Please cite this article in press as: Ouwehand AC, et al. Probiotics reduce symptoms of antibiotic use in a hospital setting: A randomized dose response study. Vaccine (2013), http://dx.doi.org/10.1016/j.vaccine.2013.11.053 ARTICLE IN PRESS G Model JVAC 14860 1–6 Vaccine xxx (2013) xxx–xxx Contents lists available at ScienceDirect Vaccine jou rn al hom ep age: www.elsevier.com/locat e/vaccine Probiotics reduce symptoms of antibiotic use in a hospital setting: A randomized dose response study Arthur C. Ouwehand a,∗ , Cai DongLian b , Xu Weijian b , Morgan Stewart c , Q1 Jiayi Ni d , Tad Stewart e , Larry E. Miller c a Active Nutrition, DuPont Nutrition & Health, Sokeritehtaantie 20, Kantvik 02460, Finland b Changhai Hospital, No. 800, Xiangyin Road, Shanghai 200433, China c Sprim, 1 Daniel Burnham Court, Suite 100C, San Francisco, 94109, CA USA d Sprim China, 200 NingHai East Rd, Shanghai 200021, China e DuPont Nutrition & Health USA, 3329 Agriculture Drive, Madison 53716, WI USA a r t i c l e i n f o Article history: Received 11 September 2012 Received in revised form 4 November 2013 Accepted 15 November 2013 Available online xxx Keywords: Antibiotic associated diarrhea Probiotics Dose response Lactobacillus acidophilus Lactobacillus paracasei Bifidobacterium lactis a b s t r a c t Probiotics are known to reduce antibiotic associated diarrhea (AAD) and Clostridium difficile associated diarrhea (CDAD) risk in a strain-specific manner. The aim of this study was to determine the dose-response effect of a four strain probiotic combination (HOWARU ® Restore) on the incidence of AAD and CDAD and severity of gastrointestinal symptoms in adult in-patients requiring antibiotic therapy. Patients (n = 503) were randomized among three study groups: HOWARU ® Restore probiotic 1.70 × 10 10 CFU (high-dose, n = 168), HOWARU ® Restore probiotic 4.17 × 10 9 CFU (low-dose, n = 168), or placebo (n = 167). Subjects were stratified by gender, age, and duration of antibiotic treatment. Study products were administered daily up to 7 days after the final antibiotic dose. The primary endpoint of the study was the incidence of AAD. Secondary endpoints included incidence of CDAD, diarrhea duration, stools per day, bloody stools, fever, abdominal cramping, and bloating. A significant dose-response effect on AAD was observed with incidences of 12.5, 19.6, and 24.6% with high-dose, low-dose, and placebo, respectively (p = 0.02). CDAD was the same in both probiotic groups (1.8%) but different from the placebo group (4.8%; p = 0.04). Inci- dences of fever, abdominal pain, and bloating were lower with increasing probiotic dose. The number of daily liquid stools and average duration of diarrhea decreased with higher probiotic dosage. The tested four strain probiotic combination appears to lower the risk of AAD, CDAD, and gastrointestinal symptoms in a dose-dependent manner in adult in-patients. © 2013 Published by Elsevier Ltd. 1. Introduction Antibiotics have provided great medical benefits and have enabled the control of numerous infectious diseases. However, the use of antibiotics may be accompanied by gastrointestinal distur- bances; most notably antibiotic-associated diarrhoea (AAD) [1]. The incidence of AAD ranges between 5 and 39% and varies according to individual susceptibility, the patient environment, and the class of antibiotics administered [2,3]. While AAD can be caused by multiple pathogens and has multi- factorial etiology, between 10 and 25% of all episodes of AAD, and virtually all those seen in antibiotic-induced pseudo-membranous colitis, are caused by C. difficile [4,5]. Incidence rates and propor- tion of severe cases of C. difficile-associated diarrhea (CDAD), and associated mortality, are on the rise [5–7]. ∗ Corresponding author. Tel.: +358 40 5956353; fax: +358 10 4315555. E-mail address: arthur.ouwehand@danisco.com (A.C. Ouwehand). Specific probiotic strains have been shown to have various ben- eficial health effects [8–11]. Recent meta-analyses concluded that probiotics produced relative risk reductions of 44–57% for AAD and 41–71% for CDAD [3,10,12]. Specific probiotics, therefore, seem to be promising as an adjunct to antibiotics to reduce the risk of AAD. Although several studies of specific probiotics against AAD exist, there is currently only one dose-response study comparing 5 and 10 × 10 10 CFU; that is limited to elderly [13]. The primary objec- tive of the present study was therefore to investigate the effect of a specific combination of probiotic strains, which has earlier been shown to stabilize the intestinal microbiota [14], on the incidence of AAD at two different doses (4.7 × 10 9 and 1.70 × 10 10 CFU) in a hospital setting in adults aged 30–70. The secondary objectives were to investigate their influence on the severity and duration of AAD and CDAD. 2. Methods All research procedures were in strict accordance with a pre-defined protocol and were registered at clinicaltrials.gov 0264-410X/$ – see front matter © 2013 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.vaccine.2013.11.053 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56