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Abstract Bacterial infection may have a pathophysiological role in refractory Detrusor Overactivity (DO). The aim of this study was to observe any impact of antibiotic therapy upon bacterial colonization of urothelial cells, and to determine whether a relationship existed between colonization and symptom severity. Mid-stream urine samples were collected as part of a clinical trial of antibiotics in women with refractory DO. Wright stained urothelial cells were categorized according to the degree of bacterial colonization as; ‘clear’ (free of bacteria), or as associated with bacteria that were ‘adjacent’ to the cell or ‘intracellular’ at low or high density. The average percentages were compared with routine microbiology cultures, over the 26 week trial, and with patient clinical outcome measures of DO severity. In patients receiving placebo, ‘high-density intracellular bacteria’ significantly increased during urinary tract infection (P = 0.0008). In antibiotic patients, ‘clear’ cells were more prevalent. Amoxicillin & Clavulanic Acid significantly decreased bacterial colonization within urothelial cells, suggesting that these antibiotics possess the greatest intracellular efficacy. ‘High-density intracellular bacteria’ positively correlated with symptom severity, measured by leakage on pad test (P = 0.014), leaks per day (P = 0.004), and voids per day (P = 0.005). Thus, by decreasing high density intracellular bacteria, antibiotic treatment may improve the refractory DO condition. In women with refractory detrusor overactivity antibiotic treatment decreases high density intracellular colonisation of urothelial cells and is associated with symptom improvement.

Background Acute uncomplicated cystitis (AUC) is an ideal target of optimization for antibiotic therapy in primary care. Because surveillance networks on urinary tract infections (UTI) mix complicated and uncomplicated UTI, reliable epidemiological data on AUC lack. Whether the antibiotic choice should be guided by a rapid urine test (RUT) for leukocytes and nitrites has not been extensively studied in daily practice. The aim of this primary care study was to investigate local epidemiology and RUT-daily use to determine the optimal strategy. Methods General practitioners included 18–65 years women with symptoms of AUC, performed a RUT and sent urines for analysis at a central laboratory. Different treatment strategies were simulated based on RUT and resistance results. Results Among 347 enrolled patients, 78% had a positive urine culture. Escherichia coli predominated (71%) with high rates of susceptibility to nitrofurantoin (100%), fosfomycin (99%), ofloxacin (97%), and even pivmecillinam (87%) and trimethoprim-sulfamethoxazole (87%). Modelization showed that the systematic use of RUT would reduce by 10% the number of patients treated. Fosfomycin for patients with positive RUT offered a 90% overall bacterial coverage, compared to 98% for nitrofurantoin. 95% for ofloxacin, 86% for trimethoprim-sulfamethoxazole and 78% for pivmecillinam. Conclusion Local epidemiology surveillance data not biased by complicated UTI demonstrates that the worldwide increase in antibiotic resistance has not affected AUC yet. Fosfomycin first line in all patients with positive RUT seems the best treatment strategy for AUC, combining good bacterial coverage with expected low toxicity and limited effect on fecal flora. Trial registration The current study was registered at clinicaltrials.gov ( NCT00958295 )

Introduction and hypothesis The glycosaminoglycan hyaluronic acid (HA) protects the urothelium; damage may increase bacterial adherence and infection risk. This study evaluated the effect of intravesical HA in recurrent bacterial cystitis (RBC). Methods Women with RBC were randomized to intravesical HA 800 mg and chondroitin sulfate (CS) 1 g (IALURIL ® , IBSA) in 50 mL of saline solution once weekly for 4 weeks then once every 2 weeks twice more (group 1) or long term antibiotic prophylaxis using sulfamethoxazole 200 mg and trimethoprim 40 mg once weekly for 6 weeks (group 2; control). Evaluations included: cystitis recurrence at 2 and 12 months; subjective pain symptoms (visual analog scale [VAS]); 3 day voiding; sexual function; quality of life (King's Health Questionnaire [KHQ]); frequency symptoms/frequency symptoms (PUF symptom scale); and maximum cystometric capacity (MCC). Means ± standard deviations were reported, with Mann-Whitney test for between-group comparison (significance P  < .05). Results Of 28 women (mean age 60 ± 13 y) randomized, 26 completed follow-up (mean follow-up 11.5 mo). Group 1 showed a significant improvement in all evaluations; cystitis recurrence (1 ± 1.2 versus 2.3 ± 1.4, P =  .02); 3-day voiding (mean 17.8 ± 3.5 vs 24.2 ± 8.3, P =  .04); symptom VAS (1.6 ± 0.8 vs 7.8 ± 1.6, P <  .001); PUF score (11.2 ± 2.7 vs 19.6 ± 2.2, P <  .001), KHQ score (18.4 ± 7.2 vs 47.3 ± 13.6, P <  .001), and MCC (380 ± 78 vs 229 ± 51 mL, P <  .001) vs group 2 at 12 mo. No adverse effects were recorded. Conclusions Intravesical HA and CS in combination significantly reduced cystitis recurrence and improved urinary symptoms, quality of life, and cystometric capacity in RBC patients at 12 mo follow-up versus antibiotic prophylaxis. Study limitations include a small sample and relatively short follow-up.

Background Women with acute uncomplicated urine infection are usually treated with antibiotics. One trial has demonstrated that delayed antibiotic treatment offered without symptom relief results in a modest reduction in antibiotic use. There is some evidence that ibuprofen provides symptom relief and reduces antibiotic use. Uva-ursi, a herbal product, has a traditional use for urinary infection symptom relief. We set out to test: in adult women with suspected UTI who accept the delayed prescription strategy: Do NSAIDs or uva-ursi (a herbal product) provide relief from urinary symptoms and reduce antibiotic use. Methods/design Adult women with suspected urinary tract infection presenting to primary care will be randomised using a factorial trial design in which patients will be randomised to one of two interventions as below: Group 1 – Uva-ursi + advice to take ibuprofen Group 2 – Placebo + advice to take ibuprofen Group 3 – Uva-ursi + no advice to take ibuprofen Group 4 – Placebo + no advice to take ibuprofen Patients and physicians will be blinded to the randomised group for the herb. The main outcome is symptom severity at days 2–4 recorded in a validated, self-report diary used in previous studies. Secondary outcomes include antibiotic use and symptom duration. In total the trial will require 328 patients in order to achieve at least 90% power for the primary endpoint and 80% for the secondary endpoint. In accordance with CONSORT guidelines all comparative analyses will be conducted on an intention-to-treat basis using SPSS or similar package. Discussion The outcomes from this trial have the potential to modify the current approach to the management of acute urinary symptoms with less dependence on the use of antibiotics. Trial registration ISRCTN registry, ID: ISRCTN43397016 . Registered on 11 February 2015.

Abstract Bladder infections affect millions of people yearly, and recurrent symptomatic infections (cystitis) are very common. The rapid increase in infections caused by multidrug-resistant uropathogens threatens to make recurrent cystitis an increasingly troubling public health concern. Uropathogenic Escherichia coli (UPEC) cause the vast majority of bladder infections. Upon entry into the lower urinary tract, UPEC face obstacles to colonization that constitute population bottlenecks, reducing diversity, and selecting for fit clones. A critical mucosal barrier to bladder infection is the epithelium (urothelium). UPEC bypass this barrier when they invade urothelial cells and form intracellular bacterial communities (IBCs), a process which requires type 1 pili. IBCs are transient in nature, occurring primarily during acute infection. Chronic bladder infection is common and can be either latent, in the form of the quiescent intracellular reservoir (QIR), or active, in the form of asymptomatic bacteriuria (ASB/ABU) or chronic cystitis. In mice, the fate of bladder infection, QIR, ASB, or chronic cystitis, is determined within the first 24 h of infection and constitutes a putative host–pathogen mucosal checkpoint that contributes to susceptibility to recurrent cystitis. Knowledge of these checkpoints and bottlenecks is critical for our understanding of bladder infection and efforts to devise novel therapeutic strategies. Urinary tract infections are an increasingly troublesome public health concern due to rapidly rising antibiotic resistance among uropathogenic bacteria worldwide. Here we highlight recent studies of intracellular and persistent uropathogenic E. coli during infections of the urinary bladder, focusing on the identification of host-pathogen checkpoints and bacterial population bottlenecks during acute and chronic cystitis that present opportunities for developing new therapeutic strategies.

Background The association of in vitro resistance with bacteriologic, clinical, and health-related quality of life (HRQoL) outcomes for acute uncomplicated cystitis is unclear. Methods We conducted a prospective study of women aged 18–40 years with acute uncomplicated cystitis symptoms for ≤7 days who subsequently grew an Enterobacteriaceae sp. and initially received trimethoprim/sulfamethoxazole (TMP/SMX) and phenazopyridine. We conducted telephone follow-up evaluating clinical cure at 1–3 days and in-person follow-up evaluating clinical, bacteriologic, and HRQoL outcomes at 3–7 days and 4–6 weeks post-treatment. Results An Enterobacteriaceae sp. was isolated in 139 (96.5%) patients (25.2% TMP/SMX-resistant). At 1–3 days post-treatment, clinical cure occurred in 56/81 (69.1%) and 14/31 (45.2%) of cases with susceptible and resistant strains, respectively (difference 23.9%; 95% confidence interval [CI], 1.5–46.4%). At 3–7 days post-treatment, bacteriologic cure occurred in 70/73 (95.9%) and 15/25 (60%) of cases with susceptible and resistant strains, respectively (difference 35.9%; 95% CI, 13.5–58.3%). Sustained clinical cure rates at 3–7 days and 4–6 weeks post-treatment were 65.4 and 56.8% with susceptible strains, and 45.2 and 45.2% with resistant strains, respectively. The HRQoL scale assessing role limitations due to physical health problems was lower in TMP/SMX-resistant versus TMP/SMX-susceptible infections, with twice as many hours of missed activities reported (mean, 18.4 vs. 9.1 h). Differences in HRQoL appeared to be largely related to differences in clinical cure rates. Conclusions Among women treated for acute uncomplicated cystitis with TMP/SMX, in vitro TMP/SMX resistance was associated with lower bacteriologic and clinical cure rates, and had greater impact on the time lost from daily activities compared to those with TMP/SMX-susceptible infections.

Urinary tract infection in women is a very common outpatient clinical problem. This report defines the implications of microbiologic analysis of midstream urine cultures in premenopausal women with acute uncomplicated cystitis. Urinary tract infection is a bacterial infection that is encountered frequently in outpatient settings in the United States, accounting for 8.6 million visits in 2007. 1 Half of all women report having had at least one urinary tract infection by 32 years of age. 2 The hallmark of such infections is the presence of bladder bacteriuria. Although a urine specimen collected by suprapubic aspiration or catheter is the reference for determining the microbial cause of infection, neither type of specimen is routinely obtained because of inconvenience, discomfort, and the potential for adverse events. Thus, when an examination of urine is indicated in . . .

Urinary tract infections (UTIs) are one of the most common bacterial infections and are predominantly caused by uropathogenic Escherichia coli (UPEC). While UTIs are typically considered extracellular infections, it has been recently demonstrated that UPEC bind to, invade, and replicate within the murine bladder urothelium to form intracellular bacterial communities (IBCs). These IBCs dissociate and bacteria flux out of bladder facet cells, some with filamentous morphology, and ultimately establish quiescent intracellular reservoirs that can seed recurrent infection. This IBC pathogenic cycle has not yet been investigated in humans. In this study we sought to determine whether evidence of an IBC pathway could be found in urine specimens from women with acute UTI. We collected midstream, clean-catch urine specimens from 80 young healthy women with acute uncomplicated cystitis and 20 asymptomatic women with a history of UTI. Investigators were blinded to culture results and clinical history. Samples were analyzed by light microscopy, immunofluorescence, and electron microscopy for evidence of exfoliated IBCs and filamentous bacteria. Evidence of IBCs was found in 14 of 80 (18%) urines from women with UTI. Filamentous bacteria were found in 33 of 80 (41%) urines from women with UTI. None of the 20 urines from the asymptomatic comparative group showed evidence of IBCs or filaments. Filamentous bacteria were present in all 14 of the urines with IBCs compared to 19 (29%) of 66 samples with no evidence of IBCs (p < 0.001). Of 65 urines from patients with E. coli infections, 14 (22%) had evidence of IBCs and 29 (45%) had filamentous bacteria, while none of the gram-positive infections had IBCs or filamentous bacteria. The presence of exfoliated IBCs and filamentous bacteria in the urines of women with acute cystitis suggests that the IBC pathogenic pathway characterized in the murine model may occur in humans. The findings support the occurrence of an intracellular bacterial niche in some women with cystitis that may have important implications for UTI recurrence and treatment.

Background Urinary tract infections (UTIs) are one of the most frequent diseases encountered by humans worldwide. The presence of multidrug-resistant (MDR) uropathogenic Escherichia coli (UPEC) harboring several virulence factors, is a major risk factor for inpatients. We sought to investigate the rate of antibiotic resistance and virulence-associated genes among the UPECs isolated from an Iranian symptomatic population. Methods A total of 126 isolates from inpatients with UTI from different wards were identified as UPEC using the conventional microbiological tests. After identification of UPECs, all the isolates were subjected to antimicrobial susceptibility test and polymerase chain reaction (PCR) to identify the presence of 9 putative virulence genes and their association with the clinical outcomes or antimicrobial resistance. Results The data showed that the highest and the lowest resistance rates were observed against ampicillin (88.9%), and imipenem (0.8%), respectively. However, the frequency of resistance to ciprofloxacin was found to be 55.6%. High prevalence of MDR (77.8%) and extended-spectrum β-lactamase (ESBL) (54.8%) were substantial. PCR results revealed the frequency of virulence genes ranged from 0 to 99.2%. Among 9 evaluated genes, the frequency of 4 genes ( fimH , sfa , iutA , and PAI marker) was > 50% among all the screened isolates. The iutA , pap GII , and hlyA genes were more detected in the urosepsis isolates with significantly different frequencies. The different combinations of virulence genes were characterized as urovirulence patterns. The isolates recovered from pyelonephritis, cystitis, and urosepsis cases revealed 27, 22, and 6 virulence patterns, respectively. A significant difference was determined between ESBL production with pap GII , iutA , and PAI marker genes. Conclusions Our study highlighted the MDR UPEC with high heterogeneity of urovirulence genes. Considering the high rate of ciprofloxacin resistance, alternative drugs and monitoring of the susceptibility profile for UPECs are recommended.

Chaperone-usher pathway pili are a widespread family of extracellular. Gram-negative bacterial fibers with important roles in bacterial pathogenesis. Type 1 pili are important virulence factors in uropathogenic Escherichia coli (UPEC), which cause the majority of urinary tract infections (UTI). FimH, the type 1 adhesin, binds mannosylated glycoproteins on the surface of human and murine bladder cells, facilitating bacterial colonization, invasion, and formation of biofilm-like intracellular bacterial communities. The mannose-binding pocket of FimH is invariant among UPEC. We discovered that pathoadaptive alleles of FimH with variant residues outside the binding pocket affect FimH-mediated acute and chronic pathogenesis of two commonly studied UPEC strains, UTI89 and CFT073. In vitro binding studies revealed that, whereas all pathoadaptive variants tested displayed the same high affinity for mannose when bound by the chaperone FimC, affinities varied when FimH was incorporated into pilus tip-like, FimCGH complexes. Structural studies have shown that FimH adopts an elongated conformation when complexed with FimC but when incorporated into the pilus tip, FimH can adopt a compact conformation. We hypothesize that the propensity of FimH to adopt the elongated conformation in the tip corresponds to its mannose binding affinity. Interestingly, FimH variants, which maintain a high-affinity conformation in the FimCGH tip-like structure, were attenuated during chronic bladder infection, implying that FimH's ability to switch between conformations is important in pathogenesis. Our studies argue that positively selected residues modulate fitness during UTI by affecting FimH conformation and function, providing an example of evolutionary tuning of structural dynamics impacting in vivo survival.