AIM: To investigate the effect of Lactobacillus-containing commercially available probiotic formulations in Germany during antibiotic treatment with an analysis of cost-efficiency.

METHODS: In an observational study, we analyzed the frequency of bowel movements from 258 patients with infections in a primary care hospital in western Germany; 107 of the patients were offered a probiotic drink containing at least 10 billion cultures of Lactobacillus casei DN 114001 b.i.d. The economic analysis was based on the costs of patient isolation vs preventive intake of probiotics. In a second pilot study, two commercially available probiotic drinks with different Lactobacillus casei strains were directly compared in 60 patients in a randomized controlled fashion.

RESULTS: In the first study, the incidence of antibiotic-associated diarrhea (AAD) was significantly reduced in the intervention group (6.5% vs 28.4%), and the duration of AAD in days was significantly shorter (1.7 ± 1.1 vs 3.1 ± 2.1). Higher age and creatinine and lower albumin were identified as risk factors for AAD. Ampicillin was the antibiotic with the highest rate of AAD (50%) and with the greatest AAD reduction in the probiotic group (4.2%, relative risk reduction 92%). The economic analysis showed a cost advantage of nearly 60000 €/year in a department of this size. The second study confirmed the preventive effect of the drink with Lactobacillus casei DN114001; however, there were no advantages found for the other tested probiotic drink containing Lactobacillus casei Shirota.

CONCLUSION: In contrast to a drink containing Lactobacillus casei Shirota, a commercially available probiotic drink containing Lactobacillus casei DN 114001 cost-efficiently reduces the prevalence of AAD during antibiotic treatment.

Antibiotic-associated diarrhea (AAD) is a common problem in the treatment of infectious diseases. During treatment with antibiotic drugs, 5%-49% of patients, depending on the type of the antibiotic used, suffer from diarrhea[1,2]; typically, a pathogenic bacterium is not identified in the diarrhea. In approximately 10%-25% of cases, AAD is caused by Clostridium difficile (C. difficile), and the incidence of this bacterium is rising[3]. The presence of diarrhea requires the isolation of the patient until C. difficile-associated diarrhea (CDAD) has been ruled out by stool cultures. In primary hospitals without their own microbiology departments, this diagnostic procedure could take two or three days. During this period, the isolation of the patient leads to a lack of availability of the adjacent beds for other patients and to higher costs of patient care through the necessity of wearing coats, masks, caps and gloves to avoid transferring bacteria to other patients. These additional costs and the discomfort for patients, relatives and staff members could be avoided by a more rapid diagnostic procedure and by the prevention of AAD and CDAD[4]. Data from surveys and our own observations suggest that isolated patients are visited less frequently and consequently are treated worse than non-isolated patients[5-7].

A recent meta-analysis of 82 randomized controlled studies detected a statistically significant reduction in AAD when probiotics were used concomitantly during the administration of antibiotics. However, the studies[8-14] were extremely heterogeneous in terms of their patient population and use of probiotics and antibiotics. Although cultures of lactobacillus[15] were used in the majority of the studies, the bacterial strains were poorly defined and characterized. Clear evidence for a standardized adjuvant probiotic administration could not be formulated, although more than 11000 patients were included in these studies[16]. Another meta-analysis found a statistically significant advantage for lactobacillus strain probiotics; however, there was significant heterogeneity in the study design (study population, probiotic used, definition of AAD, dose and duration of probiotic administration)[17]. In a systematic review, four out of six studies of the highest quality supported an effect of probiotics against AAD[18].

A recent randomized, double-blind placebo-controlled study was not able to show the effectiveness of the administration of Saccharomyces boulardii in the reduction of AAD[19]; however, older studies and a meta-analysis detected an advantage for this strain[20].

The situation regarding probiotics is unclear, and specific recommendations are lacking[21].

Eser et al[1] recently summarized the available evidence and concluded that lactobacillus rhamnosus GG and casei-based probiotics and products using Saccharomyces boulardii and probiotic mixtures could be used in the prevention of AAD; these authors assigned a grade of evidence of 1a for the lactobacillus rhamnosus GG and casei-based probiotics and a grade of 2b for the Saccharomyces boulardii and probiotic mixtures[1]. Given the present data, it is difficult to share these recommendations.

We hypothesize that the prevention of AAD could be most effective if probiotics are used that are widely distributed and accepted by the patients and are not perceived as an additional drug/tablet (low threshold for intake resulting in good compliance). In Germany and in many other countries, several formulations of lactobacillus strains are sold as food products in supermarkets. Therefore, these formulations are easily available and could be used in the outpatient setting and during hospital stays. The majority of these products have a pleasant taste, and the distribution of these probiotic drinks is experienced in a very positive manner by the patients.

Only one study using a commercial product has been published[22]. This study showed a positive effect of the probiotic drink; however, the study was supported by the manufacturer and used an AAD definition that is unsuitable for use in hospitals (AAD defined as 3 or more loose stools in at least 3 consecutive days)[22]. However, in hospitals, diarrhea of one-day duration leads to the isolation of the patient.

The aim of our study was to test the efficacy of commercially available probiotic drinks (Actimel^® and Yakult^®) in the prevention of AAD in a decision-based manner regarding necessary isolation in a primary hospital (3 loose stools on one day) independently from the manufacturer. A calculation of the economic advantage of antibiotic-accompanied prophylactic treatment with probiotics was performed after finalizing the study. Data from the patients were used to identify risk factors for AAD to tailor preventive probiotic treatment to certain risk groups.

Our data from a large number of patients show for the first time in a manufacturer-independent manner that a commercially available probiotic drink (Actimel^®) with a specific lactobacillus casei strain is able to significantly reduce the frequency and duration of AAD and that this reduction is cost-effective. In a large cohort in our department, the twice daily ingestion of this drink led to an AAD frequency of only 6.5%, whereas in the control group, AAD was approximately four times more frequent. The duration of AAD was significantly shorter in the Actimel patients. The patients and medical professionals benefited from the use of probiotic drinks because this protocol significantly reduced the necessity of isolating patients on the ward. Less isolation saves time for medical professionals and increases the quality of life for patients, relatives and medical staff. Additionally, in a cost analysis, we calculated the financial benefit for a department as large as ours to be more than 50000 € per year. Significant side effects were not recorded, suggesting that this probiotic drink is safe even for ill and old patients, taking into account the applied exclusion criteria.

Possible bias might result from the fact that the study was performed on three different wards and that the control group did not receive a placebo.

However, the second part of our study confirmed this result for Actimel in a ward-independent manner, although this part was performed with a smaller number of patients. Furthermore, we showed that another lactobacillus casei drink was not able to improve the AAD frequency. This result suggests a specific effect of the Lactobacillus casei strain used in Actimel or of the composition of the drink, including the other included bacterial strains (Lactobacillus bulgaricus and Streptococcus thermophilus). There might be some features of the study patients that caused Yakult to not be more successful than the control group of the first study. First, the patients in the Yakult group were older and had a worse performance status, although these differences did not reach significance. Additionally, the patients in the Yakult group had more pulmonary infections and more often received ampicillin as the antibiotic; ampicillin was associated with the highest AAD-frequency. This administration of ampicillin might be the reason for the three cases of CDAD in this group. In the Actimel group, no CDAD was observed, emphasizing the positive effect of the probiotic.

The second study confirmed the positive effects for one of the commercially available probiotic drinks containing the specific lactobacillus strain DN-114001; however, these results could not be transferred to all lactobacillus preparations because either the defined lactobacillus strain or the composition of the fermented milk drink might confer different effects on AAD.

In the analysis of patients with diarrhea vs the patients without diarrhea, several factors appeared to emerge as promoting AAD. In both study parts, the patients with diarrhea were older and had a lower albumin level and a higher creatinine level. The creatinine variable did not reach significance in the second study most likely because of the smaller patient number. These results, however, are in agreement with an earlier study[19], suggesting that these factors promote AAD. There could be pathophysiological explanations for these data. Doctors often forget to reduce the dose of the antibiotic according to the renal function in patients with only limited renal insufficiency. Additionally, the albumin level reflects the nutritional status and might influence the pharmacokinetics of antibiotic substances via blood protein binding. These findings and their possible explanations should lead to the careful dosing of antibiotics in older patients with mild to moderate renal insufficiency.

Treatment with antibiotics in the medical history has long been associated with CDAD[25]. Our data from the second study imply that prior antibiotic treatment might also be a risk factor for AAD. The role of concurrent PPI therapy is controversial[25,26]; however, our limited data support an association between concomitant PPI therapy and AAD. The number of patients in the second study is too low to obtain confident data regarding these factors, and future studies with higher power should examine these associations. These findings should further contribute to a reduction in the generous use of PPI.

Our data have implications for hospitals without their own microbiological departments. In such hospitals, ruling out specific infections, such as CDAD in the case of AAD, takes several days and necessitates the isolation of patients to avoid spreading the infection. In an era of increasing nosocomial infections and more severe CDAD infections, the avoidance of AAD is the best preventive measure; furthermore, the isolation of patients is a nuisance to the patients and the hospital staff and leads to worse medical care of these patients[5-7]. Additionally, cost-reduction is enormous and likely underreported because we did not include the cost of a longer hospital stay for AAD patients or for stool cultures.

The data from existing studies and our own data from the present study justify the use of probiotics for the prevention of AAD during antibiotic treatment, especially in geriatric patients with recent antibiotic use, renal insufficiency and lower albumin values. It is probable that even the generalized use of probiotics is cost-effective and safe. Our study implies that careful dose modifications in patients with lower albumin and higher creatinine levels might contribute to a lower prevalence of AAD; however, these issues should be investigated in separate studies.