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Try out PMC Labs and tell us what you think. Learn More. Language: English French. Antibiotic-associated diarrhea is an important problem in hospitalized patients. The use of probiotics is gaining interest in the scientific community as a potential measure to prevent this complication. The main objective of the present study was to assess the efficacy and safety of a fermented milk combining Lactobacillus acidophilus and Lactobacillus casei that is widely available in Canada, in the prevention of antibiotic-associated diarrhea.
In this double-blind, randomized study, hospitalized patients were randomly ased to receive either a lactobacilli-fermented milk or a placebo on a daily basis. Among 89 randomized patients, antibiotic-associated diarrhea occurred in seven of 44 patients Overall, the lactobacilli-fermented milk was well tolerated. The daily administration of a lactobacilli-fermented milk was safe and effective in the prevention of antibiotic-associated diarrhea in hospitalized patients.
Diarrhea is one of the most frequent side effects of antibiotic use. The severity of AAD may range from benign, uncomplicated diarrhea to C difficile pseudomembranous colitis or toxic megacolon 34. Patient discomfort, discontinuation of primary antibiotic therapy, longer hospitalization time, and even the need to readmit patients are serious consequences of AAD 6. Therefore, identifying preventive measures to curtail the occurrence of AAD is required.
Among these, the use of probiotics is gaining interest in the scientific community 7. The Canadian Natural Health Products Regulations 8 define a probiotic as a monoculture or mixed-culture of live microorganisms that benefit the microbiota indigenous to humans. A probiotic is limited to nonpathogenic microorganisms 8. The most frequently used species are Lactobacillus species, Bifidobacterium species and Saccharomyces species 69 — Their efficacy could be explained by various mechanisms such as the production of antimicrobial substances, competition for gastrointestinal GI colonization and available nutrients, and immunomodulation 79 — 1113 — Several studies have investigated the efficacy of prophylactic probiotics in preventing AAD but the heterogeneity of the strains and formulation used limit their external validity 569 — 1215 — The of some of these studies were also limited by their de, imprecise definition of end points and a lack of patient follow-up after discontinuing antibiotic therapy.
Because related to one specific probiotic cannot be extrapolated to another 7we chose to study a product readily available in Quebec: a fermented milk combining the CL Lactobacillus acidophilus patented strain, and Lactobacillus casei. It is noteworthy that lactobacilli have a long record of safety and have been used for many years in the fermentation process of multiple food products 21 The goal of the present study was to assess the efficacy and safety of a once-daily administration of a lactobacilli-fermented milk compared with placebo, in the prevention of AAD in hospitalized adults.
A prospective, randomized, double-blind, placebo-controlled study was conducted from September to May at Maisonneuve-Rosemont Hospital Montreal, Quebeca bed tertiary care hospital.
The internal review board of the institution approved the study protocol, and written informed consent was obtained from each patient. Patients were randomly ased to receive either a lactobacilli-fermented milk or a placebo a lactoserum devoid of microorganismsadministered once daily.
Both preparations were provided in identically labelled containers; their taste and texture were similar. The administration schedule was 49 g one-half of a container once per day for two days, followed by 98 g one container once per day to cover the entire duration of the antibiotic treatment. If patients were discharged before the completion of their antibiotic treatment, they were provided with the study containers needed to complete the prophylaxis at home. For GI tolerability purposes, both preparations were administered at a lower dosage for the first two days.
Prophylaxis was discontinued if patients developed diarrhea. All patients were instructed to avoid the use of any other probiotic and any type of yogurt for the duration of the study. The follow-up period was planned to end 21 days after the last administered antibiotic dose, unless AAD occurred before that time. The trial population consisted of hospitalized patients who were anticipated to take at least three days of any systemic antibiotic.
Prophylaxis with the study drug or placebo began within the first 48 h of antibiotic treatment. Exclusion criteria included active diarrhea at enrollment, diagnosis of C difficile -associated diarrhea CDAD within the three months, antibiotic treatment with vancomycin or an aminoglycoside in monotherapy 23confirmed lactose intolerance, underlying chronic GI tract disease, patients with stomas, use of parenteral nutrition or tube feeding 124regular probiotic intake, immunocompromised patients, and patients with artificial or damaged cardiac valves 1420 The primary outcome of the present study was the incidence of AAD during the study period.
AAD was defined as three or more liquid stools in a 24 h period. In case of diarrhea, a medical investigation was performed, including a C difficile cytotoxin assay to eliminate other potential causes. Stool frequency and consistency were retrieved from medical records every third day during antibiotic treatment.
This information was also gathered seven, 14 and 21 days after the antibiotic and probiotic regimens were completed. Data for patients discharged before the end of the study were obtained by a telephone call using a standardized questionnaire.
At discharge, patients were provided with a diary to optimize data collection. Secondary outcomes included the occurrence of CDAD, the duration of hospitalization and the adverse events associated with the lactobacilli-fermented milk. To assess the safety of the study preparation, patients were questioned about the occurrence of any adverse event on day 5 and at the end of the prophylaxis.
Analyses of the primary and secondary outcomes were based on the intention-to-treat principle. A multivariate analysis using binary logistic and general linear models were used to evaluate the adjusted between-group differences for the primary outcome measure.
The confounding variables mentioned above were included in this multivariate model. All analyses were performed with SPSS statistical software version Patient flow is summarized in Figure 1and baseline characteristics are summarized in Table 1. Participants were well matched between the two study groups regarding demographic and baseline characteristics. As for the antibiotic and prophylaxis course during the study period, both groups were comparable except for the use of beta-lactam antibiotics, which were prescribed more often in the placebo group A logistic regression model excluded any effect of this variable on the incidence of AAD.
Among 44 patients receiving the lactobacilli-fermented milk, seven developed AAD during the study Among 45 patients receiving the placebo, 16 developed AAD The difference in the rate of occurrence of AAD between the two study groups was statistically ificant OR 0. Most AAD episodes occurred when the antibiotic treatment was complete: in The mean delay between the end of antibiotic therapy and AAD occurrence was not ificantly different between the lactobacilli and the placebo groups: 4.
All analyses were performed according to the intention-to-treat principle. Among all study patients, one patient in the lactobacilli group 2. At least one adverse event was reported by 21 patients in the lactobacilli group There was no ificant difference between the lactobacilli and placebo groups with respect to the incidence of treatment-related adverse events Table 4.
The majority of the adverse events concerned the GI tract. Adverse events were reported as the reason for withdrawal for four patients in the lactobacilli group 9. During the study, three patients in the lactobacilli group died. However, none of those deaths could be related to the use of the study preparation. We found that the lactobacilli preparation was effective in reducing the incidence of AAD when compared with a placebo, even though only 89 patients were recruited in the predeated study period.
This study protocol was conducted as part of a pharmacy residency program and was therefore limited to nine months. In spite of a relatively small group, we were able to reach a statistical conclusion by witnessing a higher baseline risk of AAD A meta-analysis 20 has shown an overall benefit of administering probiotics as a preventive method for AAD.
However, of the nine studies retained for the analysis, only three studies showed some statistically ificant advantage; two involved a Saccharomyces species, and one involved a Lactobacillus species. The latter was one of the studies with the biggest weight in the global analysis. Those studies were heterogenous in the duration of treatment, dosage and antibiotics being used. Because our study was placebo-controlled and randomized, it strengthened the role of lactobacilli-based probiotics as prophylactic agents in the prevention of AAD.
Furthermore, the proportion of AAD due to C difficile infection was very high compared with that observed in studies This observation concurs with the to fourfold increase in the of CDAD cases that affected the Montreal area 26 The prevention of CDAD is an important outcome to consider, because this condition has been associated with an increased mortality and morbidity 2. Although there was a trend in the reduction of the incidence of CDAD in the lactobacilli group compared with the placebo group, this difference was not statistically ificant.
However, the present study was not specifically deed to assess this as a primary outcome and too few patients were randomized to adequately detect such an effect of the lactobacilli preparation. The lactobacilli-fermented milk did not have any impact on the hospital length of stay. It is worth mentioning that 12 of 23 AAD cases The long-term follow-up of patients after their antibiotic courses enabled us to witness that the majority of all the episodes occurred for both groups after the end of antibiotic therapy.
It would have been useful to determine the efficacy of the lactobacilli preparation with regard to specific antibiotics classes, because the incidence of AAD may have varied according to which antibiotic was prescribed. However, it was not feasible because of the variety of antibiotic combinations used concurrently, and the relatively small of patients with diarrhea. In the present study, the use of beta-lactams was more frequent in the placebo group.
However, this disparity was not found to affect the AAD occurrence according to a logistic regression analysis adjusting for potential confounders. Almost one-half of the patients in both groups reported at least one adverse event. Because the placebo was a lactoserum and the study preparation a fermented milk, they would be expected to cause GI disturbances. In fact, most of the adverse events were related to the GI tract. No severe or life-threatening adverse event related to the use of the lactobacilli preparation was reported, although there were some withdrawals associated with the occurrence of an adverse event.
Because some studies 14 have reported the development of septicemia and endocarditis with the use of lactobacilli, the present study voluntarily excluded immunocompromised patients, patients at risk for aspiration and GI translocation, and patients with damaged or artificial heart valves. Therefore, the fermented milk was well tolerated, and should not cause any problem if given to patients with no potential risk factors.
Our findings demonstrate that the daily administration of a fermented milk combining L acidophilus CL and L casei is safe and effective in the prevention of AAD. It also suggests a possible protective effect against CDAD, but the study was not deed to evaluate this hypothesis.
Therefore, we currently cannot advocate the use of this probiotic as a preventive measure to decrease the risk of CDAD. A study with a larger patient sample has to be conducted for this purpose. Am J Gastroenterology ;99 S10 National Center for Biotechnology InformationU. Journal List Can J Gastroenterol v.
Can J Gastroenterol. Author information Article notes Copyright and information Disclaimer. Telephone extfaxe-mail ac. Received Jan 16; Accepted Mar 2. All rights reserved. This article has been cited by other articles in PMC. METHODS: In this double-blind, randomized study, hospitalized patients were randomly ased to receive either a lactobacilli-fermented milk or a placebo on a daily basis.
Keywords: Antibiotic-associated diarrhea, C difficile, Lactobacillus, Probiotic. Study population The trial population consisted of hospitalized patients who were anticipated to take at least three days of any systemic antibiotic. Outcome measures The primary outcome of the present study was the incidence of AAD during the study period. Statistical analysis Analyses of the primary and secondary outcomes were based on the intention-to-treat principle. Open in a separate window. Figure 1.
The flow of patients through the study. NPO Nil per os nothing by mouth. Mechanisms and management of antibiotic-associated diarrhea. Clin Infect Dis. Infect Control Hosp Epidemiol. Bartlett JG. Clinical Practice. Antibiotic-associated diarrhea. N Engl J Med. Clostridium difficile -associated diarrhea in adults. Effect of Lactobacillus GG yoghurt in the prevention of antibiotic associated diarrhoea. Ann Med. Meta-analysis: The effect of probiotic administration on antibiotic-associated diarrhea. Aliment Pharmacol Ther. Probiotics as biotherapeutic agents: Present knowledge and future prospects.
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