4 Graves Study: Assumptions: Available bed-days= 525,000 Length of stay for patients without hospital-acquired infection (HAI) = 10 days Length of stay for patients with HAI= 15 days Revenue earned per patient treated = $1,250 Calculations: 1.) Incidence of wound infection 10% 5% 0% 2.) Total Admissions 50,000 51,220 52,500 3.) Number of patients that acquire HAI 5,000 2,561 0 4.) Number of patients that do not acquire HAI 45,000 48,659 52,500 5.) Bed-days used by those that do not acquire HAI 450,000 486,590 525,000 6.) Bed-days used by those that acquire HAI 75,000 38,415 0 7.) Revenue earned from all admissions $62,500,000 $64,025,000 $65,625,000 8.) Gross cost(loss of revenue due to the incidence of HAI) $3,125,000 $1,600,000 $0

36 TABLE 5 GRAVES STUDY CONTINUED: Incidence of wound infection 10% 5% 0% 1.) Total admissions achieved 50,000 51,220 52,500 2.) Extra cases that could be treated if incidence was 0% 2,500 1,280 0 3.) Number that acquire HAI 5,000 2,561 0 4.) Lost revenue (gross cost of HAI) $3,125,000 $1,600,000 $0 5.) Variable costs if extra cases were treated $1,875,000 $960,000 $0 6.) Variable costs for each case of infection $500,000 $256,100 $0 7.) Net cost of HAI $1,750,000 $896,100 $0

37 Clearly the greater the incidence of infection the less financially feasible it is for the hospital. By decreasing the number of hospital acquired infections (HAI), more patients were able to be treated, more revenue from admissions was made, and the net cost of hospital to the hospital due to HAI s became non-existent. By placing patients on a probiotic regimen to decrease the number of infections, the hospital would have a financial gain despite the cost of a probiotic therapy.

38 RECOMMENDATIONS After reviewing the current literature on probiotics we would advocate the use of a probiotic regimen in our post cardiac surgery patients. There is no current protocol for the use of probiotics in post-cardiac surgery patients, but we believe their use should be standard of care. For safety concerns, we would advocate a probiotic regimen of only 1 billion/g CFU (colony forming units) for initial trials. This mild probiotic treatment would replenish the patient s guts microflora that is often damaged by antibiotics administered during the surgery. Initial trials should be on routine cardiac surgery patients, such as coronary artery bypass grafting (CABG s) and valve repair/replacement. We would not advise introducing a probiotic regimen into immune compromised heart transplant patients until further research suggests that probiotics are beneficial in post-cardiac surgery patients.

39 Given that probiotics are naturally occurring microorganisms and are readily obtainable as an OTC nutritional supplement, we strongly urge that all cardiac patients consider implementing a probiotic regimen. Furthermore, if individuals were to begin using probiotics prior to developing cardiovascular disease the gut flora would be more resilient to complications that are often seen after surgery such as constipation. The current literature available indicates that probiotics are safe for all healthy individuals and it is our belief that their benefit can be incorporated in the treatment of our cardiac patients. We not only believe that our patients would benefit from such, but that it should be standard of care practice to have post-cardiac surgery patients on a preventative probiotic treatment. We recommend establishing a study comparable to the Levitsky study and implement a probiotic regimen in our cardiac patients where subjects are divided into categories of patients who receive fiber (the control group) and those

40 who receive fiber and probiotics (the experimental group). For efficiency of the study we would advise using a probiotic that is already on the market and is available over the counter. Food and beverage probiotic administration have shown to have the greatest impact on the gut s microflora. Thus we would deter the use of supplemental pills and advocate a snack that the subject looks forward to consuming. We are currently in the process of IRB approval to begin a probiotic trial in our cardiac surgery patients.

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