Recurrent urinary tract infections (RUTIs) are a highly burdensome condition among older women. Patients with RUTIs have different levels of bladder wall involvement ranging from infection of solely the trigone (trigonitis) to whole bladder inflammation (pancystitis). Those with higher stages of bladder inflammation fare worse to treatments such as electrofulguration (EF).[1]

Bacterial motility properties have been implicated in mouse models as an attributing factor to the spread and pathogenesis of RUTI [2]. In bladder biopsies of women undergoing EF, tissue resident bacteria were demonstrated using a bladder specific FISH procedure [3]. Why do some RUTI patients exhibit cystitis changes beyond the trigone? Are these tissue resident bacteria equipped to spread past the trigone?  In this exploratory study, we sought to compare motile and non-motile bacteria in urinary cultures of women with RUTI at different stages of bladder involvement. We hypothesized that those with higher stages will have more motile bacteria.

After IRB approval, a retrospective review of non-neurogenic women with symptomatic antibiotic recalcitrant RUTI (≥3 UTIs/y) who underwent EF for cystitis was undertaken. Those with non-retrievable or negative urinary cultures, chronic intermittent catheterization, and indwelling catheters were excluded. Preoperative office cystoscopy served to categorize the different stages of cystitis based on bladder surface involvement:  trigone (Stage 1), trigone + bladder base (Stage 2), trigone + bladder base + one or both lateral walls (Stage 3), and the whole bladder (Stage 4). Demographics and positive urine cultures prior to EF were reviewed for the type of bacteria (motile vs nonmotile) and compared amongst the different stages of bladder wall involvement. 

Statistical methods: Descriptive statistics were provided as medians and interquartile ranges for continuous values and frequencies and percentages for categorical values. Association of cystitis stage with patient and urine culture data were tested using linear regression F-tests for continuous values and Fisher’s exact test for categorical values. Unadjusted post-hoc t-tests were used to determine which pairs of stages were significantly different than each other for significant results from the linear regression F-test. All analyses were completed at the 0.05 significance level using SAS 9.4 (SAS Institute Inc., Cary NC).

From 2006 to 2020, 139 women with RUTI met study criteria. Median age was 67 with 95% being Caucasian. Those with Stage 4 cystitis were older (p=0.0009), had higher parity (p=0.019), and were less sexually active (p=0.038). 

There was no significant difference in overall motility between stages. Escherichia Coli was the most common strain detected in all 4 stages. Excluding uropathogenic E. Coli (UPEC), there  was still a preponderance of more motile bacteria observed in Stage 4 cystitis such as Proteus Mirabilis (p=0.013), Pseudomonas Aeruginosa (p=0.013), Enterobacter Cloacae (p=0.077) and Citrobacter (p=0.026). The non-motile strains were dominated by Klebsiella pneumoniae at higher stages (p= 0.024)

Our study provides the first translational work examining the relation between bacterial motility properties and the spread of cystitis throughout the bladder in RUTI women. Our staging system for cystitis was new and simple, based on observation of patterns of cystitis. In our EF experience, the dominant pattern is trigonitis; but some bacteria are able to expand beyond its confines to the bladder base first, sometimes laterally to the bladder walls, and less frequently (fortunately) to the whole bladder. While E.coli was the dominant strain detected in all stages, we did observe more unique types of motile bacteria at higher stages of bladder wall inflammation suggesting that motility may contribute to the spread of cystitis past the trigone. The mechanisms behind E Coli motility has been shown to be complex with differences observed between nonpathogenic E Coli and UPEC with regards to appendage usage (fimbrae vs flagella) and other metabolic requirements such as glucose requirements. In our present study, we did not differentiate between the different strains of E Coli.

Excluding UPEC, common organisms responsible for RUTIs in our series included both motile and non-motile strains, such as Proteus mirabilis, Enterococcus sp., Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus spp. Interestingly, we observed a preponderance of the motile types (Proteus and Pseudomonas) at higher stages of cystitis. Bacterial surface motility involving swarming or twitching have been reported. In vitro, Pseudomonas aeruginosa exhibits twitching characterized by pilus retraction and Proteus mirabilis exhibits swarming characterized by multicellular flagella-mediated movements. An interesting theory suggested by our study could be that different types of motility, such as swarming and twitching, may contribute over time to the spread of bladder infection. Since women treated with EF for stage 1 (trigonitis alone) fare well, early detection of these women before a possible extension to the rest of their bladder seems highly desirable.

This large series comparing bacterial motility properties in women with RUTI at different stages of bladder involvement identified unique characteristics and bacterial strains associated with each stage. RUTI women with higher stages of cystitis had more unique types of motile urinary strains. These findings suggest that bacterial motility may play a role in the spread of cystitis beyond the trigone, however, further study into motility properties amongst each stage is needed.

Crivelli, J. J., et al. (2019). "Electrofulguration in the advanced management of antibiotic-refractory recurrent urinary tract infections in women." Int J Urol 26(6): 662-668.
Klein, R. D. and S. J. Hultgren (2020). "Urinary tract infections: microbial pathogenesis, host-pathogen interactions and new treatment strategies." Nat Rev Microbiol 18(4): 211-226
De Nisco, N. J., et al. (2019). "Direct Detection of Tissue-Resident Bacteria and Chronic Inflammation in the Bladder Wall of Postmenopausal Women with Recurrent Urinary Tract Infection." J Mol Biol 431(21): 4368-4379