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Antimicrobial resistance in the bladder (2)

By Professor Scott Glickman

Three principles that underpin contemporary drug treatment development strategies are:

  • The nearer to the root cause a disease is challenged the more effective the solution.

  • The more direct the treatment the better.

  • Maximise efficacy while minimising side effects and burdens.


Antibiotics get to the root cause of infection by undermining mechanisms that sustain bacterial life. However, AMR development occurs in circumstances when the pathogens survive long enough to produce it while exposed to the antibiotic, indicating inadequate treatment quality, irrespective of overuse. Unfortunately, tissue toxicities from systemic drug exposure constrains dosing that could overwhelm the pathogens quickly enough to minimise AMR risks as we would wish.


Oral antibiotic administration to treat cystitis is the most indirect route for treating any human infection. Pharmacokinetic processing prevents maximizing efficacy, while their exposure to the gut and systemic tissues contravenes the principle of side effects minimisation. They also are associated with recurrences and AMR.


Fortunately, bladder urothelium:

Has a tolerance to xenobotics and a wide chemical acidity range.

  • Can be emptied before instillation dosing to maximise treatment concentration.

  • Has features that resist absorption of weakly charged chemicals e.g., antibiotics.

  • Separation from the gut microbiome now recognised as symbiotic with us.

  • Direct accessibility from the outside.


These factors make it an excellent candidate tissue for investigating topical antibiotic administration for treating cystitis at potencies (concentrations) higher than would be safe with standard oral administration. The opportunity to deliver them directly in bactericidal concentrations immediately where needed, and at lesser systemic exposure than oral alternatives could maximise antibiotic efficacy against both infection and AMR at lower burdens, while getting as near as possible to tackling their root causes in accordance with the 3 aforementioned principles.

 

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