Probiotics: targeting the paediatric population to reduce antibiotic consumption and resistance

In the early 19th century microbiologists observed the indigenous microflora of healthy vs. diseased individuals, noting distinct differences.¹ They proposed that the re-inoculation and normalisation of unbalanced indigenous microflora might prevent disease and restore health. Lactobacillus bulgaricus, discovered by Metchinkoff in 1905, was the first microbe used for this purpose and was subsequently promoted as a life-sustaining cultured dairy product.² The term ‘probiotic’ is derived from the Greek language, meaning ‘for life’. The term was first used in 1965 to describe ‘substances secreted by one microorgan-ism which stimulate the growth of another’ as opposed to the term ‘antibiotic’.³ Since this time, many definitions for the term ‘probiotic’ have been suggested. Currently, it is perhaps best defined as ‘a live microbial culture or cultured dairy product which beneficially influences the health and nutrition of the host’.⁴

Common probiotic strains available to the general public via dairy products or encapsulated supplements include Lactobacillus acidophilus, L. bulgaricus, L. casei, L. rhamnosus, Bifidobacterium bifidum, B. longum, Streptococcus ther-mophilus, Saccharomyces boulardii and Clostridium butyicum. Lactobacilli is the genus of the bacteria and contains several species, such as L. acidophilus, bulgaricus, casei and rhamnosus, whereas Saccharomyces represents the genus of a yeast and contain species such as S. boulardii and cerevisiae. Individually each of these represents a probiotic strain.

Probiotics may be especially useful in the prevention of paediatric diarrhoea and upper respiratory tract infections.⁵,⁶ Their potential usefulness in children is particularly compelling since children are frequently prescribed antibiotics. In 2003 the Canadian Paediatric Society released prescription information from administrative databases for over one million paediatric claimants.⁷ Among the top 20 drugs dispensed, 14 were antibiotics. Seventy-six per cent of children in the study population had a least one antibiotic prescription, with amoxicillin used by 45% of all children that were prescribed an antibiotic. On average 7% of Canadian children received five or more courses of antibiotics over a 1-year period.

Up to 50% of antibiotics may be prescribed unnecessarily and may, in fact, do substantial harm.⁸ For example, with the overuse of antibiotics for childhood infections, bacteria continue to acquire antibiotic resistance. Streptococcus pneumoniae, a bacterium that can cause ear infections, pneumonia and meningitis, is becoming increasingly resistant to some antibiotic treatments.⁹ In 1987 antibiotic-resistant pneumococci were unknown. By 1997 as many as 40% of pneumococcus isolates were resistant to penicillin and other commonly used antibiotics.⁹ Should overuse continue, many of our most effective antibiotics may lose their place in our armamentarium.¹⁰ Although there has been a sharp decline in paediatric antibiotic prescriptions in many Western countries,¹¹,¹² in developing countries antibiotic overuse and misuse for upper respiratory tract infections in children is widespread.¹³

The emergence of new microorganisms with acquired antibiotic resistance has resulted in a search for therapies that do not involve unnecessary use of antibiotics. The WHO has promoted drastic reductions in the use of antibiotics and has recommended microbial interference therapy via the use of non-pathogens to eliminate pathogens.¹⁴ Although a cross-sectional survey of invited expert opinion on the most important strategies to contain antimicrobial resistence involves training healthcare providers on preventing infection, antimicrobial use and resistance,¹⁵ probiotics represent perhaps the most promising adjunct to the WHO strategy.¹⁶ Probiotic agents have demonstrated many potential mechanisms of action, including immune modulation, down-regulation of inflammatory responses, secretion of antimicrobial substances and inhibition of pathogen mucosal adherence.¹⁷ For instance, L. acidophilus inhibits a number of pathogenic bacteria, including Clostridium, Bacteroides, Pseudomonas, Staphylococcus, Streptococcus, Enterobacteria-ceas, Yersinia enterocolitica, Bacillus cereus, Escherichia coli, Salmonella and Listeria monocytogenes.¹⁸ Attention to the potential for probiotic therapy to combat antibiotic resistance has never been more pressing. There are few new antibiotics under development and hopes that a vaccine for the methicillin-resistance strain of S. aureus (MRSA) might be developed soon have recently been dashed.¹⁹

The use of probiotics in preventing antibiotic prescription is relevant in both developed and developing countries. At least seven RCTs involving 3302 infants and children (most attending daycare) in developed countries have been published on the ability of probiotic agents to prevent infectious diarrhoea and upper respiratory tract infections.⁶,²⁰–25 As a secondary analysis, three of the above trials have also demonstrated a decreased frequency of antibiotic prescriptions in treatment vs. control groups.⁶,²⁰,²² For example, Weizman (2005) studied 201 healthy term daycare infants aged 4 to 10 months, assigned randomly to formula supplemented with B. lactis, L. reuteri or no probiotics. Compared with those administered B. lactis or L. reuteri, the controls had significantly more febrile diarrhoea episodes. The L. reuteri group, compared with B. lactis or controls, had a significant decrease in antibiotic prescriptions.²⁰ Hatakka (2001), in a study of 571 healthy children aged 1–6 years, demonstrated a 19% relative reduction in antibiotic treatments for respiratory infection in the Lactobacillus group.⁶ Prophylactic probiotics may be as relevant in developing countries. For example, a placebo-controlled trial of Lactobacillus GG of 204 undernourished Peruvian children, 6 to 24 months of age, demonstrated the agents’ prophylactic potential in children at high risk for acute diarrhoea, especially in those children not breastfed.²⁶ With a reduction in the incidence of acute diarrhoea, total antibiotic consumption may also decline.

Probiotics may also be of direct use in preventing antibiotic resistance. For instance, the use of beta-lactam antibiotics can induce an increase in beta-lactamase production in the fecal flora, thereby increasing bacterial resistance to other beta-lactam drugs.²⁷ A study of six different commercially available preparations of probiotics compared whether their action prevented or corrected imbalances in the intestinal ecosystem (dysbiosis) during parenteral therapy with ceftriaxone, a beta-lactam.²⁷ A lower incidence of beta-lactamase positive samples (30–40%) was observed with B. bifidum and L. acidophilus, or a mixture of various lactobacilli and bifidobacteria at high concentrations.²⁷

From the studies presented, it is evident that close examination of probiotics may well provide new therapeutic opportunities for lowering antibiotic consumption and resistance. Indeed, prophylactic probiotics may help to decrease antibiotic consumption in both children attending daycare and children in developing countries at high risk of acute diarrhoea. The important question is not whether or not more research involving probiotic prophylaxis should be pursued, but whether or not we can continue to risk the current laissez-faire approach to antibiotic consumption and development. Probiotics represent a therapy that can prevent antibiotic consumption and thus resistance. If these agents can continue to demonstrate safety and efficacy, then their use in prevention should be encouraged. A research agenda is needed to determine which probiotic species and dosages might provide effective prophylaxis and which paediatric population(s) would benefit most. This emerging therapy as a potential combatant against antibiotic consumption, and resistance, deserves full investigation.

Funding

Bradley Johnston is Sick Kids Foundation Duncan L Gordon Fellow. Sunita Vohra is an Alberta Heritage Foundation for Medical Research (AHFMR) Population Health Investigator and recipient of a Canadian Institute of Health Research (CIHR) New Investigator Award.

References

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