From July 2020 to March 2022, 94 women with 118 UTI events were screened. Twenty-five patients did not meet the inclusion criteria: 6 were greater than 85 years old, 9 were on baseline antibiotics at the time of screening, 3 were on self-start antibiotic regimens, 1 had neurogenic bladder, 2 had indwelling catheters, and 4 had known allergies to NF. One additional patient was excluded who did not receive NF despite being in the ET group. Given that the majority of the women were post-menopausal, 3 pre-menopausal patients were also ultimately excluded to focus the analysis on post-menopausal women. Sixty-five patients with 80 UTI events were included for final analysis, with CB treatment used for 57 UTIs and ET used for 23 UTIs. Due to the COVID-19 pandemic, we were unable to meet enrollment goals. Additionally, the reality of real-life practice led to 8 UTI events in the ET group and 24 UTI events in the CB group being given treatment that did not correspond to study methodology as to the day that they contacted the clinic.

Median age was 69 years old, with 74% of patients having had a history of RUTI and 26% a history of UTI (as defined in the methods). Patient characteristics were not significantly different between the two groups (Table 1). For the 64 UTI events with a 7-day questionnaire available, there was not a significant association between treatment group and failure, accounting for UTI events coming from the same patient (P = 0.076). The questionnaire failure rate was 44% (20/45) for the CB group and 16% (3/19) for the ET group. For the 60 UTI events with a 14-day questionnaire available, there was not a significant association between treatment group and failure (P = 0.3). The questionnaire failure rate was 31% (13/42) for the CB group and 17% (3/18) for the ET group.

In 23 cases of UTIs receiving ET, there were 5 instances where NF resistance was unable to be determined: 2 urine cultures had no growth and 3 had no culture results available for review. Out of the remaining 18 cultures from the ET group, only 2 cultures (11%) were found to have pathogens resistant to NF. There was a significant difference in the number of class resistances in the patients who received ET (3.9; 95% CI 2.7, 5.2) versus CB treatment (1.8; 95% CI 1.1, 2.6; P = 0.011). The baseline organisms present in each group were similar. In the CB group 19% (11/57) of baseline cultures were polymicrobial, 47% (27/57) grew Escherichia coli, and 14% (8/57) grew Enterococcus faecalis. In the ET group, 21% (4/19) were polymicrobial at baseline, 53% (10/19) grew Escherichia coli, and 11% (2/19) grew Enterococcus faecalis. All 7 cases of Klebsiella pneumoniae were in the CB group. Three patients reported side effects at the 7-day follow-up (all in the CB group; one with nausea and vomiting, one with stomach cramps, and one with stomachache and headache). One patient in the ET group reported side effects at her 14-day follow-up (diarrhea). All four women who reported side effects were on NF.

The same organisms from 11 UTIs were present in a follow-up culture: 9 from the CB group and 2 from ET group. The results of these cultures are shown in Table 2. There were 5 additional follow-up cultures that had new organisms compared to baseline: 5 in the CB group and 1 in the ET group.

This study examined the real-world use of empiric and culture-based antibiotic therapy in an ambulatory urology tertiary care urology practice. Due to COVID-19, the study was terminated before all expected goals were met. Nonetheless, we found no significant difference in treatment outcomes between empiric and culture-based treatment of UTIs.

We chose to administer the UTISA questionnaire at 7 and 14 days following start of treatment given the questionnaire’s ability to detect small changes in symptoms following completion of therapy for a UTI [10]. While not significantly different, questionnaire failure rate at 7 days was more than double (44% vs. 16%) in the CB group compared to the ET group. At 14 days, there was only a 14% difference in the failure rate between the two groups (31% CB vs. 17% ET). These observations suggest that treating patients empirically may lead to a faster improvement in UTI-related symptoms. This is presumably due to a lesser amount of planktonic bacterial load to eradicate early on, as opposed to a larger amount when the infection has had more time to develop. In addition, no patients in the study reported hospitalization due to urosepsis or pyelonephritis during the study duration. This is consistent with recently reported findings that only 0.3% of patients presenting in an outpatient setting for acute cystitis progress to sepsis within 7 days [11].

Culture-based therapy continues to be the gold standard for UTI therapy given the risk of over or inappropriate treatment with empiric antibiotics [12]. We found that of 23 patients treated empirically, 18 (78%) had positive culture results with 2/18 (11%) of these cultures revealing pathogens with NF resistance requiring a change in antibiotic therapy. In a recent retrospective review, Dokter et. al reported that of women treated empirically for suspected UTIs, 43% of cultures were positive with 26% of empirically treated patients requiring a change in antibiotics due to bacterial resistance on culture [13]. This study is comparable to our findings as it occurred in an outpatient clinic run by Female Pelvic Medicine and Reconstructive Surgery (FPMRS)-trained urologists. The higher culture positivity rates in our study may be due to the high number of women with a history of RUTIs.

In this study, we chose to treat all patients in the ET group with NF given its strong safety profile, low rates of resistance, and affordability compared to other first-line therapies [8, 9]. In a randomized trial comparing NF to fosfomycin, Huttner et al. found that NF led to a resolution of UTI symptoms in 70% of patients at 28 days with side effects reported in 4% of patients [14]. While our rates of NF resistance were higher than previously reported, bacteria isolated from urine cultures of the patients in the ET group did have significantly more class resistances than bacteria cultured from the urine of patients in the CB group. The higher rates of resistance in the ET group may indicate that women who received ET had greater exposure to antibiotics in the past.

Antibiotic resistance is increasing with the most recent data from the U.S. Center for Disease Control and Prevention reporting over 2 million people in the USA diagnosed with an antibiotic-resistant infection annually. Approximately 23,000 of these antibiotic-resistant cases have resulted in death [15,16,17]. UTIs with highly resistant bacteria are estimated to account for $20 billion in direct healthcare costs per year [18]. In practice many providers utilize ET, current guidelines from the IDSA and AUA do not provide clear guidance on the appropriate use of ET [7, 12].

With the increased use of telehealth resulting from the COVID-19 pandemic, ET is likely to continue to be common practice for the treatment of uncomplicated cystitis. Larger-scale studies are needed to determine when ET is indicated. This study may help in informing future guidelines that provide specific recommendations on the use of ET for uncomplicated cystitis. The limitations of this study include the inclusion of mainly Caucasian menopausal women at a tertiary center, FPMRS-based, practice. Furthermore, participation in this study was stopped before reaching enrollment goals due to low numbers related to the COVID-19 pandemic. Additionally, due to continuous flux of staff during this period, proper education of clinic staff about study procedures for selecting ET or CB treatment based on the day of the week proved untenable.