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RS3543_shutterstock_127315718 - antibiotics-scr.jpgWho’s afraid of the antibiotic tolerant biofilm?

A team from St Jude’s Hospital in Memphis, Tennessee have identified a genetic mutation within a VRE bacteria that appears to confer wide ranging antibiotic tolerance, particularly in a biofilm presentation.

Published in January’s edition of mBIO (American Society for Microbiology) the research findings came about due to an extremely difficult case of bacteraemia in a 6 week old girl being treated for leukaemia. The course of chemotherapy had eliminated the child’s neutrophils leaving her immunocompromised. She acquired an Enterococcus faecium infection which blood cultures identified as Vancomycin resistant. The antibiotic treatment regime was changed from an initial application of Vancomycin and Meropenem to Linozelid supplemented with Daptomycin, Gentamicin and Quinupristin-dalfopristin. This failed to resolve the infection and the investigators began searching for an explanation. Interestingly in-vitro susceptibility testing indicated that the bacteraemia was sensitive to all the antibiotics administered expect for the initial Vancomycin / Meropenem. The bacteraemia could not be treated with antibiotics and only resolved once the patient had received several rounds of donor granulocyte transfusions and rebuilt their neutrophil levels (i.e. their own immune system).

The investigators genetically characterised the VRE isolate and found that the genome and plasmid makeup of the bacteria contained multiple antibiotic resistance systems and particularly a mutation in a gene called relA. This gene is known to regulate the “stringent response” – a state where the bacteria is more capable of dealing with environmental stresses. Simply put, the mutation primes the bacteria for exposure to antibiotics making them less effective. Mutations which confer an advantage such as antibiotic tolerance are often not sustained because the increased metabolic activity required to produce the effect of the mutation often means the bacteria can be out-competed by the wild-type strains – the fitness of the bacteria is reduced. In the immunocompromised patient the environment is less challenging meaning that the decreased fitness associated with the mutation may be less / not relevant allowing the mutation to continue. The authors saw this “fitness” effect in the relA mutants when growing as a biofilm. The biofilms produced by the mutants were smaller in size, thinner and less robust than wild type strains. However, the wild type biofilms could be eradicated by treatment with antibiotics (Linozelid, Vancomycin, Daptomycin), but the mutant biofilms could not. The authors state that the data shows that the mutation confers a selective advantage to the in-vitro survival of antibiotic-tolerant persister cells within the biofilm.

In summary the relA mutation conferred a disadvantage in the bacteria’s ability to form a biofilm, but the biofilm that did form was highly resistant to antibiotics. Clinically this resulted in the inability to treat the patient with known antibiotics and it was only the re-establishment of the patients own immune system that was able to resolve the infection.

Biofilms are present within the hospital environment and due to their protective matrix of extracellular polymeric substances pose a significant challenge to elimination by chemical disinfectants. This study adds a further scary dimension to biofilms – mutations can occur that make these chemically tolerant bacterial communities resistant to all antibiotics. Anyone frightened?

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