Abstract
The crystalline biofilms of Proteus mirabilis can seriously complicate the care of patients undergoing long-term indwelling urinary catheterisation. Expression of bacterial urease causes a significant increase in urinary pH, leading to the supersaturation and precipitation of struvite and apatite crystals. These crystals become lodged within the biofilm, resulting in the blockage of urine flow through the catheter. Here, we describe an infection-responsive surface coating for urinary catheters, which releases a therapeutic dose of bacteriophage in response to elevated urinary pH, in order to delay catheter blockage. The coating employs a dual-layered system comprising of a lower hydrogel 'reservoir' layer impregnated with bacteriophage, capped by a 'trigger' layer of the pH-responsive polymer poly(methyl methacrylate-co-methacrylic acid) (EUDRAGIT®S 100). Evaluation of prototype coatings using a clinically reflective in vitro bladder model system showed that catheter blockage time was doubled (13 h to 26 h (P < 0.05)) under conditions of established infection (108 CFU ml-1) in response to a 'burst-release' of bacteriophage (108 PFU ml-1). Coatings were stable both in the absence of infection, and in the presence of urease-negative bacteria. Quantitative and visual analysis of crystalline biofilm reduction show that bacteriophage constitute a promising strategy for the prevention of catheter blockage, a clinical problem for which there is currently no effective control method.
Highlights
Catheter-associated urinary tract infection (CAUTI) is the most common healthcare-associated infection worldwide, accounting for approximately 150–250 million cases globally per year,[1] manifesting as an estimated cost of d125 million per year in the UK alone.[2]
Previous work developed an infection-responsive coating for diagnosis of CAUTI, showing that molecules of the selfquenching dye 5(6)-carboxyfluorescein can be successfully incorporated into a hydrogel coating and released in response to elevated urinary pH caused by P. mirabilis infection.[43]
Previous studies have utilised simple static models of biofilm formation on catheter sections,[21] flow models that use only the central catheter lumen,[31,42] or those that do not accurately represent the full closed drainage system. Whilst these studies have provided fundamental information about the general properties of biofilm formation and the success of various treatment options, the in vitro bladder models used in this study assess biofilm formation and catheter blockage under conditions in which the design features of the catheter and the hydrodynamics of the catheterised bladder are taken into consideration
Summary
Catheter-associated urinary tract infection (CAUTI) is the most common healthcare-associated infection worldwide, accounting for approximately 150–250 million cases globally per year,[1] manifesting as an estimated cost of d125 million per year in the UK alone.[2] The most severe CAUTI sequelae occur as a result of infection by the urease-producing motile bacteria Proteus mirabilis (P. mirabilis), which colonise the catheter surface, forming extensive biofilm communities embedded within an exopolymeric matrix. Under these conditions, local supersaturation and precipitation of struvite [MgNH4PO4Á6H2O] and apatite [Ca10(PO4)6CO3] causes accumulation of crystalline aggregates, which become embedded within the organic matrix surrounding the cells on the luminal surfaces. The continued development of such biofilms and accretion of crystalline material leads to the eventual obstruction of the flow of urine through the catheter. Incontinence can develop owing to urine leakage around the catheter, and reflux of infected urine to the kidneys may result in serious symptomatic episodes such as pyelonephritis, endotoxic shock and septicaemia.[3,4,5]
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