Clostridium difficile infections are a global clinical concern and are one of the leading causes of nosocomial outbreaks. Preventing these infections has benefited from multidisciplinary infection control strategies and new antibiotics, but the problem persists. Probiotics are effective in preventing antibiotic-associated diarrhea and may also be a beneficial strategy for C. difficile infections, but randomized controlled trials are scarce. This meta-analysis pools 21 randomized, controlled trials for primary prevention of C. difficile infections (CDI) and four trials for secondary prevention of C. difficile recurrences and assesses the efficacy of specific probiotic strains. Four probiotics significantly improved primary CDI prevention: (Saccharomyces boulardii, Lactobacillus casei DN114001, a mixture of L. acidophilus and Bifidobacterium bifidum, and a mixture of L. acidophilus, L. casei and L. rhamnosus). None of the tested probiotics significantly improved secondary prevention of CDI. More confirmatory randomized trials are needed to establish if probiotics are useful for preventing C. difficile infections. v Antibiotics (Basel) Antibiotics (Basel) 2908 antibiot antibiotics Antibiotics 2079-6382 Multidisciplinary Digital Publishing Institute (MDPI) PMC4790329 PMC4790329.1 4790329 4790329 27025619 10.3390/antibiotics4020160 antibiotics-04-00160 1 Review Probiotics for the Primary and Secondary Prevention of C. difficile Infections: A Meta-analysis and Systematic Review McFarland Lynne V. Chang Yung-Fu Academic Editor Department of Medicinal Chemistry, University of Washington, VA Puget Sound Healthcare System, 1660 S. Introduction Clostridium difficile infections (CDI) have been a difficult clinical issue for over four decades, with a nearly one-half a million cases per year in the U.S., resulting in 29,000 deaths per year, increased costs of healthcare, outbreaks of CDI in hospitals and long-term care facilities and 83,000 cases of recurrent CDI per year the U.S. [ 1 ]. Prevention of CDI has relied on multidisciplinary infection control practices, but guidelines have been found to be difficult to implement globally [ 2 , 3 ]. An innovative strategy to prevent CDI involves using probiotics at the same time antibiotics are given. One recent quasi-experimental study was done in Canada, which gave the mixture of L. acidophilus , L. casei and L. rhamnosus (BioK+) to all patients receiving antibiotics at two hospitals over time and found a significant reduction in the incidence of CDI cases and recurrences at these facilities [ 4 ]. Some probiotic strains have been found to be effective for prevention of antibiotic-associated diarrhea (AAD) and for the treatment of CDI [ 5 ]. Since CDI accounts for nearly one-third of all AAD cases, this strategy is worth evaluating since CDI persists in impacting our healthcare systems. antibiotics-04-00160-t001_Table 1 Table 1 Prevention of Clostridium difficile infections (CDI) for trials with only one study for specific probiotic type. Probiotic Eligible Antibiotic Exposures Daily Dose of Probiotic (cfu/day) Duration of Probiotic Treatment Duration Follow-up CDI in Probiotic Group (%) CDI in Control Group (%) Reference Primary prevention of CDI L. casei Shirota nr 6.5 × 10 9 duration + 1 week 4 weeks 9/76 (0%) ns 1/82 (1.2%) Wong 2014 [ 7 ] L. acidophilus mixed, 77% beta-lactams 6 × 10 10 2 weeks 0 0/23 (0%) ns 1/16 (6.2%) Safdar 2008 [ 8 ] L. antibiotics-04-00160-t002_Table 2 Table 2 Study design description for primary prevention of C. difficile infections from studies of Probiotics for the Prevention of Antibiotic-associated diarrhea. Enrolled population % Attrition Single or Multiple Types of Inciting Antibiotics Most Common Type of Antibiotic Type(s) of Infections Reference adults, I 43 59% multiple 36% cepha mixed, nr Surawicz 1989 [ 17 ] adults, I 38 82% multiple beta-lactams mixed, nr McFarland 1995 [ 18 ] elderly, I 4.2 nr nr nr Lewis 1998 [ 19 ] adult, O 3.3 100% multiple amox and clarithromycin H. Probiotics were given in conjunction with the antibiotics (usually started within 48–72 h of the antibiotic) and continued for either the duration of the antibiotic (12 treatment arms, 52%) or continued for 3–14 days after antibiotics were discontinued (7 arms, 30%). Four treatment arms gave the probiotic for a prescribed period (ranging from 14–21 days), regardless of the duration of antibiotics [ 23 , 27 , 32 , 34 ]. The duration of follow-up post-antibiotic and probiotic intervention ranged from 0–90 days. Eight (35%) of the treatment arms did not follow patients after the intervention had been discontinued. The three treatment arms in one trial combined S. boulardii or placebo in three separate antibiotic adjunctive treatments [either low dose vancomycin (500 mg/day), high dose vancomycin (2 g/day) or metronidazole (1 g/day)] [ 39 ]. The doses of vancomycin or metronidazole adjuncts were The duration of probiotic intervention varied from 3–4 weeks, except in one trial that gave the intervention during adjunctive antibiotic therapy (typically 10–14 days), then extended the intervention for another three weeks [ 41 ]. The duration of follow-up was usually four weeks post-intervention, except for one trial that followed patients for 8.6 weeks [ 41 ]. antibiotics-04-00160-t004_Table 4 Table 4 Secondary prevention by probiotic type for treatment of Clostridium difficile infections (CDI). rhamnosus GG) had sufficient numbers of trials for to assess secondary prevention of CDI by meta-analysis, but none of the pooled results reached statistical significance. It may be that neither of these strains were effective in this analysis for preventing CDI recurrences, but based on prior experience and use of these probiotics (mechanism of action studies, case series, etc. ), there are indications that these probiotic strains may be effective if an effective combination of probiotic and anti- C. difficile antibiotics can be determined [ 57 , 58 ].

Abstract To ensure effective administration of probiotics in clinical practice, it is crucial to comprehend the specific strains and their association with human health. Therefore, we conducted a systematic review and meta-analysis to evaluate the scientific evidence on the impact of Lactiplantibacillus plantarum probiotic consumption on human health. Out of 11,831 records, 135 studies were assessed qualitatively, and 18 studies were included in the meta-analysis. This systematic review demonstrated that probiotic supplementation with L. plantarum , either alone or in combination, can significantly improve outcomes for patients with specific medical conditions. Meta-analysis revealed notable benefits in periodontal health, evidenced by reduced pocket depth and bleeding on probing ( p &lt; 0.001); in gastroenterological health, marked by significant reductions in abdominal pain ( p &lt; 0.001); and in infectious disease, through a reduction in C-reactive protein levels ( p &lt; 0.001). Cardiovascular benefits included lowered total cholesterol and low-density lipoprotein cholesterol in the L. plantarum intervention group ( p &lt; 0.05). Our study’s clinical significance highlights the importance of considering probiotic strain and their application to specific diseases when planning future studies and clinical interventions, emphasizing the need for further research in this area. Cardiovascular benefits included lowered total cholesterol and low-density lipoprotein cholesterol in the L. plantarum intervention group ( p < 0.05). Our study’s clinical significance highlights the importance of considering probiotic strain and their application to specific diseases when planning future studies and clinical interventions, emphasizing the need for further research in this area. Supplementary Information The online version contains supplementary material available at 10.1007/s12602-024-10287-3. In 2017, a survey conducted among 965 patients at a tertiary medical center in California, USA, reported that the use of probiotics among patients was as high as 55%, including food products and supplements [ 2 ]. However, the results from recent research have supported the concept that probiotics are not equally effective [ 3 ]. Clinical trials have investigated the health benefits of many single or multi-strain probiotic mixtures to meet patients’ health needs [ 4 ]. Types of intervention: consumption of L. plantarum probiotic Types of comparison: Individuals (children and adults) who received L. plantarum probiotics. Individuals (children and adults) who did not receive L. plantarum probiotic (placebo), with or without receiving the standard treatment care protocol for their health condition. Types of outcomes: health benefits (e.g., mental health, upper respiratory system, oral health, gastrointestinal health) Types of studies: randomized controlled trials. However, two articles observed unfavorable effects of L. plantarum administration in patients with IBS symptoms [ 57 , 58 ], and two studies showed no significant difference between the intervention and control groups [ 59 , 60 ]. All studies reported more practical benefits of adjunctive probiotic L. plantarum supplementation combined with standard H. pylori eradication therapy by increasing eradication rates and reducing antibiotic side effects [ 61 – 63 ], except one [ 64 ]. L. Plantarum Consumption: Benefits or Limitations on Gastroenterology Probiotics have been demonstrated to affect IBS in several trials [ 117 ] L. plantarum 299v has been found to alleviate abdominal pain in IBS patients [ 110 ]. However, it is important to consider the strain-specific efficacy of probiotics, as different strains may have varying outcomes. Among 22 strains of lactobacilli isolated from fermented food products, L. plantarum MF1298 was found to have the best in vitro probiotic characteristics [ 130 , 131 ], suggesting it is a potential probiotic strain. The observed alterations in IL-10 levels may have a significant impact on the emergence of necrotizing enterocolitis (NEC). Further research should focus on elucidating the biological significance of probiotics' interactions with other antimicrobial substances and with each other. L. Plantarum Consumption: Benefits or Limitations on Pulmonary Disease In a population of COPD patients with a history of frequent antibiotic use, consumption of a multispecies probiotic containing L. plantarum did not significantly influence the composition of the dominant fecal microbiota, in contrast to earlier findings in healthy volunteers. However, both the probiotic and placebo groups showed a significant but minor antibiotic impact, with increased yeasts and decreased Bifidobacterium. Comparison between the probiotic and placebo groups did not reveal any significant differences. Nonetheless, the probiotic group did show changes in certain bacterial groups over time. L. Plantarum Consumption: Benefits or Limitations on Nephrology The initial findings from this study suggest that the administration of L. plantarum probiotic may have a favorable immunomodulatory effect in individuals with dyslipidemic nephrotic syndrome, as indicated by a tendency towards decreased serum levels of TNF-α and increased IL-10. plantarum group and the control group in preventing postoperative infection complications. In contrast, another trial using a multi-strain probiotic formulation, which included L. plantarum , showed a reduced incidence of postoperative complications. This highlights the importance of reporting strain specificity of probiotics, as they are believed to be both strain-specific and disease-specific. Further research is needed to better understand the potential benefits of L. plantarum in preventing postoperative complications and to identify optimal strains, dosages, and treatment durations. [ 3 ]. L. The identified constraints underscore the need for further research to address these shortcomings and contribute to a more