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Behavioral Objectives

After completing this continuing education article, the pharmacist should be able to:

1. Describe the factors that put a patient at risk for antibiotic- associated diarrhea (AAD).
2. Outline the pathophysiology of AAD.
3. Distinguish between the clinical presentation of AAD and other causes of diarrhea.
4. Evaluate the evidence-based research related to the efficacy of probiotics in the prevention of AAD.
5. Estimate the adverse effects and risks associated with the utilization of probiotics in the prevention and treatment of AAD.
6. Assess therapeutic issues when recommending probiotics to patients.

The intestine is among the largest bacterial reservoirs in humans. The organisms present there normally are delicately balanced to benefit both the organisms and the host. A multitude of factors can disrupt this balance, including food, drugs, general health, and alteration of the types and numbers of bacteria present.

One of the most significant causes of disturbances in the gastrointestinal (GI) flora is antibiotic therapy. During antibiotic therapy, the susceptible normal flora is killed off, allowing resistant organisms to overgrow, thus disturbing the delicate balance. This imbalance can then lead to diarrhea.

Antibiotic-associated Diarrhea

Antibiotic-associated diarrhea (AAD) generally is defined as diarrhea that is correlated with the administration of antibiotics and is without another obvious cause.¹ The frequency of AAD, according to most sources, appears to be 5% to 25%,^2-4 but it has been reported to be as high as 40%.⁵ Of course, the occurrence of AAD is dependent on the definition of diarrhea, the antibiotic agent(s), the number of daily doses, the duration of treatment, the time from previous antibiotic treatment, and host factors. The most common culprits are broad-spectrum antibiotics and those that act on anaerobes, which include penicillins, cephalosporins, and clindamycin.^2,3,6

Prolonged or repeated antibiotic treatment and/or combination antibiotic therapy appears to increase the risk of AAD occurring.^2,6 Some of the host factors that can affect incidence are immune status, age, route, and inpatient/outpatient status.⁷ Bergogne-Berezin² proposed that risk increases if the patient is <6 years old or >65 years old, has had AAD in the past, has severe underlying diseases, has chronic diseases of the GI system, is immunosuppressed, has had GI surgery, or is receiving the antibiotics via nasogastric tube.

The exact mechanism of AAD is still unknown, but it is believed that the use of antibiotics may cause one or many of the following changes that contribute to AAD.^1,2,8-10

• Disruption of the equilibrium of the normal gut flora
• Opportunistic pathogenic bacteria taking advantage of the situation and causing inflammation and diarrhea
• Decreased metabolism and absorption of carbohydrates or short-chain fatty acids by colonic bacteria
• Decreased bile acid metabolism
• Alterations in intestinal mucosa
• Alterations in motility

Sakata et al⁸ and Young et al⁹ both showed that the species and numbers of bacteria present in the feces of patients on various oral and intravenous (IV) antibiotics changed. Most notably, the numbers of Bifidobacterium, Streptococcus, and Lactobacillus organisms declined, and Escherichia coli organisms were replaced by Klebsiella organisms with penicillin antibiotics. The yeast count increased substantially with all antibiotics.⁸ Two weeks after therapy, Bifidobacterium had not yet recovered—indicating that the colon probably requires a significant amount of time to recover the normal flora after antibiotic therapy.⁹ The alterations in the normal flora may allow for pathogenic organisms to overgrow in some patients, thus causing AAD.

Colonic bacteria are known to metabolize carbohydrates as an energy source. The anaerobes specifically use the carbohydrates to produce lactic acid and short-chain fatty acids.¹⁰ Decreased bacterial carbohydrate metabolism may lead to osmotic diarrhea, especially in patients who ingest poorly absorbable carbohydrates such as fiber, fructose, and sorbitol.¹⁰

Bacteria in the colon also are known to break down primary bile acids that are not absorbed.¹⁰ Primary bile acids such as chenodeoxycholic acid are potent colonic secretory agents and may cause secretory diarrhea. Finally, oral penicillins or penicillin derivatives have been associated with acute segmental hemorrhagic colitis, which is characterized by mucosal edema and submucosal hemorrhage of the colon in the absence of Clostridium difficile.¹⁰

The clinical presentation of AAD can range from mild diarrhea to severe pseudomembranous colitis, which can lead to complications such as dehydration, toxic megacolon, perforation, or septic shock.^2,3,11 The primary differences between mild AAD and severe antibiotic-associated colitis are delineated in Table 1.

What Exactly Are Probiotics?

Probiotics have been used for thousands of years for their health benefit. The term probiotics has been defined by the Food and Agriculture Organization and World Health Organization as "live microorganisms which when administered in adequate amounts confer a health benefit on the host."¹² In the United States, probiotics are considered dietary supplements. Therefore, premarket review and approval by the FDA are not required unless the supplements are specifically marketed for the treatment or prevention of a disease. If they are, then they are considered biological products and are reviewed and approved by the FDA.⁷

Probiotics have been used to accomplish various therapeutic benefits, such as modulating immunity, lowering cholesterol, and treating rheumatoid arthritis, cancer, lactose intolerance, Crohn's disease, diarrhea, and candidiasis.⁷ The focus here, however, is on the use of probiotics in the management of AAD.

The species of bacteria that have been used in probiotics marketed and/or studied are Bifidobacterium, Lactobacillus, Bacillus, and Enterococcus.^7,12 Yeasts in the Saccharomyces family, which are nonpathogenic, also have been used in probiotic formulations. The strains used may be those that are used in dairy fermentation, or they may be derived from the intestinal microbiota of healthy humans.⁷ Enterococcus species are not commonly used because there have been some safety concerns about antibiotic resistance being transferred or opportunistic infections occurring, especially with Enterococcus species that can be pathogenic.^7,12

The most commonly used species in probiotics are Bifidobacterium, Lactobacillus, and Saccharomyces.¹² Of the strains reported to have therapeutic benefits during diarrhea, only a few have been studied both in vitro and in vivo and actually have scientific data available to support the claim. Lactobacillus rhamnosus GG is the most extensively studied probiotic in adults as well as in children. Studies have shown that oral administration of this strain in >10⁹ colony-forming units (CFUs) per day colonizes the intestine and reduces diarrhea.^13-18 Lactobacillus reuteri strain (ATCC 55730), on the other hand, has been reported to prevent community-acquired diarrhea in Mexico¹⁹ and rotavirus-induced diarrhea in Finnish children.²⁰ Finally, the benefit of Lactobacillus casei strain CRL431 in the treatment and prevention of diarrhea has been well-documented by Gonzalez and coworkers.^21,22

Probiotics and AAD

Probiotics have been reported to work for 4 important forms of diarrhea. They include AAD,²³ diarrhea caused by rotavirus,²⁴ C difficile diarrhea,²⁵ and traveler's diarrhea.²⁶ Because AAD generally is believed to be due to an imbalance of microflora in the intestines and gut, research has been focused on restoring the normal flora. Probiotics are believed to help do so. One factor that should be taken into consideration is that probiotics act only transiently: They must be ingested regularly for benefits to persist.

So, how exactly do probiotics work? The jury is still out, but they are believed to have antimicrobial, immunomodulatory, anticarcinogenic, antidiarrheal, antiallergenic, and antioxidant properties. The antimicrobial property of the probiotics is believed to be due to their ability to colonize the colon and reinforce the barrier function of the GI mucosa. The mechanism of action of probiotics as an antidiarrheal is still unknown, however. A study on Saccharomyces boulardii for AAD revealed that this probiotic secretes a protease that digests 2 protein exotoxins that mediate diarrhea and colitis caused by C difficile.²⁷ Most likely the antimicrobial and antidiarrheal mechanisms work together to prevent AAD.

Evaluating Evidence

Studies that exist on the use of probiotics in AAD focus primarily on prevention. The media used to administer the probiotics in the primary literature may be capsules, granules, or yogurt. The strain of probiotics used in various studies consisted largely of Lactobacillus or Saccharomyces species, although a few studies did include Bifidobacterium. Dosing varied greatly in all of the studies.⁵

Pediatric Studies

There were 4 studies in children ranging in age from 2 weeks to 12 years.^4,5,11,28 All of these studies were randomized, placebo-controlled trials that used the percentage of patients with AAD as the primary end point. Three of the studies found that the active treatment group had significantly less AAD than placebo (P < .05)^4,5,11 and one did not²⁸ (Table 2).

Correa et al¹¹ performed a double-blind, randomized, placebo-controlled, parallel trial to determine whether or not an oral probiotic formula containing B lactis and Streptococcus thermophilus reduced the frequency of AAD in 157 infants. The infants received formula with either probiotics added or nothing added, starting at the initiation of antibiotic therapy for a total of 15 days. The infants were on various oral and/or IV antibiotics. Only 16.3% of the probiotic group developed AAD versus 31.2% of the control group (P = .044), which means that the probiotic formula was 47.7% effective in preventing AAD. An additional interesting finding was that patients receiving placebo who developed AAD had increased episodes (P = .039).

Another study, by Vanderhoof et al,⁵ looked at the efficacy of Lactobacillus GG in reducing the incidence of AAD in children aged 6 months to 10 years who were receiving various oral antibiotics for 10 days. This study was double-blind, randomized, and placebo-controlled. The 188 children received either placebo or Lactobacillus GG capsules (1 or 2 capsules based on weight) once a day with a meal. Twenty-six percent of the patients who received placebo developed AAD, while only 8% of the active treatment group developed AAD (P = .05). Interestingly, the stool consistency score of the active group was higher than that of the placebo group (P < .001), indicating overall firmer stools, and the active group had much less frequent stools by day 10 (P < .02).

The third study, by Arvola et al,⁴ was randomized, controlled, and patient-blinded. It looked at preventing AAD with Lactobacillus GG also. One hundred nineteen children completed the study, all of whom were on various oral antibiotics for 7 to 10 days to treat respiratory infections. The placebo or Lactobacillus GG capsules were given twice a day during antibiotic therapy. Only diarrheal episodes that occurred during the first 2 weeks were counted. Five percent of the active group and 16% of the placebo group developed AAD (P = .05), indicating a reduced incidence of one third in the treatment group.

The study that did not show significance was a double-blind, randomized controlled trial conducted by Tankanow et al.²⁸ The trial was completed by only 38 participants. The participants received Lactobacilli or placebo 4 times a day for 10 days with their amoxicillin therapy. The dose used in this study was considerably less than in the other studies (2 billion CFUs daily versus 20-40 billion CFUs). The patients in the active treatment group did have a decreased incidence of diarrhea during the last 4 days of antibiotic therapy, compared with the placebo group. Also, the term diarrhea was loosely defined as "one or more abnormally loose bowel movements per day," ²⁸ whereas the authors of the other 3 studies defined diarrhea as at least 2 or 3 watery or loose stools per day for 2 consecutive days.^4,5,11 It also was noted that many of the patients who experienced diarrhea consumed apple cider and fruit, which are commonly associated with diarrhea in children and could have skewed the results.²⁸ The researchers did note that the incidence of diarrhea diminished in the active group, compared with the placebo group.

Adult Studies with S boulardii

Ten studies in adults were evaluated (Table 3). Four studies evaluated S boulardii, 2 evaluated Lactobacillus GG, 2 evaluated a combination of L bulgaricus and L acidophilus, 1 evaluated Lactobacillus GG and S boulardii both independently and in combination, and the final study evaluated a combination of B longum and L acidophilus and B longum independently.

The studies performed with S boulardii were very large, with a range of 180 to 376 patients. All studies used the percentage of patients who developed AAD as the primary end point and found significant results. Of the 2 studies with Lactobacillus GG, 1 study found a significant decrease in side effects (taste disturbance, diarrhea, nausea) in the activetreatment group, and the other found no significant difference in the occurrence of AAD in probiotic-treated patients. Surprisingly, the largest study was the one that did not show significance; however, many of the patients were on high doses of IV antibiotics. In one study, 21.8% on the placebo and 9.5% on the active treatment (P = .038) developed AAD, giving S boulardii a prevention efficacy of 56.7%.

The first study using S boulardii, by Surawicz et al,²⁹ was a double-blind, randomized, placebo-controlled trial performed in a hospital where the incidence of AAD was high. Placebo or S boulardii treatment was started within 48 hours of the beginning of antibiotic therapy and was continued for 2 weeks after the last antibiotic dose. As a result, 21.8% on the placebo and 9.5% on the active treatment (P = .038) developed AAD, giving S boulardii a prevention efficacy of 56.7%. It was noted that nasogastrictube- feeding patients had an increased risk of diarrhea. A possible explanation for this increased risk is an alteration in fecal flora and the impact this has on carbohydrate metabolism, which may lead to an osmotic diarrhea. When they were eliminated from the results, the rate of diarrhea decreased to 4.6% in the S boulardii group and 22% in the placebo group (P < .001).

The second study, by McFarland et al,³⁰ tested the prevention of AAD with S boulardii in patients on oral or IV ß-lactams. The trial was double-blind, randomized, and placebo-controlled. Patients received placebo or S boulardii capsules twice a day within 72 hours of starting the ß-lactam and were kept on them for 3 days after the ß-lactam therapy was completed. Of the 193 patients who completed the study, 10.9% overall experienced AAD—7.2% of the active-treatment and 14.6% of the placebo group (P = .02). Overall S boulardii decreased the incidence of AAD by 51% and decreased the duration of AAD. Finally, more placebo patients (7 vs 0) complained of intestinal gas.

The third study that used S boulardii looked at adults on various antibiotics (route not specified). The treatment or placebo was started 48 hours after antibiotic therapy was initiated. A total of 151 patients completed the study, and 9% of the placebo group and 1.4% of the S boulardii group (P < .05) developed AAD.³¹

Adult Studies with H pylori Eradication

Finally, Duman et al³ tested the efficacy of S boulardii in preventing AAD associated with Helicobacter pylori eradication in outpatients. This study was a multicenter, open-label, randomized, controlled trial, with 376 patients completing the study. All of the patients were on 14-day H pylori eradication therapy that consisted of clarithromycin 500 mg + amoxicillin 1000 mg + omeprazole 20 mg twice a day. The patients were then assigned to either S boulardii or no treatment to be taken for the 14 days of the H pylori treatment. The results showed that the treatment group had significantly fewer (6.9% vs 15.6%) cases of diarrhea (P = .007).

Another double-blind, randomized, placebo-controlled study was done using probiotics in patients on H pylori eradication treatment. This study, by Cremonini et al,³² tested Lactobacillus GG or S boulardii or Lactobacillus + Bifidobacteria or placebo. The H pylori treatment these patients received consisted of clarithromycin 500 mg + tinidazole 500 mg + rabeprazole 20 mg twice a day for 7 days. The probiotic or placebo was taken for the week of plus 1 week after. The incidence of side effects was 15% in those receiving Lactobacillus GG or S boulardii, 24% in those receiving Lactobacillus + Bifidobacteria, and 60% in the placebo group (P = .0025). The incidences of diarrhea (P = .018) and taste disturbances (P = .0027) were significantly lower in all the probiotic groups. Eradication rates were not affected by probiotics.

A third study was done in H pylori-eradication patients by Armuzzi et al.³³ This particular study was a double-blind, randomized, placebo-controlled trial looking at the effect of Lactobacillus GG on antibiotic-associated side effects in these patients. All patients were receiving, for 7 days, clarithromycin 500 mg + tinidazole 500 mg + rabeprazole 20 mg twice a day along with either Lactobacillus GG or placebo during those 7 days and 7 days after. Overall patients on Lactobacillus GG therapy tolerated the H pylori treatment much better, without any differences in eradication. They had decreased nausea (P = .01), taste disturbances (P = .03), and diarrhea (P = .01), compared with placebo.

Other Adult Studies

Gotz et al³⁴ did a double-blind, randomized, placebo-controlled trial in adult patients taking oral or IV ampicillin to see whether L acidophilus + L bulgaricus decreased the incidence of AAD. Patients received placebo or the treatment 4 times a day for the first 5 days of their ampicillin treatment. In this study, diarrhea was defined as >3 bowel movements more than the patient's normal number regardless of consistency (quite different from any definition used in other studies). According to these terms, 21% of the placebo group and 8.8% of the active group had AAD (P = .21)—which does not show a significant decrease. The authors then classified the diarrhea according to its most likely cause and found that there was significance—14% in the placebo group and 0% in the treatment group (P = .03).

Thomas et al³⁵ conducted a large (N = 267), double-blind, randomized, placebo-controlled trial in hospitalized patients receiving various oral and IV antibiotics. Patients received either Lactobacillus GG or placebo for 14 days. The primary outcome measure was the number of patients who experienced at least 1 diarrheal episode in the first 21 days after enrollment in the study. The result was 29.3% in the Lactobacillus group and 29.9% in the placebo group, thus showing no significance. The lack of significance in this study is striking, compared with the results in the other literature available. It is possible that the high doses of antibiotics given to patients in the hospital may have killed the probiotic strain. Laboratory studies revealed that the Lactobacillus strain used was resistant only to cephalosporins.

Beniwal et al³⁶ did a randomized, controlled trial using yogurt that contained L acidophilus, L bulgaricus, and S thermophilus to see whether it decreased AAD, compared with no treatment, when given twice a day for 8 days in hospitalized patients. Two hundred two patients completed the study. There was an incidence of AAD of 12.4% in the active group, compared with 23.7% in the placebo group (P = .04), thus decreasing the risk of AAD by nearly 50%. Also, the control-group patients had diarrhea for a total of 60 days, compared with only 23 days in the probiotic group.

One final study looked at the effect of B longum and L acidophilus on intestinal microbiota, fatty acids, and diarrhea in patients receiving clindamycin. The study was double-blind and placebo- controlled, but no mention of randomization was made. Only 30 subjects participated in the study—10 receiving B longum + L acidophilus, 10 receiving B longum, and 10 receiving placebo for 21 days, starting at the same time as the clindamycin therapy (which lasted only 7 days). The group receiving B longum + L acidophilus had the least reduction in anaerobic bacteria and the smallest change in fatty acids (differences between this group and the placebo group were significant [P < .05]).³⁷

A recent meta-analysis of 9 controlled studies has revealed that both Lactobacilli and S boulardii are effective probiotics in the management of AAD.³⁸ A recent meta-analysis of randomized, placebo-controlled trials in pediatric patients, however, did not offer any conclusive evidence.³⁹

Risks and Adverse Effects with Probiotics

Overall most studies found that probiotics are safe and have no side effects.^{3,4,23,32,35,40} In fact, Cremonini et al³² actually reported that Lactobacillus GG and S boulardii both decreased taste disturbances and diarrhea in patients being treated for H pylori with rabeprazole, clarithromycin, and tinidazole. Patients receiving Saccharomyces had less gas than those receiving placebo, according to McFarland et al.²³ There are a few case reports of bacteremia or sepsis occurring in patients. These adverse events occurred in patients who were immunocompromised or severely debilitated and had multiple comorbidities.^7,40,41 The bacteremia or sepsis was not fatal in any of the patients. These cases are rare and should not discourage the use of probiotics but merely serve as a reminder that caution should be used when recommending their use. Srinivasan et al⁴⁰ specifically studied the safety of Lactobacillus in critically ill children and found no evidence of colonization or bacteremia in sterile body fluids and surfaces. Boyle et al⁷ reviewed adverseevent cases reported in the literature and found that there appeared to be risk factors for adverse events such as bacteremia and sepsis in patients. They classified risk factors as major or minor, and the presence of a single major or more than 1 minor risk factor warranted caution regarding the use of probiotics. The major and minor risk factors are listed in Table 4.

Therapeutic Considerations

Compliance is a serious issue with regard to antibiotic therapy. Noncompliant patients can cause resistant strains of bacteria to form. One common cause of noncompliance in patients, especially in pediatric patients, is GI side effects such as AAD. If taking a probiotic capsule can prevent or reduce the occurrence of this side effect, compliance may improve. In addition to discussing the benefits of probiotic therapy, the pharmacist can assist with dosing and scheduling administration to maximize the potential benefit of these products. For children, the capsule contents may be emptied into food that is at room temperature or cooler. Yogurt that contains live culture also may be a useful way to supply children with probiotics, but the number of CFUs should be a consideration. The pharmacist can help ensure that parents and patients understand that not all yogurt contains the active cultures of probiotic strains.

A study has shown a temporary colonization in infants during pregnancy.⁴² Therefore, it would be prudent not to recommend their use in that population. Providing probiotics to patients with impaired immune status or with multiple comorbidities or who are severely debilitated should be approached cautiously.

A few brands of probiotics generally available are Acidophilus Pearls from Enzymatic Therapy Natural Medicines (1 billion CFUs), Nature Made Acidophilus Dietary Supplement (500 million CFUs per tablet), Nature's Way Primadophilus Optima (35 billion CFUs), and Culturelle with Lactobacillus GG (10 billion+ CFUs). The potency of probiotic products is an important issue. ConsumerLab.com has completed a testing program for probiotic potency (www.consumerlab.com). The duration of therapy generally should extend for several days after the discontinuation of the antibiotic to provide the gut with continued exposure to these healthy bacteria.

Summary

There is a paucity of quality studies researching the effectiveness of probiotics to prevent or treat AAD. Of the studies that have been performed, the majority appear to show that probiotics are likely to be effective for the prevention of AAD in most patients receiving oral antibiotics. Side effects attributed to probiotics are not common. The potential reduction in the side effects of antibiotic therapy may increase compliance in patients who might otherwise discontinue therapy due to significant GI side effects.

William R. Hamilton, PharmD: Associate Professor, Creighton University School of Pharmacy and Health Professions; Creighton University Medical Center, Omaha, Nebraska; Alekha K. Dash, RPh, PhD: Professor and Chair, Department of Pharmacy Sciences, Creighton University School of Pharmacy and Health Professions; Creighton University Medical Center; Jennifer M. S. Meyer, PharmD Candidate: School of Pharmacy and Health Professions, Creighton University Medical Center; Sara J. Spicka, PharmD Candidate School of Pharmacy and Health Professions, Creighton University Medical Center

For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. A. Rybovic, Pharmacy Times, Ascend Media Healthcare, 103 College Road East, Princeton, NJ 08540; or send an e-mail request to: arybovic@ascendmedia.com.

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