Use of Probiotics in the Management of Antibiotic-associated Diarrhea

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Behavioral Objectives

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

• Describe the factors that put a patient at risk for antibiotic-associated diarrhea (AAD).
• Outline the pathophysiology of AAD.
• Distinguish between the clinical presentation of AAD andother causes of diarrhea.
• Evaluate the evidence-based research related to the efficacyof probiotics in the prevention of AAD.
• Estimate the adverse effects and risks associated with theutilization of probiotics in the prevention and treatmentof AAD.
• Assess therapeutic issues when recommending probioticsto patients.

The intestine is among the largestbacterial reservoirs in humans.The organisms present there normallyare delicately balanced to benefitboth the organisms and the host. A multitudeof factors can disrupt this balance,including food, drugs, general health, andalteration of the types and numbers ofbacteria present.

One of the most significant causes ofdisturbances in the gastrointestinal (GI)flora is antibiotic therapy. During antibiotictherapy, the susceptible normal flora iskilled off, allowing resistant organisms toovergrow, thus disturbing the delicatebalance. This imbalance can then lead todiarrhea.

Antibiotic-associated Diarrhea

Antibiotic-associated diarrhea (AAD)generally is defined as diarrhea that iscorrelated with the administration ofantibiotics and is without another obviouscause.¹ The frequency of AAD, accordingto most sources, appears to be5% to 25%,^2-4 but it has been reported tobe as high as 40%.⁵ Of course, the occurrenceof AAD is dependent on the definitionof diarrhea, the antibiotic agent(s),the number of daily doses, the duration oftreatment, the time from previous antibiotictreatment, and host factors. Themost common culprits are broad-spectrumantibiotics and those that act onanaerobes, which include penicillins,cephalosporins, and clindamycin.^2,3,6

Prolonged or repeated antibiotic treatmentand/or combination antibiotic therapyappears to increase the risk of AADoccurring.^2,6 Some of the host factorsthat can affect incidence are immunestatus, age, route, and inpatient/outpatientstatus.⁷ Bergogne-Berezin² proposedthat risk increases if the patient is<6 years old or >65 years old, has hadAAD in the past, has severe underlyingdiseases, has chronic diseases of the GIsystem, is immunosuppressed, has hadGI surgery, or is receiving the antibioticsvia nasogastric tube.

The exact mechanism of AAD is stillunknown, but it is believed that the useof antibiotics may cause one or many ofthe following changes that contribute toAAD.^1,2,8-10

• Disruption of the equilibrium of thenormal gut flora
• Opportunistic pathogenic bacteriataking advantage of the situation andcausing inflammation and diarrhea
• Decreased metabolism and absorptionof carbohydrates or short-chainfatty acids by colonic bacteria
• Decreased bile acid metabolism
• Alterations in intestinal mucosa
• Alterations in motility

Sakata et al⁸ and Young et al⁹ bothshowed that the species and numbers ofbacteria present in the feces of patientson various oral and intravenous (IV) antibioticschanged. Most notably, the numbersof Bifidobacterium, Streptococcus, andLactobacillus organisms declined, andEscherichia coli organisms were replacedby Klebsiella organisms with penicillinantibiotics. The yeast count increasedsubstantially with all antibiotics.⁸ Twoweeks after therapy, Bifidobacterium hadnot yet recovered?indicating that thecolon probably requires a significantamount of time to recover the normalflora after antibiotic therapy.⁹ The alterationsin the normal flora may allow forpathogenic organisms to overgrow insome patients, thus causing AAD.

Colonic bacteria are known to metabolizecarbohydrates as an energy source.The anaerobes specifically use the carbohydratesto produce lactic acid andshort-chain fatty acids.¹⁰ Decreased bacterialcarbohydrate metabolism may leadto osmotic diarrhea, especially in patientswho ingest poorly absorbable carbohydratessuch as fiber, fructose, andsorbitol.¹⁰

Bacteria in the colon also are known tobreak down primary bile acids that arenot absorbed.¹⁰ Primary bile acids suchas chenodeoxycholic acid are potentcolonic secretory agents and may causesecretory diarrhea. Finally, oral penicillinsor penicillin derivatives have been associatedwith acute segmental hemorrhagiccolitis, which is characterized bymucosal edema and submucosal hemorrhageof the colon in the absence ofClostridium difficile.¹⁰

The clinical presentation of AAD canrange from mild diarrhea to severepseudomembranous colitis, which canlead to complications such as dehydration,toxic megacolon, perforation, orseptic shock.^2,3,11 The primary differencesbetween mild AAD and severeantibiotic-associated colitis are delineatedin Table 1.

What Exactly Are Probiotics?

Probiotics have been used for thousandsof years for their health benefit.The term probiotics has been defined bythe Food and Agriculture Organizationand World Health Organization as "livemicroorganisms which when administeredin adequate amounts confer ahealth benefit on the host."¹² In theUnited States, probiotics are considereddietary supplements. Therefore, premarketreview and approval by the FDA arenot required unless the supplements arespecifically marketed for the treatmentor prevention of a disease. If they are,then they are considered biological productsand are reviewed and approved bythe FDA.⁷

Probiotics have been used to accomplishvarious therapeutic benefits, suchas modulating immunity, lowering cholesterol,and treating rheumatoid arthritis,cancer, lactose intolerance, Crohn'sdisease, diarrhea, and candidiasis.⁷ Thefocus here, however, is on the use of probioticsin the management of AAD.

The species of bacteria that have beenused in probiotics marketed and/or studiedare Bifidobacterium, Lactobacillus,Bacillus, and Enterococcus.^7,12 Yeasts inthe Saccharomyces family, which arenonpathogenic, also have been used inprobiotic formulations. Thestrains used may be those thatare used in dairy fermentation,or they may be derived fromthe intestinal microbiota ofhealthy humans.⁷ Enterococcusspecies are not commonly usedbecause there have been somesafety concerns about antibioticresistance being transferredor opportunistic infectionsoccurring, especially with Enterococcusspecies that can bepathogenic.^7,12

The most commonly usedspecies in probiotics are Bifidobacterium,Lactobacillus, andSaccharomyces.¹² Of the strainsreported to have therapeuticbenefits during diarrhea, only afew have been studied both invitro and in vivo and actuallyhave scientific data available tosupport the claim. Lactobacillusrhamnosus GG is the mostextensively studied probiotic inadults as well as in children.Studies have shown that oraladministration of this strain in>10⁹ colony-forming units(CFUs) per day colonizes theintestine and reduces diarrhea.^13-18 Lactobacillus reuteristrain (ATCC 55730), on theother hand, has been reportedto prevent community-acquireddiarrhea in Mexico¹⁹ androtavirus-induced diarrhea inFinnish children.²⁰ Finally, thebenefit of Lactobacillus caseistrain CRL431 in the treatmentand prevention of diarrhea hasbeen well-documented byGonzalez and coworkers.^21,22

Probiotics and AAD

Probiotics have been reportedto work for 4 importantforms of diarrhea. They includeAAD,²³ diarrhea caused byrotavirus,²⁴ C difficile diarrhea,²⁵and traveler's diarrhea.²⁶Because AAD generally isbelieved to be due to an imbalanceof microflora in the intestinesand gut, research hasbeen focused on restoring thenormal flora. Probiotics arebelieved to help do so. One factorthat should be taken intoconsideration is that probioticsact only transiently: They mustbe ingested regularly for benefitsto persist.

So, how exactly do probioticswork? The jury is still out, butthey are believed to haveantimicrobial, immunomodulatory,anticarcinogenic, antidiarrheal,antiallergenic, and antioxidantproperties. The antimicrobialproperty of the probiotics isbelieved to be due to their abilityto colonize the colon andreinforce the barrier function ofthe GI mucosa. The mechanismof action of probiotics as anantidiarrheal is still unknown,however. A study on Saccharomycesboulardii for AADrevealed that this probioticsecretes a protease that digests2 protein exotoxins that mediatediarrhea and colitis causedby C difficile.²⁷ Most likely theantimicrobial and antidiarrhealmechanisms work together toprevent AAD.

Evaluating Evidence

Studies that exist on the useof probiotics in AAD focus primarilyon prevention. Themedia used to administer theprobiotics in the primary literaturemay be capsules, granules,or yogurt. The strain of probioticsused in various studiesconsisted largely of Lactobacillusor Saccharomycesspecies, although a few studiesdid include Bifidobacterium.Dosing varied greatly in all ofthe studies.⁵

Pediatric Studies

There were 4 studies in childrenranging in age from 2weeks to 12 years.^4,5,11,28 All of thesestudies were randomized, placebo-controlledtrials that used the percentage ofpatients with AAD as the primary endpoint. Three of the studies found that theactive treatment group had significantlyless AAD than placebo (P < .05)^4,5,11 andone did not²⁸ (Table 2).

Correa et al¹¹ performed a double-blind,randomized, placebo-controlled,parallel trial to determine whether ornot an oral probiotic formula containingB lactis and Streptococcus thermophilusreduced the frequency of AADin 157 infants. The infants received formulawith either probiotics added ornothing added, starting at the initiationof antibiotic therapy for a total of 15days. The infants were on various oraland/or IV antibiotics. Only 16.3% of theprobiotic group developed AAD versus31.2% of the control group (P = .044),which means that the probiotic formulawas 47.7% effective in preventing AAD.An additional interesting finding wasthat patients receiving placebo whodeveloped AAD had increased episodes(P = .039).

Another study, by Vanderhoof et al,⁵looked at the efficacy of LactobacillusGG in reducing the incidence of AAD inchildren aged 6 months to 10 years whowere receiving various oral antibioticsfor 10 days. This study was double-blind,randomized, and placebo-controlled.The 188 children received either placeboor Lactobacillus GG capsules (1 or 2capsules based on weight) once a daywith a meal. Twenty-six percent of thepatients who received placebo developedAAD, while only 8% of the activetreatment group developed AAD (P =.05). Interestingly, the stool consistencyscore of the active group was higherthan that of the placebo group (P <.001), indicating overall firmer stools,and the active group had much less frequentstools by day 10 (P < .02).

The third study, by Arvola et al,⁴ wasrandomized, controlled, and patient-blinded.It looked at preventing AADwith Lactobacillus GG also. One hundrednineteen children completed the study,all of whom were on various oral antibioticsfor 7 to 10 days to treat respiratoryinfections. The placebo or LactobacillusGG capsules were given twice aday during antibiotic therapy. Only diarrhealepisodes that occurred during thefirst 2 weeks were counted. Five percentof the active group and 16% of theplacebo group developed AAD (P = .05),indicating a reduced incidence of onethird in the treatment group.

The study that did not show significancewas a double-blind, randomizedcontrolled trial conducted by Tankanowet al.²⁸ The trial was completed by only38 participants. The participants receivedLactobacilli or placebo 4 times aday for 10 days with their amoxicillintherapy. The dose used in this study wasconsiderably less than in the other studies(2 billion CFUs daily versus 20-40 billionCFUs). The patients in the activetreatment group did have a decreasedincidence of diarrhea during the last 4days of antibiotic therapy, comparedwith the placebo group. Also, the termdiarrhea was loosely defined as "one ormore abnormally loose bowel movementsper day," ²⁸ whereas the authorsof the other 3 studies defined diarrheaas at least 2 or 3 watery or loose stoolsper day for 2 consecutive days.^4,5,11 Italso was noted that many of thepatients who experienced diarrhea consumedapple cider and fruit, which arecommonly associated with diarrhea inchildren and could have skewed theresults.²⁸ The researchers did note thatthe incidence of diarrhea diminished inthe active group, compared with theplacebo group.

Adult Studies with S boulardii

Ten studies in adults were evaluated(Table 3). Four studies evaluated Sboulardii, 2 evaluated Lactobacillus GG, 2evaluated a combination of L bulgaricusand L acidophilus, 1 evaluated LactobacillusGG and S boulardii both independentlyand in combination, and thefinal study evaluated a combination of Blongum and L acidophilus and B longumindependently.

The studies performed with Sboulardii were very large, with a range of180 to 376 patients. All studies used thepercentage of patients who developedAAD as the primary end point and foundsignificant results. Of the 2 studies withLactobacillus GG, 1 study found a significant decrease in side effects (taste disturbance,diarrhea, nausea) in the activetreatmentgroup, and the other found nosignificant difference in the occurrenceof AAD in probiotic-treated patients.Surprisingly, the largest study was theone that did not show significance; however,many of the patients were on highdoses of IV antibiotics. In one study,21.8% on the placebo and 9.5% on theactive treatment (P = .038) developedAAD, giving S boulardii a prevention efficacyof 56.7%.

The first study using S boulardii, bySurawicz et al,²⁹ was a double-blind,randomized, placebo-controlled trialperformed in a hospital where the incidenceof AAD was high. Placebo or Sboulardii treatment was started within48 hours of the beginning of antibiotictherapy and was continued for 2 weeksafter the last antibiotic dose. As a result,21.8% on the placebo and 9.5% on theactive treatment (P = .038) developedAAD, giving S boulardii a prevention efficacyof 56.7%. It was noted that nasogastrictube-feeding patients had anincreased risk of diarrhea. A possibleexplanation for this increased risk is analteration in fecal flora and the impactthis has on carbohydrate metabolism,which may lead to an osmotic diarrhea.When they were eliminated from theresults, the rate of diarrhea decreasedto 4.6% in the S boulardii group and 22%in the placebo group (P < .001).

The second study, by McFarland et al,³⁰tested the prevention of AAD with Sboulardii in patients on oral or IV ?-lactams.The trial was double-blind, randomized,and placebo-controlled. Patientsreceived placebo or S boulardii capsulestwice a day within 72 hours of startingthe ?-lactam and were kept on them for3 days after the ?-lactam therapy wascompleted. Of the 193 patients whocompleted the study, 10.9% overall experiencedAAD?7.2% of the active-treatmentand 14.6% of the placebo group(P = .02). Overall S boulardii decreasedthe incidence of AAD by 51% anddecreased the duration of AAD. Finally,more placebo patients (7 vs 0) complainedof intestinal gas.

The third study that used S boulardiilooked at adults on various antibiotics(route not specified). The treatment orplacebo was started 48 hours afterantibiotic therapy was initiated. A totalof 151 patients completed the study,and 9% of the placebo group and 1.4%of the S boulardii group (P < .05) developedAAD.³¹

Adult Studies with H pylori Eradication

Finally, Duman et al³ tested the efficacyof S boulardii in preventing AAD associatedwith Helicobacter pylori eradication inoutpatients. This study was a multicenter,open-label, randomized, controlled trial,with 376 patients completing the study. Allof the patients were on 14-day H pylorieradication therapy that consisted of clarithromycin500 mg + amoxicillin 1000 mg+ omeprazole 20 mg twice a day. Thepatients were then assigned to eitherS boulardii or no treatment to be taken forthe 14 days of the H pylori treatment. Theresults showed that the treatment grouphad significantly fewer (6.9% vs 15.6%)cases of diarrhea (P = .007).

Another double-blind, randomized,placebo-controlled study was doneusing probiotics in patients on H pylorieradication treatment. This study, byCremonini et al,³² tested LactobacillusGG or S boulardii or Lactobacillus +Bifidobacteria or placebo. The H pyloritreatment these patients received consistedof clarithromycin 500 mg + tinidazole500 mg + rabeprazole 20 mg twicea day for 7 days. The probiotic or placebowas taken for the week of plus 1week after. The incidence of side effectswas 15% in those receiving LactobacillusGG or S boulardii, 24% in those receivingLactobacillus + Bifidobacteria, and 60%in the placebo group (P = .0025). Theincidences of diarrhea (P = .018) andtaste disturbances (P = .0027) were significantlylower in all the probioticgroups. Eradication rates were notaffected by probiotics.

A third study was done in Hpylori-eradication patients by Armuzzi etal.³³ This particular study was a double-blind,randomized, placebo-controlledtrial looking at the effect of LactobacillusGG on antibiotic-associated side effectsin these patients. All patients werereceiving, for 7 days, clarithromycin 500mg + tinidazole 500 mg + rabeprazole 20mg twice a day along with eitherLactobacillus GG or placebo during those7 days and 7 days after. Overall patientson Lactobacillus GG therapy tolerated theH pylori treatment much better, withoutany differences in eradication. They haddecreased 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 inadult patients taking oral or IV ampicillinto see whether L acidophilus + Lbulgaricus decreased the incidence ofAAD. Patients received placebo or thetreatment 4 times a day for the first 5days of their ampicillin treatment. Inthis study, diarrhea was defined as >3bowel movements more than thepatient's normal number regardless ofconsistency (quite different from anydefinition used in other studies).According to these terms, 21% of theplacebo group and 8.8% of the activegroup had AAD (P = .21)?which doesnot show a significant decrease. Theauthors then classified the diarrheaaccording to its most likely cause andfound that there was significance?14%in the placebo group and 0% in thetreatment group (P = .03).

Thomas et al³⁵ conducted a large (N =267), double-blind, randomized, placebo-controlledtrial in hospitalized patientsreceiving various oral and IV antibiotics.Patients received either LactobacillusGG or placebo for 14 days. The primaryoutcome measure was the number ofpatients who experienced at least 1 diarrhealepisode in the first 21 days afterenrollment in the study. The result was29.3% in the Lactobacillus group and29.9% in the placebo group, thus showingno significance. The lack of significancein this study is striking, comparedwith the results in the other literatureavailable. It is possible that the highdoses of antibiotics given to patients inthe hospital may have killed the probioticstrain. Laboratory studies revealedthat the Lactobacillus strain used wasresistant only to cephalosporins.

Beniwal et al³⁶ did a randomized,controlled trial using yogurt that containedL acidophilus, L bulgaricus, and Sthermophilus to see whether itdecreased AAD, compared with notreatment, when given twice a day for 8days in hospitalized patients. Two hundredtwo patients completed the study.There was an incidence of AAD of12.4% in the active group, comparedwith 23.7% in the placebo group (P =.04), thus decreasing the risk of AAD bynearly 50%. Also, the control-grouppatients had diarrhea for a total of 60days, compared with only 23 days inthe probiotic group.

One final study looked at the effectof B longum and L acidophilus on intestinalmicrobiota, fatty acids, and diarrheain patients receiving clindamycin.The study was double-blind and placebo-controlled, but no mention of randomizationwas made. Only 30 subjectsparticipated in the study?10receiving B longum + L acidophilus, 10receiving B longum, and 10 receivingplacebo for 21 days, starting at thesame time as the clindamycin therapy(which lasted only 7 days). The groupreceiving B longum + L acidophilus hadthe least reduction in anaerobic bacteriaand the smallest change in fattyacids (differences between this groupand the placebo group were significant[P < .05]).³⁷

A recent meta-analysis of 9 controlledstudies has revealed that bothLactobacilli and S boulardii are effectiveprobiotics in the management ofAAD.³⁸ A recent meta-analysis of randomized,placebo-controlled trials inpediatric patients, however, did notoffer any conclusive evidence.³⁹

Risks and Adverse Effects withProbiotics

Overall most studies found that probioticsare safe and have no sideeffects.^{3,4,23,32,35,40} In fact, Cremonini et al³²actually reported that Lactobacillus GGand S boulardii both decreased taste disturbancesand diarrhea in patients beingtreated for H pylori with rabeprazole,clarithromycin, and tinidazole. Patientsreceiving Saccharomyces had less gasthan those receiving placebo, accordingto McFarland et al.²³ There are a few casereports of bacteremia or sepsis occurringin patients. These adverse eventsoccurred in patients who were immunocompromisedor severely debilitated andhad multiple comorbidities.^7,40,41 The bacteremiaor sepsis was not fatal in any ofthe patients. These cases are rare andshould not discourage the use of probioticsbut merely serve as a reminder thatcaution should be used when recommendingtheir use. Srinivasan et al⁴⁰specifically studied the safety ofLactobacillus in critically ill children andfound no evidence of colonization or bacteremiain sterile body fluids and surfaces.Boyle et al⁷ reviewed adverseeventcases reported in the literature andfound that there appeared to be risk factorsfor adverse events such as bacteremiaand sepsis in patients. They classifiedrisk factors as major or minor, andthe presence of a single major or morethan 1 minor risk factor warranted cautionregarding the use of probiotics. Themajor and minor risk factors are listed inTable 4.

Therapeutic Considerations

Compliance is a serious issue withregard to antibiotic therapy. Noncompliantpatients can cause resistantstrains of bacteria to form. One commoncause of noncompliance in patients,especially in pediatric patients, is GI sideeffects such as AAD. If taking a probioticcapsule can prevent or reduce the occurrenceof this side effect, compliance mayimprove. In addition to discussing thebenefits of probiotic therapy, the pharmacistcan assist with dosing and schedulingadministration to maximize thepotential benefit of these products. Forchildren, the capsule contents may beemptied into food that is at room temperatureor cooler. Yogurt that containslive culture also may be a useful way tosupply children with probiotics, but thenumber of CFUs should be a consideration.The pharmacist can help ensurethat parents and patients understandthat not all yogurt contains the active culturesof probiotic strains.

A study has shown a temporary colonizationin infants during pregnancy.⁴²Therefore, it would be prudent not torecommend their use in that population.Providing probiotics to patientswith impaired immune status or withmultiple comorbidities or who areseverely debilitated should beapproached cautiously.

A few brands of probiotics generallyavailable are Acidophilus Pearls fromEnzymatic Therapy Natural Medicines (1billion CFUs), Nature Made AcidophilusDietary Supplement (500 million CFUsper tablet), Nature's Way PrimadophilusOptima (35 billion CFUs), and Culturellewith Lactobacillus GG (10 billion+ CFUs).The potency of probiotic products is animportant issue. ConsumerLab.com hascompleted a testing program for probioticpotency (www.consumerlab.com).The duration of therapy generally shouldextend for several days after the discontinuationof the antibiotic to provide thegut with continued exposure to thesehealthy bacteria.

Summary

There is a paucity of quality studiesresearching the effectiveness of probioticsto prevent or treat AAD. Of the studiesthat have been performed, the majorityappear to show that probiotics arelikely to be effective for the prevention ofAAD in most patients receiving oralantibiotics. Side effects attributed to probioticsare not common. The potentialreduction in the side effects of antibiotictherapy may increase compliance inpatients who might otherwise discontinuetherapy due to significant GI sideeffects.

William R. Hamilton, PharmD: Associate Professor, Creighton University School of Pharmacyand 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, CreightonUniversity 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: ReferencesDepartment, Attn. A. Rybovic, PharmacyTimes, Ascend Media Healthcare, 103 CollegeRoad East, Princeton, NJ 08540; or send ane-mail request to: arybovic@ascendmedia.com.

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