Prescribing an Antibiotic? Do Not Forget the Probiotic

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Engelbrektson A, Korzenik JR, Pittler A, et al. (Environmental Biotechnology Institute, California Polytechnic State University, San Luis Obispo, California). Probiotics to minimize the disruption of faecal microbiota in healthy subjects undergoing antibiotic therapy. J Med Microbiol 2009;58:663–670.

Engelbrektson et al performed a randomized, placebo-controlled study to determine whether administration of probiotics during and for 10 days after antibiotic therapy can help maintain intestinal microbiota at the pre-antibiotic baseline. Out of 51 subjects enrolled, 40 completed the study. Three stool samples were obtained before starting antibiotics to assess (days 0, 7, and 14) and establish baseline microbiota followed by the concomitant administration of twice daily amoxicillin/clavulanic acid for 7 days. Patients were followed until day 48. At day 14, patients were randomized to take either a capsule of dried probiotic material (Bifidobacterium lactis Bl-04, B. lactis Bi-07, Lactobacillus acidophilus NCFM, Lactobacillus paracasei Lpc-37, and Bifidobacterium bifidum Bb-02) or placebo. The probiotic or placebo capsules were administered twice daily for a total of 20 days (days 14–34). Stool samples were collected at the completion of antibiotic therapy (day 21) and at 3 more time points (days 25, 34, and 48). In addition to stool culture, the authors employed terminal restriction length polymorphism data (TRLFP) for analyzing fecal microbiota.

Baseline instability (based on the 3 stool samples taken before antibiotic/probiotic administration) was detected in the microbiota of 30% to 40% of the subjects enrolled in the study, as indicated by culture and TRLFP. There was a statistically significant difference between the probiotic and placebo group microbiota at days 21–34, with the probiotic group microbiota closer to its original baseline than the placebo group. This effect was only statistically significant when the stool culture (P = .046), rather than the TRLFP (P = .066), data were used, and not maintained at day 48, postantibiotic and postprobiotic or placebo treatments. The authors then sought to determine the effect of probiotics on specific bacteria using culture and TRLFP techniques. Significant increases in colony counts on MacConkey agar (Enterobactereaceae) (P = .006) and bifidobacterium iodoacetate medium agar (Bifidobacterium; P = .030) were noted in the probiotic group. Although antibiotics decreased Bacteroides and Prevotella representation in TRLFP data, there was no difference between probiotic and placebo groups. By TRLFP, changes in Enterobactereaceae were more pronounced in the probiotic group than in the placebo group.

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Antibiotic-associated diarrhea (AAD) is thought to be due to a perturbation in normal intestinal microbiota, which allows the development of pathogenic bacterial strains. AAD includes Clostridium difficile–associated diarrhea. Risk factors for AAD include broad spectrum antibiotics, immunosuppression, nutritional status, age, proton pump inhibitor therapy, and a hospital environment. Onset of symptoms may be delayed sometimes 2–3 months after antibiotic treatment. With the ubiquity of antibiotic use, AAD, and specifically development of C difficile–related diarrhea, are not uncommon (26% to 60% during hospital outbreaks to 0.1% in the outpatient setting), sometimes leading to severe morbidity, mortality, and increased health care costs. It is believed that maintaining the intestinal microbial homeostasis would prevent AAD, and probiotics are hypothesized to aid in this process. Probiotics are defined by the World Health Organization as live micro-organisms ingested in sufficient quantities to confer a beneficial effect on the host. Several probiotics have been evaluated for the prevention and treatment of AAD and include several species of Lactobacillus and Bifidobacterium, Streptococcus thermophilus with Bifidobacterium lactis, Saccharomyces boulardii, lactic acid–producing Enterococcus SF68, Bacillus clausii, Bacillus longum, and Clostridium butyricum. Several of these studies showed probiotics prevent AAD, although it is not yet known if this is true for C difficile–associated diarrhea. It also is still unknown which probiotic or combination of probiotics is best for maintaining intestinal homeostasis and prevention of disease.

Safdar et al sought to address some of these points. They enrolled 40 subjects, all hospitalized, elderly American veterans receiving antibiotics, in a randomized, double-blind study of either a placebo or Florajen (commercially available probiotic of Lactobacillus acidophilus), which was administered 3 times a day starting on the first day of antibiotic ingestion and for 2 weeks after the completion of the antibiotic regimen. Although the specific antibiotic used was at the discretion of the treating physicians, the discrepancy in antibiotic use in the probiotic versus placebo group did not achieve significance. The incidence of AAD was 37% in the placebo versus 17% in the Florajen group, but this difference did not reach significance (P = .15). Likewise, the incidence of C difficile diarrhea was 25% (out of the diarrhea samples analyzed) in the placebo versus 0% in the probiotic group, but the P value was 0.27.

In another study, Beausoleil et al used a fermented milk solution containing Lactobacillus acidophilus and Lactobacillus casei to conduct a double-blind, placebo-controlled study evaluating the incidence of AAD. The average age was 71, 90% of patients were taking antibiotics for respiratory infections, and the 2 arms of the study were well-matched except for more β-lactam use in the placebo group. Seventeen percent of patients in the probiotic group and 37% in the placebo group had AAD (P = .05); 2.3% in the probiotic group and 15.6% in the placebo group developed C difficile–associated diarrhea, but this did not reach significance (P = .06).

In the study by Engelbrektson et al, subjects were treated with probiotics, Lactobacillus and Bifidobacterium species, to maintain intestinal bacterial homeostasis during a course of antibiotic therapy. Intestinal bacterial content was assessed by culture and newer technology, namely, TRLFP, which captures a broader diversity of bacterial content that may otherwise go unnoticed if only culture techniques are used. This technique involves polymerase chain reaction amplification of a small subunit of bacterial DNA (the 16S rRNA subunit) using primer pairs in which 1 or both members are tagged with fluorescent dye, followed by digestion with specific enzymes and analysis of the resulting fluorescent fragments with a DNA sequencer. The preantibiotic intestinal microbiota were described using 3 stool samples taken at 1-week intervals to ensure an adequate characterization of the baseline. This revealed that there may be variation in intestinal bacterial content within certain individuals without significant dietary change, yet another possibility for this finding is variation in handling of specimens for processing of bacterial content. Intestinal microbiota vary between individuals, and another strength of this study was that each subject was his or her own control. The postantibiotic follow-up period was longer compared with other studies; although, because AAD can occur up to 6 weeks after the completion of antibiotic therapy, one can argue that 27 days is still not long enough. Short falls to the study include the small sample size and a skewed sample toward young (average age, 37) females (31/40). This makes it difficult to apply the findings to a broader population, especially the hospitalized elderly, who have the highest rate of ADD-related mortality and morbidity and in whom disease prevention would be most important. Diarrhea and yeast infections were assessed as secondary end points and no difference between the 2 groups was found, although the study was underpowered for these outcomes.

This study shows that probiotics may prevent significant intestinal bacterial change in the setting of antibiotic use and shows us the tools/methods of assessing intestinal microbiota. Unanswered questions include which probiotics, and which dose and duration of probiotics are most effective to maintain microbial homeostasis and minimize ADD.