EAT-UP: Extended Antibiotic Treatment in chronic UTI Patients; a phase II safety and efficacy trial

Urinary tract infection (UTI) is a highly-prevalent global problem, particularly in an ageing population. Post-menopausal women are one of the groups most often affected. Nearly 50% of women will experience at least one UTI in their lifetime. Forty percent of those affected will suffer recurrent urinary tract infections (rUTI), characterised by frequent and debilitating infections and periods of quiescence without symptoms. In contrast to rUTI, some women develop chronic urine infection, the hallmark of which is daily symptoms that are persistent and without respite. Recommended management strategies for rUTI include lifestyle advice, short courses of antibiotics in response to infective episodes, and longer-term low-dose daily oral antibiotic prophylaxis. These approaches are ineffective for some patients, especially those with chronic UTI and there are no current guidelines or treatment recommendations for the management of women with chronic UTI. NHS data demonstrates rising numbers of patients seen repeatedly by their GP or admitted to hospital for UTI. Patients with recurrent and chronic UTI are often subject to multiple invasive investigations and long-term treatments that place a significant financial burden on the healthcare budget. Hospital admissions for UTI alone cost the NHS £400 million Contemporary studies point to UTI being a complex disturbance of the natural bladder microbiome with infections becoming embedded in the bladder cells, a process called urothelial parasitisation. Both short courses of treatment dose antibiotics and extended courses of low-dose antibiotics may not eradicate these colonising bacteria. It is not surprising that treatments fail and UTIs persist. Besides their limitation in the management of rUTI or chronic UTI, low-dose suppressive antibiotics increase the risk of microbial resistance. Up to 50% of patients with rUTI need to modify antibiotic treatment in response to resistant organisms. Amongst our patient population with chronic UTI, women describe previous unsuccessful treatment with low-dose antibiotics of the type prescribed for rUTI. We have demonstrated that much longer courses of antibiotic treatment - and at full therapeutic dose - are associated with the resolution of inflammation in the urinary tract and consequent symptoms of infection. We propose a safety and efficacy trial to examine a combination-treatment regime currently used in our service to treat patients with chronic UTI. The treatment comprises common urinary antibiotics (cefalexin, trimethoprim, nitrofurantoin) in combination with the urinary antiseptic methenamine hippurate. This treatment approach evolved during the treatment of 7000 patients in our service over the last two decades. The antibiotics that we use are recommended by NICE for the treatment of acute and recurrent UTI and have an excellent safety record. We will compare our treatment approach with standard low-dose antibiotic prophylaxis for rUTI. We will use the urinary white blood cell count - pyuria - as our principal biomarker to indicate urinary tract inflammation. This trial will enable us to establish the safety and efficacy of this chronic UTI treatment strategy to inform a future large randomised controlled trial (RCT). This future RCT would compare extended, full-dose antibiotic treatment and methenamine hippurate with low-dose antibiotic prophylaxis in the treatment of chronic UTI.