Clinical Briefs

With Comments from Russell H. Greenfield, MD Dr. Greenfield is Clinical Assistant Professor, School of Medicine, University of North Carolina, Chapel Hill, NC; and Visiting Assistant Professor, University of Arizona, College of Medicine, Tucson, AZ.

Pro vs. Anti: Diarrhea with Antibiotics

Source: Hickson M, et al. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: Randomized double blind placebo controlled trial. BMJ 2007;335:80. Epub 2007 Jun 29.

Goal: To determine whether ingestion of a commercially available probiotic drink protects against antibiotic-associated diarrhea (AAD) in older hospitalized patients.

Design: Randomized, double-blind, placebo-controlled clinical trial.

Subjects: Older hospitalized patients (n = 135, mean age = 74 years) recruited from three London hospitals and taking antibiotics (data analyzed on 113 subjects).

Methods: Subjects were divided into two groups: Those randomized to the placebo intervention received a long-life sterile milkshake (Yazoo), while those in the active group consumed a yogurt drink (Actimel®) containing Lactobacillus casei, L. bulgaricus, and Streptococcus thermophilus. The drinks were ingested twice a day beginning within 48 hours of initiation of antibiotic therapy (oral or intravenous) and continued for one week past completion of the course. The primary outcome was occurrence of diarrhea; secondary outcome measures focused on diarrhea due to Clostridium difficile and presence of its toxin (A, B, or both) in a stool sample. Final follow-up was five weeks after completion of antibiotic therapy. Lactobacillus counts were carried out on probiotic drink samples to ensure the presence of viable organisms, baseline stools samples were screened for C. difficile, and subjects' compliance was assessed.

Results: Subjects in the probiotic group developed AAD at a lesser rate than those in the placebo group (12% vs. 34%, odds ratio of 0.25 for use of the probiotic). The absolute risk reduction with probiotic use was 22%. While 17% of subjects in the placebo group had diarrhea due to C. difficile, no one in the active group did (absolute risk reduction with probiotic use = 17%). No adverse events related to study drinks were reported.

Conclusion: Consumption of a specific commercially available probiotic drink reduces the incidence of AAD and C. difficile diarrhea in older hospitalized patients receiving antibiotic therapy.

Study strengths: Close follow-up of subjects who were discharged from the hospital; checking for viability of microbes; use of commercially available drinks; intention-to-treat analysis; screening for C. difficile.

Study weaknesses: Significant problems with recruitment; possible (albeit unlikely) bias through unblinding; incomplete data on 16% of initial participants; compliance (only 75% in the probiotic group, reported to be mainly due to delivery and distribution failures).

Of note: A total of 1,760 patients were screened with only 135 subjects taking part in the trial; the most common reason for exclusion was likelihood of diarrhea from causes unrelated to antibiotic therapy; patients and researchers were blind to the study drinks, and individual hospital pharmacies were in charge of dispensing; for purposes of this trial, diarrhea was defined as two or more liquid stools/day for three or more days; subjects were mainly on orthopedic, "elderly care," and general medical wards; 40% of subjects were receiving more than one antibiotic; Yazoo is an "ultra high temperature treated product and has no bacterial count" exclusion criteria included antibiotic use within the prior four weeks, history of valvular heart disease, and bowel surgery; part-way through the trial researchers received approval to recruit patients with cognitive impairment (total of seven, with three in the active group); low albumin and low sodium levels were also associated with an increased risk of diarrhea; estimated cost for a 17-day course of Actimel is $20; estimated costs for treating C. difficile diarrhea run to $3,700, mainly due to use of vancomycin and the requisite increase in duration of hospitalization.

We knew that: Probiotics are defined as live microorganisms which, upon ingestion by a host in sufficient amounts, exert health benefits beyond basic nutrition; multiple studies suggest that probiotic therapy is effective at preventing AAD and is safe; diarrhea associated with antibiotic use is a common complication occurring in 5-25% of patients, with C. difficile the causative agent in 15-25% of cases, most often in older patients; C. difficile diarrhea typically occurs 2-3 weeks after cessation of antibiotic therapy.

Clinical import: AAD is a cause of significant morbidity for patients at each end of the age spectrum. While a number of studies have examined specific microbes for the prevention of AAD, few trials have been performed in older patients, fewer still using a commercially available probiotic drink. The results of this trial are convincing, and many questions persist.

It is well known that antibiotics can interfere with colonic microflora homeostasis. Probiotic therapy may offer benefits in the setting of antibiotic administration in a number of ways, including stimulation of the host immune response, competition with neighboring pathogens for nutrients and receptor sites, increased mucin production (thereby blocking mucosal adhesion), production of antimicrobial substances, and interference with toxins. Which, if any, of these actions is at work is yet to be agreed upon. The therapy does, however, appear to be successful. It also appears to be safe, though caution is warranted in the immunocompromised (live bacteria do translocate). It seems reasonable to utilize probiotics in the setting of antibiotic administration even while the mechanism of action of probiotic therapy is still being worked out. And yet, which organisms to employ?

The effects of probiotic therapy are strain-specific. As the authors readily point out, it is not possible from the data to determine whether a synergistic interaction between the three microbes helped prevent illness, or if a single microbe was especially effective, or any combination of factors in between. All that can be stated from the trial is that the specific combination of the three microbes in the dosages employed seems effective.

Duration of therapy has also been a question. In this trial, probiotic administration during antibiotic therapy and continued for one week thereafter offered benefit.

The authors intimate that some form of probiotic therapy should be considered routinely for older patients on antibiotics. A wealth of data on probiotics is now on hand, and this recommendation seems more than reasonable, but specific information on recommended strains and dosage is still somewhat haphazard.

What to do with this article: Keep a hard copy in your file cabinet.

Rice is Nice: Red Yeast Rice and Lipids

Source: Huang CF, et al. Efficacy of Monascus purpureus Went rice on lowering lipid ratios in hypercholesterolemic patients. Eur J Cardiovasc Prev Rehab 2007;14:438-440.

Goal: To determine the effect of red yeast rice (RYR) on lipid ratios.

Design: Randomized, double-blind, placebo-controlled trial performed over eight weeks in Taiwan.

Subjects: Women and men with hypercholesterolemia aged 23-65 years (n = 79).

Methods: All participants followed an American Heart Association Step I diet program for four weeks as lead-in to the trial. Subjects meeting study criteria were then randomized to receive either RYR 600 mg or a rice powder placebo twice daily. Twelve-hour fasting blood samples were taken at the time of randomization, as well as four and eight weeks into the trial period.

Results: The placebo group did not experience significant improvements in lipid levels or lipid ratios. Those receiving RYR showed a significant improvement over the placebo group in LDL-C levels, as well as total cholesterol (TC)/HDL-C, LDL-C/HDL-C, and Apo B/Apo A-I ratios. After eight weeks, TC decreased by 20%, LDL-C by 26%, and Apo B by 25%. The active group also saw decreases in the percentage of subjects with TC/HDL-C > 5 (from 64% to 33%), LDL-C/HDL-C > 5 (from 33% to 8%), and Apo B/Apo A-I ³ 1 (from 67% to 28%).

Conclusion: RYR can effectively lower lipid ratios in patients with dyslipidemia.

Study strength: Consideration of multiple lipid measures.

Study weaknesses: Short duration; no information on adverse events or side effects (if any); no data on HDL-C or triglyceride levels.

Of note: Subjects had to have an LDL-C > 160 mg/dL, TC > 240 mg/dL, and triglycerides < 400 mg/dL to participate; participants received dietary instruction from a registered dietitian during the intervention phase of the trial; data suggest that patients with low LDL-C levels but a high TC/HDL-C ratio have a significantly higher incidence of coronary artery disease than those with similar LDL-C levels, but low TC/HDL-C ratios; the dose employed in the trial is lower than what is commonly recommended (1,200 mg twice daily).

We knew that: Lipid ratios may reflect the proportion of atherogenic to antiatherogenic lipids and lipoproteins; a small number of trials have shown RYR to be effective in improving lipid profiles; prior study suggests that for each 1% decrease in TC/HDL-C there is an associated 1.3% reduced risk for coronary artery disease, and that each unit difference in the same ratio is associated with an 18% reduction in risk for a coronary event; additional data suggest that for each one unit increase in the LDL-C/HDL-C ratio, there is an associated 1.2-fold increase in risk of cardiovascular disease; Apo B/Apo A-I is an indicator of non-HDL particle size divided by HDL particle size; many experts have called for the Apo B/Apo A-I ratio to be included in the standard lipid profile, but recent data call into question whether the ratio is as predictive of cardiovascular risk when evaluated on its own as previously believed.

Clinical import: Most research articles on management of lipid disorders focus on the impact of treatment on specific levels of lipids or lipoproteins. This trial addressed the use of RYR on lipid ratios, parameters that have been growing in popularity among specialists. Most of us are familiar with the TC/HDL-C ratio (optimally < 3.5), and are becoming more familiar with measurements of Apo B (a protein component of LDL-C and VLDL-C), Apo A-I (the major protein fraction of HDL-C), and the Apo B/Apo A-I ratio. This trial suggests that RYR is effective in modifying cardiovascular risk based on its effects on lipid parameters, including specific ratios.

Statin therapy is quite effective for management of most forms of dyslipidemia, but often is associated with untoward side effects on liver and muscle. RYR possesses statin activity at a very low dosage (but enough to solicit a warning letter from the FDA, see for details), yet existing data suggest it to be similarly effective and likely associated with fewer side effects. RYR seems a reasonable option, but relatively little research exists using the supplement and more is necessary. The trial at hand contains significant flaws, but its results are strong.

One challenge for practitioners is that we need to be able to steer patients toward trusted manufacturers of RYR if this therapy is to be employed. It should be kept in mind that elevation of liver enzymes has been seen with RYR, and a similar level of repeat clinical evaluation as warranted with statin therapy would seem prudent. In addition, use of coenzyme Q10 is a consideration, as it is with statins.

What to do with this article: Keep a copy on your computer.