I have long been interested in therapeutic approaches that support natural immunity to infection as a means of either negating the use of antibiotics, or working in harmony with antibiotics to treat infection. Our immune system is, after all, rather well equipped to deal with almost any potential microbial threat. So it was with keen intrigue that I read the recent Nature Communications paper by Wheatley et al. in which they provide a detailed picture of how antibiotic treatment, the emergence (and resolution) of AMR, and the host immune system are dynamically linked over time.
The authors were able to monitor the rise and fall of AMR within a single patient with acute Pseudmonas aeruginosa infection before, during, and after treatment with antibiotics. P. aeruginosa infections are a significant cause of nosocomial infection, and represent one of the so called ESKAPE priority pathogens. The authors collected isolates from the lung and gut over three weeks and combined phenotypic approaches with whole genome sequencing of the isolates to build a dynamic picture of the response of the pathogen to treatment with meropenem, colistin, and piperacillin/tazobactam.
First, they observed that host immunity was responsible for reducing bacterial burden by at least one log prior to the onset of treatment. This is important, because antibiotics are most effective when used against a smaller number of bacteria; but also, the pool of potentially resistant bacteria is reduced. Most of us are familiar with the concept that antibiotics are typically able to eradicate the majority of a given bacterial population while failing to eradicate the small proportion that carry a resistant phenotype. This small, AMR proportion then multiplies due to natural selection; and indeed, this was observed by the authors. But what happens next?
Wheatley et al were able to experimentally demonstrate one of the phenomena that we often predict but rarely observe, especially in vivo in a clinical scenario, that resistance can carry a fitness cost. In this latest research, it is clearly shown that once antibiotic treatment ends, some of the resistant bacteria, those expressing a drug efflux pump, are rapidly outcompeted by their sensitive counterparts. Those resistant mutations that do not carry a fitness cost remain in the population, however. The eventual elimination of the entire lung microbiome, including P. aeruginosa, was not driven by antibiotic treatment, but rather by the host immune system.
This excellent work serves to remind us that antibiotics do not cure infection in and of themselves – our bodies are not petri dishes. There are other forces at play, and strategies that support host immunity alongside effective antimicrobial use are surely favourable in overcoming the limitations of either when acting alone.
There cannot be any complacency as to the need for global action.
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