Approaches to control infection, encrustation, and blockage of urinary catheters

Proteus mirabilis forms extensive crystalline biofilms on urethral catheters that occlude urine flow and frequently complicate the management of long-term-catheterized patients.

Here, using random transposon mutagenesis in conjunction with in vitro models of the catheterized urinary tract, researchers elucidate the mechanisms underpinning the formation of crystalline biofilms by P. mirabilis.

Mutants identified as defective in blockage of urethral catheters had disruptions in genes involved in nitrogen metabolism and efflux systems but were unaffected in general growth, survival in bladder model systems, or the ability to elevate urinary pH. Imaging of biofilms directly on catheter surfaces, along with quantification of levels of encrustation and biomass, confirmed that the mutants were attenuated specifically in the ability to form crystalline biofilms compared with that of the wild type.

A wide range of bladder conditions in elderly individuals are managed using long-term catheterisation, and this simple strategy usually provides substantial improvements in quality of life. However, these benefits are frequently undermined by infections. The bacterial species Proteus mirabilis is a particular problem in this regard, and often causes blockage of catheters, which leads to other serious complications.

At the time this project was planned, there were no approaches that provided good control of these infections, and effective strategies were urgently needed. Based on previous work, University of Brighton researchers had shown that specialised components of the P. mirabilis cell, which act like “pumps” and referred to as efflux systems, are important to the ability of P. mirabilis to infect and block catheters.

The overall aim of the project was, then, to determine if chemical inhibition of efflux systems in P. mirabilis could prevent or reduce catheter blockage. The impact of efflux inhibition on susceptibility to antibiotics commonly used to treat UTI, and the potential for synergistic EPI: antibiotic treatment will also be explored, as well as the use of EPIs for prevention of biofilm formation in a range of other common uropathogens.

In the UK alone, around 3.2 million individuals over the age of 65 are incontinent. It is estimated that as many as 200,000 may undergo long-term help to manage this condition, and up to 40 per cent of older people in residential care undergo long-term urethral catheterisation. As the aged population grows this figure will continue to rise.

Associated infections were linked with increased morbidity and mortality as well as spread of antibiotic resistance, and a significant financial burden to the NHS (~£123 million p.a.). Proteus mirabilis is a particular problem in this regard, implicated in over 40 per cent of cases, and leads to chronic infections with serious complications.

The development of effective countermeasures against such infections would have a considerable positive impact on the wellbeing of many older people, and provide substantial savings for the NHS. Because many drugs already in clinical use are potential inhibitors of bacterial efflux systems (EPIs), confirming the efficacy of such EPIs for controlling catheter infections has clear potential to provide an effective intervention within 5-10 years.

N. Holling, D. Lednor, S. Tsang, A. Bissell, L. Campbell, J. Nzakizwanayo, C. Dedi, J. A. Hawthorne, G. Hanlon, L. A. Ogilvie, J. P. Salvage, B. A. Patel, L. M. Barnes and B. V. Jones* (2014). Elucidating the genetic basis of crystalline biofilm formation in Proteus mirabilis. Infection and Immunity, 82: 1616-1626

Holling N., Dedi C., Jones C. E., Hawthorne J. A., Hanlon G., Salvage J. P., Patel B. A., Barnes L. M., Jones B. V.* (2014) Evaluation of environmental scanning electron microcopy in conjunction with energy dispersive x-ray spectroscopy for analysis of crystalline biofilms. FEMS Microbiology Letters, 355: 20-27.

Savory N., Lednor D., Tsukakoshi K., Abe K., Yoshida W., Ferri S., Jones B. V*., Ikebukuro K. (2013) In silico maturation of binding-specificity of DNA aptamers against Proteus mirabilis. Biotechnology and Bioengineering,110:2573-80.