Why Probiotics Should Accompany Antibiotics

The microbiome is the composite of the genetic material of microorganisms that live in and on humans.¹The microbiome has been shown to change over time, especially in the first year of life,²as well as in response to various foods.^3,4Perhaps most notable are the effects that antibiotics have on microbiota in the gut.

Ciprofloxacin, a common antibiotic prescribed for skin, urinary tract, and lower respiratory tract infections, can change the intestinal microbiota within 3 days of the first dose. Four weeks after finishing the 5-day antibiotic course, the microbiota returns to its pretreatment state.⁵However, in one study where patients took 2 different 5-day courses of oral ciprofloxacin within 10 months of each other, the gut microbiota did not return to the pretreatment state as it did with just one 5-day course.⁶

In another study where clarithromycin and metronidazole were used in conjunction with the proton pump inhibitor omeprazole to treatHelicobacter pylori, portions of the microbiota never fully recovered from the antibiotics, even up to 4 years after treatment.⁷More alarmingly, antibiotic use affects not only the flora of the patient taking the antibiotic, but also the ecology of the microbiome of others who live in the same household.⁸

Perhaps one of the most notable and deleterious effects that antibiotics can have isClostridium difficileinfection. Although some antibiotic classes increase the risk forC. difficileinfection more than others, clindamycin, cephalosporins, and fluoroquinolones have been found to generate the highest risk.⁹When these and other broad-spectrum antibiotics are taken, they kill off and greatly reduce the number of healthy bacteria in the gut, along with their intended pathogen. This allowsC. difficile, a bacteria that is always present in the gut, to proliferate out of control, causing infection. The patient’s suffering, cost, duration of illness, and health care burden are obvious to anyone who has taken care of someone withC. difficileinfection.

It may be easy for retail clinicians to overlook these seemingly transient changes in the gut microbiome and believe it is not a big deal to prescribe an antibiotic for bronchitis, even though the condition is most likely viral and antibiotic use is not supported by clinical evidence. Results of numerous studies have shown that significant damage can occur with microbial changes in the gut, which can lead to chronic disease states such as obesity,¹⁰malnutrition,¹¹diabetes,¹²and chronic inflammatory diseases such as ulcerative colitis and Crohn’s disease.¹³Thus, it is imperative for retail clinicians to acknowledge that antibiotics greatly affect the microbiome and to always carefully consider whether or not an antibiotic is truly necessary.

Why Co-Prescribe Probiotics?

One way to mitigate some of the damage rendered by antibiotics is to prescribe probiotics along with them. Probiotics are live microorganisms that confer a health benefit on the host when administered in adequate amounts.¹⁴The majority of the time, probiotics are strains of bacteria that are considered staples of the gut microbiome. If the normal gut flora is significantly reduced during a round of antibiotics, it is essential to replace these microbiota via a probiotic to prevent or reduce long-term sequelae.

When taken with an antibiotic, probiotics not only help the microbiome retain homeostasis, but may also help prevent or reduce common short-term side effects and augment the action of the antibiotic. The results of numerous studies have demonstrated that probiotics may reduce the risk for antibiotic- induced superinfections in the gastrointestinal tract and vagina, increase the antibiotic’s ability to function, enhance mucosal immunity, and reduce antibiotic-associated diarrhea and vaginal yeast infections.¹⁵

How to Choose a Probiotic to Co-Prescribe

Perhaps the greatest conundrum for retail clinicians at this point is picking the right probiotic and ensuring that the patient understands the importance of taking it along with the prescribed antibiotic. The following factors are involved in making a quality probiotic so that it will have its intended effects.

Colony-Forming Units

A colony-forming unit (CFU) is a lot more complex than it appears. CFU does not simply refer to how many millions or billions of bacterial cells are present. Rather, a colony is used as a unit and, depending on the bacteria growing, that can mean it is derived from a single cell or from clumps of cells. CFUs are counted by growing the bacteria in a Petri dish; once the bacteria grow to a visible size (1-5 mm in diameter), that is considered 1 CFU. One CFU could contain hundreds of thousands or millions of bacterial cells.

One of the most important components to consider when choosing a probiotic is the total number of CFUs, which should be clearly marked on the product’s packaging. It is not enough to measure the CFUs at the time of manufacture, however, because it is also crucial to see the expected CFUs by the expiration date. Many poor-quality probiotics tout billions of CFUs per capsule when they are made, but that does no good if the CFUs do not last on the shelves.

The basic tenet from most manufacturers and researchers is that the more CFUs a probiotic contains, the more likely it will be to withstand time on the shelf and stomach acidity and deliver enough bacteria to the intestines to make a significant difference. However, different strains have been shown to be effective at different doses. One study onBifidobacterium infantis35624 found that a dose of 1x10⁸produced statistically better outcomes for women with inflammatory bowel syndrome compared with 1x10⁶and, surprisingly, 1x10¹⁰doses.¹⁶Unfortunately, most studies that look at probiotic therapy do not specify or compare CFU doses; rather, they merely test a placebo against a specific species or combination of species. With that in mind, most resources conclude that a good-quality probiotic should contain 10 to 40 billion CFUs per capsule at the time of expiration.

Species

The gut microbiome is one of the most complex and microbial-dense ecosystems, with 395 known bacterial phylogenetic types.¹⁷However, the overwhelming majority belong to the Firmicutes (38.8%) and Bacteroidetes (27.8%) phyla, with small amounts of Actinobacteria (8.2%) and Proteobacteria (2.1%).¹⁸The most common genera found in probiotics areLactobacillus, which belongs to the phylum Firmicutes, andBifidobacterium, which belongs to the phylum Actinobacteria.Lactobacillusis a facultative anaerobe and is generally found in the small intestines, whereasBifidobacteriumis anaerobic and found largely in the colon.

In a large systematic review and meta- analysis of randomized, controlled trials that mostly studiedLactobacillusalone, with some combined with other genera such asBifidobacterium, probiotic use reduced antibiotic-associated diarrhea compared with no probiotic use in 63 of the 82 trials examined.¹⁹Nevertheless, there are insufficient data to determine which species is superior at preventing antibiotic-associated diarrhea or other sequelae associated with antibiotic use.²⁰

Some probiotics boast 15 to 20 species, and although it can be easy to believe that more is better, bacteria will compete with each other for nutrients, oxygen, and physical space. Some species are also much hardier and, if combined with other species in a capsule, will steal the resources, and then all the other species in the capsule will be significantly reduced or die. Quality of species (and strain) is significantly more important than quantity, although a variety of 3 to 8 can be beneficial. A good product should specify not only the species, but also the specific strain.

Storage

Some commercially available probiotic products require refrigeration, whereas many others can be kept at room temperature. Although some species (eg,Bacillus coagulans) are hardier than others and can endure a long shelf-life without refrigeration, most species are sensitive to increased temperatures. The short answer is that it’s best to buy and keep the probiotic refrigerated.

Quality packaging is also essential. Cheap white plastic bottles, which can degrade and allow in moisture and oxygen, should be avoided. Dark-colored glass bottles with moisture and oxygen absorption packets are preferred.

Delivery Form

Probiotics come in a variety of forms, including pill, tablet, capsule, gummy, chewable, and powder. The biggest concern is getting the bacteria to the small and large intestines without the acidity of the stomach killing it first. Some companies offer enteric-coated capsules intended to protect the bacteria as they travel through the stomach and then open up to release the bacteria once they reach the small intestine. Others claim that their strains of bacteria have been genetically altered to withstand the acidity of the stomach. Probiotics in gummy and chewable should be avoided. Capsules and specially formulated powders (for infants and children) are generally the most effective.

When Should Patients Take Co-Prescribed Probiotics?

Unfortunately, the literature leaves much to be desired in pinpointing the best time to take probiotics while on antibiotics. Most resources, including the websites of probiotic manufacturers, suggest taking them at least 2 to 4 hours after the antibiotic based on the theoretical evidence that antibiotics will kill the probiotics. To stay on the safe side, it may be prudent to tell patients to take their antibiotic in the morning and their probiotic in the evening. Patients on twice- or thrice-daily dosing should be advised to space the probiotic out between antibiotic doses as best as possible. It is also important that the patient continues to take the probiotic for 2 to 4 weeks after discontinuing the antibiotic.

Probiotics in Food

One additional consideration is the role of food while on antibiotic treatment. Many experts recommend consuming probiotic-rich fermented foods such as kefir, yogurt, tempeh, kombucha, natto, kimchi, and fermented vegetables. Although these can be very good sources of beneficial microorganisms, it is important to remember that processed foods often sneak in sugar, coloring, and other additives that may cause more harm than good. If encouraging patients to eat these foods, the items should be purchased through a natural grocer that sources products cautiously. The most important thing for patients on antibiotics to remember is to significantly reduce their sugar intake, as sugar causes inflammation in the body, competes with binding sites for vitamin C, and causes yeast to proliferate.

Conclusion

Probiotics should always be prescribed along with antibiotic treatment. Due to overcommercialization of probiotic supplements, it is advisable to encourage patients to purchase a specific brand to ensure that they get an effective probiotic.

Hillary Lowe Taggart, BSN, DNP, is a family nurse practitioner. She attended Weber State University for her BSN and received her DNP at the University of Utah. She focuses on functional medicine, with an emphasis in gut health and bio-identical hormone replacement therapy.

References

1. Turbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. The human microbiome project.Nature. 2007;449(7164):804-810.
2. Palmer C, Bik EM, DiGiulio DB, Relman DA, Brown PO. Development of the human infant intestinal microbiota.PLoS Biol. 2007;5:177.
3. Koenig JE, Spor A, Scalfone N, et al. Succession of microbial consortia in the developing infant gut microbiome.Proc Natl Acad Sci U S A. 2011;108(suppl 1):4578-4585. doi: 10.1073/pnas.1000081107.
4. DeFilippo C, Cavalieri D, DiPaola M, et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa.Proc Natl Acad Sci U S A. 2010;107(33):14691-14696. doi: 10.1073/pnas.1005963107.
5. Dethlefsen L, Huse S, Sogin ML, Relman DA. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing.PLoS Biol. 2008;6(11):e280. doi: 10.1371/journal .pbio.0060280.
6. Dethlefsen L, Relman DA. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation.Proc Natl Acad Sci U S A. 2011;108(suppl 1):4554-4561. doi: 10.1073/pnas.1000087107.
7. Jakobsson HE, Jernberg C, Andersson AF, Sjölund-Karlsson M, Jansson JK, Engstrand L. Shortterm antibiotic treatment has differing long-term impacts on the human throat and gut microbiome.PLoS One. 2010;5(3):e9836. doi: 10.1371/journal .pone.0009836.
8. Samore MH, Tonnerre C, Hannah EL, et al. Impact of outpatient antibiotic use on carriage of ampicillin- resistant Escherichia coli.Antimicrob Agents Chemother. 2011;55(3):1135-1141. doi: 10.1128/ AAC.01708-09.
9. Owens RC Jr, Donskey CJ, Gaynes RP, Loo VG, Muto CA. Antimicrobial-associated risk factors for Clostridium difficile infection.Clin Infect Dis. 2008;46(suppl 1):S19-S31.
10. Ley R, Turbaugh P, Klein S, Gordon J. Microbial ecology: human gut microbes associated with obesity.Nature. 2006:1022-1023.
11. Kau A, Ahern P, Friggin N, Goodman A, Gordon J. Human nutrition, the gut microbiome and the immune system.Nature. 2011;474:327-336. doi: 10.1038/ nature10213.
12. Qin J, Li Y, Cai Z, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes.Nature. 2012;490(7418):55-60. doi: 10.1038/nature11450.
13. Frank D, St. Amand A, Feldman R, Boedeker E, Harpaz N, Pace N. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases.Proc Natl Acad Sci U S A. 2007;104(34):13780-13785.
14. Sanders ME. Probiotics: definition, sources, selection, and uses.Clin Infect Dis. 2008;46:58-61; discussion S144-51. doi: 10.1086/523341.
15. Reid G. Probiotics to prevent the need for, and augment the use of, antibiotics.Can J Infect Dis Med Microbiol. 2006;17(5):291-295.
16. Whorwell PJ, Altringer L, Morel J, et al. Efficacy of an encapsulated probiotic Bifidobacterium infantis 35624 in women with irritable bowel syndrome.Am J Gastroenterol. 2006:1581-1590.
17. Gordon JI, Ley RE, Wilson R, et al. Extending our view of self: the Human Gut Microbiome Initiative (HGMI). National Human Genome Research Institute website. genome.gov/Pages/Research/Sequencing/ SeqProposals/HGMISeq.pdf. Published 2005.
18. D’Argenio V, Salvatore F. The role of the gut microbiome in the healthy adult status.Clin Chim Acta. 2015;451:97-102. doi: 10.1016/j.cca.2015.01.003.
19. Hempel S, Newberry S, Maher AR, et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea.JAMA. 2012;307(18):1959-1969. doi: 10.1001/jama.2012.3507.
20. Johnston BC, Goldenberg JZ, Vandvik PO, Sun X, Guyatt GH. Probiotics for the prevention of pediatric antibiotic-associated diarrhea.Cocrane Database Syst Rev. 2011;11:CD004827. doi: 10.1002/14651858. CD004827.pub3.