A paper today in PLoS Biology argues that developing antibiotic alternatives for mild infections rather than severe infections may be a better strategy for combating antibiotic resistance.
Given the challenge of discovering and developing new antibiotics for the most serious multidrug-resistant pathogens, and how quickly antibiotic resistance can emerge, scientists and biotechnology companies have in recent years turned their attention to alternative therapies to target these bacteria. These antibiotic alternatives include bacteriophages, phage lysins, antimicrobial peptides, antibodies, probiotics, and vaccines. The hope is that, ultimately, products other than classic antibacterial agents will help provide a long-term solution to the antibiotic resistance crisis.
Yet as a 2016 review by the Wellcome Trust found, many of these alternative therapies are a long way off, and even those in phase 2 and 3 clinical trials will likely be used as adjuncts to antibiotics, rather than true alternatives. "If we have to depend on alternatives to antibiotics in the future, we need to build capacity and substantially increase the number of projects now," the authors of the review wrote in The Lancet Infectious Diseases.
But what if researchers instead turned their attention to alternatives for the type of milder bacterial infections, such as strep throat, that drive antibiotic use? That's the suggestion made by microbiologists Kristofer Wollein Waldetoft, PhD, and Sam Brown, PhD, of Georgia Tech University.
Mild infections drive antibiotic prescribing
In reviewing the published literature from 21 countries on antibiotic prescribing in the community—i.e. outpatient prescribing—Waldetoft and Brown found that in most countries, a large proportion of prescriptions are for infections that in otherwise healthy individuals are typically mild and self-limiting. These are generally respiratory tract infections (ear infections, sinus infections, bronchitis, and sore throats), urinary tract infections, and skin infections.
One reason Waldetoft and Brown offer for developing non-antibiotic alternatives to treat these conditions is that they are not as hard to treat as invasive, multidrug-resistant infections and might be easier targets for new therapies. "By turning our attention to infections that are mild and self-limiting (e.g., strep throat), we can set the bar lower and thus plausibly increase the success rate," they write.
But they also suggest that using antibiotics for these type of infections may be playing a large role in promoting antibiotic resistance than previously thought.
Although the antibiotics used to treat mild bacterial infections remain effective, Waldetoft and Brown use a thought experiment based on evolutionary theory to argue that widespread and clinically appropriate use of these drugs contributes to the evolution of antibiotic resistance, not just in the target bacteria but also in other bacteria present in the patient's microbiota.
They present a scenario in which a patient being treated with amoxicillin for strep throat might also be colonized with a strain of Escherichia coli carrying a beta-lactamase enzyme that confers resistance to amoxicillin. While use of amoxicillin in this scenario will effectively treat the strep throat, it could also exert selective pressure that enables the beta-lactamase-producing E coli to grow in frequency and spread to another part of the body or even to another patient, potentially causing a more severe infection that could require the use of more powerful antibiotics.
In addition, they argue that because bacteria frequently carry resistance genes for several different antibiotics, use of a single antibiotic can contribute to rising resistance in a whole range of drugs.
"In summary, the evolutionary consequences of antibiotic treatment go beyond the antibiotic used and pathogen at which it is aimed, and it is plausible that prescription in the community makes a relevant contribution to resistance," Waldetoft and Brown write.
Reducing this selection pressure for antibiotic resistance, they add, would help retain the efficacy of current antibiotics and allow clinicians to keep using them for the type of severe infections for which alternatives have not yet been developed. They suggest that developing non-antibiotic alternatives for mild infections could be one part of a broader strategy aimed at reducing selection pressure, along with use of narrower-spectrum antibiotics and shorter antibiotic courses.
Dec 27 PLoS Biol study
February 2016 Lancet Infect Dis study