Therapeutic effect of Antibodies against Antibiotic Associated Diarrhea (AAD): A Systematic Review and Meta-analysis Thirumalai Diraviyam 1, Jin-xin He 1, Bin Zhao 1, 2, Ruediger Schade 3, Antonysamy Michael 4, and Xiaoying Zhang 1* 1 College of Veterinary Medicine, Northwest A&F University, Yangling, China 2 College of Science, Northwest A&F University, Yangling, China 3 Institute of Pharmacology, Charité - Universitätsmedizin Berlin, Germany 4 PSG College of Arts and Science, Bharathiar University, Coimbatore, Tamil Nadu, India * Corresponding author: Tel./Fax:+86 29 8709 1239. E-mail address: zhang.xy@nwsuaf.edu.cn (Dr. X.-Y. Zhang)
1. Background: Antibiotics are the most commonly and frequently prescribed medications for prophylactic and active treatment of bacterial diseases in humans and animals. It is not surprising that antibiotics may disturb the gut microbial community. In severe condition, it can be a cause of significant morbidity and mortality. Clostridium difficile (C. difficile) is the most common and frequently occurring pathogen in Antibiotic Associated Diarrhea (AAD) cases. Current treatment for AAD is discontinuing the inciting antibiotics or switching to narrower spectrum antibiotics. In addition, the relapsing AAD increases markedly and the organisms isolated following a recurrent episode are resistant to antimicrobial therapy. In the recent decades, therapeutic agents against bacterial pathogens are gaining interest as an alternative to antibiotics for the treatment of infectious diseases. Particularly antibodies from different origin have been focused and reported as a promising alternative for the control and treatment of AAD. Hence, this study is aimed to evaluate the effect of antibody therapy against AAD in animal experiments and human clinical trials. 2. Objectives i. To collect published relevant literatures from different databases ii. To select potential studies based on the inclusion criteria and extract data for analysis iii. To systematically consolidate the research outputs from selected studies and perform statistical analysis in order to evaluate the effect of antibody therapy against AAD iv. To present our study as systematic review and meta-analysis and publish for the reference of further research focuses in AAD 3. Methods 3.1. Literature search: Research reports on antibody (immunoglobulin) therapy against AAD were retrieved from different electronic data bases such as PubMed, EMBASE, Web of Science and WILEY. In order to avoid the missing of potential studies (which do not retrieved by the electronic search), bibliographies of narrative reviews and eligible reports were analyzed manually. The search components (SC) used for literature search in PubMed has been designed as per the method prescribed by Leenaars et al., (2012). The same search strategy has been translated to other databases by copying the search string for each SC and stripping the field indicators such as [MeSH] and [tiab]. The removed filed indicators were replaced by the suitable
equivalents according to the database. Boolean operators ( AND / OR ) and truncations (*) have been used appropriately. Search Strategy used for PubMed: Search Query Results #1 Immunization, passive [MeSH] OR Immunizations, passive [MeSH] OR Passive 30175 hits Immunizations [MeSH] OR Passive Immunization [MeSH] OR Passive Antibody Transfer [MeSH] OR Passive Antibody Transfers [MeSH] OR Passive Immunotherapy [MeSH] OR Passive Immunotherapies [MeSH] OR Immunoglobulin Therapy [MeSH] OR Immunoglobulin Therapies [MeSH] OR Serotherapy [MeSH] OR Serotherapies [MeSH] OR Passive antibody administration [tiab] OR oral passive immunization [tiab] OR oral passive immunotherapy [tiab] OR Passive immunisation [tiab] OR Passive immunisations [tiab] OR Antibody treatment [tiab] #2 Pseudomembranous Enterocolitis [MeSH] OR Pseudomembranous Colitis [MeSH] OR Antibiotic-Associated Colitis [MeSH] OR Antibiotic Associated Colitis [MeSH] OR Clostridium Enterocolitis [MeSH] OR Pseudomembranous 8659 hits Enteritis [MeSH] OR Antibiotic-Associated Diarrhea [tiab] OR Antibiotic Associated Diarrhea [tiab] OR Clostridium difficile colitis [tiab] OR antibioticassociated pseudomembranous colitis [tiab] OR antibiotic associated pseudomembranous colitis [tiab] OR Clostridium difficile Associated Diarrhea [tiab] OR Clostridium difficile -Associated Diarrhea [tiab] OR AAPMC [tiab] OR AAD [tiab] OR CDAD [tiab] #3 #1 AND #2 ( with some modifications to obtain relevant hits) 1523 hits Passive Immunotherapy[MeSH] OR Passive Immunotherapies[MeSH] OR Immunoglobulin Therapy[MeSH] OR Immunoglobulin Therapies[MeSH] OR Serotherapy[MeSH] OR Serotherapies[MeSH] OR Passive antibody administration[tiab] OR oral passive immunotherapy[tiab] AND Antibiotic- Associated Diarrhea[tiab] OR Antibiotic Associated Diarrhea[tiab] OR Clostridium difficile colitis[tiab] OR antibiotic-associated pseudomembranous colitis[tiab] OR antibiotic associated pseudomembranous colitis[tiab] OR Clostridium difficile Associated Diarrhea[tiab] OR Clostridium difficile - Associated Diarrhea[tiab] #4 Search filter reported by Hoojimans et al., (2010) to select all animals studies in PubMed has been used 5,966, 108 hits #5 #3 AND models, animal [MeSH] 27 hits #6 Human Experimentation [MeSH] OR Therapeutic Human Experimentation [MeSH] OR Clinical Trials [MeSH] OR Therapeutic Research [MeSH] OR randomized controlled trial [MeSH] OR controlled clinical trials [MeSH] OR Human Experiments [tiab] OR Clinical studies [tiab] OR Clinical study [tiab] 375452 hits #7 Clinical Trials [MeSH] OR Human Experiments [tiab] 275612 hits #8 #3 AND #7 463 hits 3.2. Selection of potential studies: Research reports that were selected and included for the analyses if they met following inclusion criteria:
a. Study should be aimed to evaluate the effect of antibody therapy against Antibiotic Associated Diarrhea (AAD) or Clostridium difficile Associated Diarrhea (CDAD) b. Antibody should be used as therapeutic element against AAD or CDAD for the intervention c. Animals or Human subjects should be used to evaluate the efficacy of antibody treatment d. Experimental design should be properly designed and performed as well in accordance with respective guidelines e. Outcome measures should be clearly described with sufficient data including number of animals or humans subjects used in both intervention and control group 3.4. Data Extraction: Outcome of the each included potential studies were extracted using a standardized data extraction form (prepared by ourselves). Missing information was discussed with the corresponding authors by contacting through e-mail or telephonic conversation. Reviewers assessed the risk of bias, inconsistency and indirectness of the study included for the systematic review. List of information extracted from the each study as follows, i. Author and year of publication (to access the chronological development of research) ii. Purpose of the study iii. Type of trial (uncontrolled or controlled or clinical or pre-clinical) iv. Experimental subject (animals or humans) v. Type of antibiotic associated diarrhea (experimental or natural) vi. If experimental, methods of inducing diarrhea, antibiotics dose, single antibiotic or antibiotic cocktail, duration of antibiotic course, pathogen challenge dose, duration, time and mode of administration vii. Antibody treatment procedure source of antibody (route of administrations (oral or IV), dose, duration, etc viii. Method of outcome assessment, results of experimental group and control groups ix. Inference of the study
3.5. Assessing the quality of the Studies: Potential studies used animal as subject for analyses will be assessed for methodological quality using the Animal Research: Reporting of In-vivo Experiment (ARRIVE) Guidelines developed as a part of NC3Rs (National Centre for the Replacement, Refinement and Reduction of Animals in Research) to improve the design, analysis and reporting of research using animals. Selected studies used human subjects (clinical trials) will be assessed for the quality as per Cochrane Systematic Review guidelines. 3.6. Data Analysis: The relative risk (RR) and the 95% confidence interval (CI) will be calculated in trails reporting the binary outcome (as primary outcome measure) i.e., incidence of diarrhea or mortality. To estimate the amount of heterogeneity I 2 value will be calculated. 4. Expected Outcome: This study is expected to systematically summarize the usefulness of antibody as an alternative therapeutic agent for the treatment of AAD with statistical approach such as meta-analysis. Contact details for further information Prof. Dr. Xiao-Ying Zhang, Post Box 19, College of Veterinary Medicine, Northwest A&F University (North Campus), Xinong Rd 22, Yangling, Shaanxi Province, 712100, China Tel & Fax: +86 29 8709 1239; E-mail: zhang.xy@nwsuaf.edu.cn Anticipated or actual start date 1st March 2014 Anticipated Completion date 30th August 2014 Funding sources/sponsors: This work was supported by the Research Fellowship for International Young Scientists (No. 31350110512), China National Science Foundation. Ph.D. Programs Foundation of Ministry of Education of China (20130204110023), Ministry of Education and State Administration of Foreign Experts Affairs "overseas teacher" project (No.MS2011XBNL057), China Conflicts of interest: None Known Stage of review at time of this protocol submission Started Completed Literature search in electronic data base - Yes Study selection process - Yes Screening according to eligibility criteria - Yes Data extraction Yes -
Quality Assessment Yes - Data analysis - -