Activity impairment, health-related quality of life, productivity, and self-reported resource use and associated costs of uncomplicated urinary tract infection among women in the United States

Background Uncomplicated urinary tract infections (uUTIs) are among the most common infections in the US. Only a few studies, however, describe the impact of uUTIs from the patient perspective. Methods A cross-sectional online survey of US women aged ≥18 years was performed assessing uUTI burden regarding activity impairment, health-related quality of life (HRQoL), workplace productivity, healthcare resource use (HRU), and costs. Participants who self-reported a uUTI in the prior 60 days treated with ≥1 oral antibiotic were included. Activity impairment was assessed with the Activity Impairment Assessment scale. HRQoL was assessed using a modified Short Form 36 (SF-36). Direct costs were sum of out-of-pocket expenditures and monetized HRU; indirect costs were calculated using Work Productivity and Activity Impairment (WPAI). Participants were stratified by uUTI recurrence, number of prescribed antibiotics for recent uUTI and therapy appropriateness (1 first-line/1 second-line/multiple antibiotics). Multivariable regression analysis assessed the relationship between stratifications and outcomes while controlling for demographic/clinical characteristics. Propensity score matching was used to compare participants to a matched population from the 2020 National Health and Wellness Survey (NHWS), to control for any impact of COVID-19 on responses. Results Among 375 participants, impaired activities included sexual intercourse (66.9%), sleep (60.8%) and exercise (52.3%). HRQoL was worse (p<0.0001) than the NHWS population (46.4 vs. 51.3 [physical component score]; 40.0 vs. 46.9 [mental component score]; 0.63 vs. 0.72 [health utility index]). All included WPAI assessments were worse for uUTI cohort vs. NHWS (p<0.0001). Adjusted direct costs were higher for participants receiving 2 vs. 1 antibiotic ($2090 vs. $776; p<0.0001) and receiving multiple antibiotics vs. 1 first-line ($1642 vs. $875; p = 0.002). Recurrent uUTI was associated with increased activity impairment, worse HRQoL, and costs vs. non-recurrent. Conclusions uUTIs were associated with increased activity impairment, worse productivity, and reduced HRQoL. Higher costs were found vs. a matched population.


Introduction
Symptomatic uncomplicated urinary tract infections (uUTI) are one of the most common infections in the United States (US) [1]. They are defined by the presence of dysuria, urinary frequency, urgency, and suprapubic pain in women lacking fever and functional or anatomical abnormalities of the urinary tract, with no recent urinary instrumentation [2]. Urinary tract infections (UTIs) account for a substantial proportion of antibiotics prescribed in primary care [3], and account for 10.5 million ambulatory care visits due to UTI or cystitis in the US, or 0.9% of all ambulatory care visits [4]. The majority of uUTIs are caused by Escherichia coli (E. coli) [1] and standard of care for uUTIs is empiric oral antimicrobial agents with activity against certain Gram-positive and Gram-negative bacteria, including: fosfomycin, nitrofurantoin, trimethoprim-sulfamethoxazole, and β-lactams (amoxicillin-clavulanate, cefdinir, cefaclor, cefpodoxime-proxetil, and cephalexin) as alternate agents in patients with allergies/ intolerance to first line [5]. There is, however, increasing antimicrobial resistance among E. coli, which is a global problem [6].
UTIs are common infections, occurring in an estimated 1 in 3 women by the age of 24 years, or 50-60% of all women in a lifetime [1]. UTIs have a substantial effect on quality of life and represent a considerable healthcare burden [7]. For example, in a population survey conducted in England in 2014, Butler et al. [3] found that 15% of patients reported UTIs impacting their daily lives "a great deal", 37% reported it affecting their daily lives "a fair amount", and 95% reported contacting a healthcare professional about their most recent UTI [3]. Furthermore, Ellis and Verma [8] found that quality of life scores (based on the Short-Form 36 questionnaire) were lower across all domains of the assessment for US women with outpatient UTI compared with healthy controls [8]. The evaluation and treatment of UTI costs several billion dollars per year globally, and approximately $2 billion per year in the US [9].
While the effects of UTI on quality of life have been investigated previously [7,8], contemporary studies regarding the key drivers of health-related quality of life (HRQoL), work productivity loss, healthcare resources use, direct and indirect costs, activity impairment, and treatment satisfaction are lacking. Furthermore, earlier studies on UTI and have not made a clear distinction between complicated UTI and uUTI. Thus, in order to better understand these factors, we conducted a survey examining patient-reported activity impairment, HRQoL, workplace productivity, uUTI-related healthcare resource use (HRU), and costs in US women with a self-reported uUTI in the past 60 days that was treated with an oral antibiotic.

Study design
This was a cross-sectional survey of women who self-reported a UTI episode in the past 60 days that was treated with an oral antibiotic. Women who had previously agreed to participate in general population surveys conducted by Dynata, EMI, Lucid/Federated or Kantar Profiles, were invited via email to participate. Details of the source populations are provided in S1 Table in S1 File. After online screening of inclusion/exclusion criteria, eligible participants (i.e., those with a uUTI within the study recall period) provided informed consent prior to completing an online questionnaire regarding their most recent uUTI. Respondents were permitted to complete the online survey only once and were compensated for their participation time.

Participants
Women were eligible to participate in the survey if they were aged � 12 years (although no respondents were younger than 18 years), living in the US, able to read English, and reported a UTI in the 60 days prior to participation for which they received oral antibiotic therapy. In order to ensure that the inclusion UTI episode was uncomplicated, participants were excluded if they self-reported a diagnosis of any of the following, indicative of complicated UTI (cUTI), in the 6-month period before oral antibiotic treatment for the inclusion episode: urologic abnormalities, ureteral abnormalities, interstitial cystitis, pyelonephritis, kidney stones, renal failure, congenital urological abnormalities, organ transplant, or neurological disease. Additional exclusion criteria were the following: self-reported diabetes with an unknown or uncontrolled glycosylated hemoglobin level (� 7%); self-reported receipt of any immunosuppressive therapy at the time of developing a UTI; any UTI identified in the previous 60 days as having occurred during an inpatient hospitalization or stay at a long-term care facility; antibiotic treatment received for inclusion UTI during an inpatient hospitalization; pregnancy at the time of recent uUTI; asymptomatic bacteriuria (i.e., positive urine culture with no UTI symptoms present); and diagnosis of COVID-19 in the previous 12 months.

Study data
Data collected during the survey included demographics (age, insurance type, marital status, race/ethnicity, employment type, education, type of residence [rural/urban], US region, household income); health characteristics (i.e., height, weight, body mass index, smoking status, alcohol use); comorbidities; healthcare resource utilization; UTI history (with � 2 selfreported UTIs in the previous 6 months or � 3 uUTIs in the past year considered recurrent); symptom severity; activities impacted by inclusion uUTI; treatments used for recent uUTI and any prior UTI (including antibiotics used); HRU; and self-reported direct costs.

Objectives
The primary objective of the study was to assess activity impairment associated with uUTI. Secondary endpoints were assessment of HRQoL, workplace productivity, HRU and associated costs (direct and indirect) associated with the participants' most recent uUTI event. Treatment satisfaction with the most recent oral antibiotic received was examined as an exploratory endpoint (See Supplementary methods).
The Activity Impairment Assessment (AIA) was used to measure the impact of uUTI on daily activities. The AIA is a validated 5-item self-administered questionnaire assessing the amount of time that daily activities have been impaired by uUTI symptoms [10]. Responses are given on a 5-point Likert-type scale from 0-4 ("none of the time"-"all of the time"). AIA scores range from 0 to 20 with higher scores denoting higher impairment. HRQoL was assessed using a modified version of the Short Form 36 version 2 (SF-36v2) with a recall period adjusted to the time of the most recent uUTI. The SF-36v2 is a 36-item self-administered questionnaire covering measures of 8 health domains [11]. We utilized the Physical Component Score (PCS), Mental Component Score (MCS) and health utility index (SF-6D) from this questionnaire. HRU was measured as the number of self-reported healthcare visits utilized to treat the inclusion uUTI, encompassing: primary care provider (PCP) office visits, specialist (obstetrician/gynecologist) office visits, urgent care visits, emergency room (ER) visits, and hospitalizations. Direct costs were calculated as the sum of self-reported out-of-pocket costs (including payments for doctor(s) visits, prescription medications, over-the-counter treatments, costs associated with travel to receive treatment, childcare costs, etc.) and HRU monetized with Medical Expenditure Panel Survey estimates [12]. Indirect costs were calculated via Work Productivity and Activity Impairment (WPAI) metrics [13] monetized with Bureau of Labor Statistics estimates [14].

Statistical analyses
Outcomes were reported with descriptive statistics, chi-squared tests, and t-tests. Participants were stratified by recurrent uUTI (yes/no); the number of oral antibiotics prescribed for their most recent uUTI (1, 2 or � 3); and by appropriateness of therapy, defined as 1 appropriate (first-line) antibiotic only, 1 inappropriate (not first-line) antibiotic only, or multiple antibiotics (any line) per Infectious Diseases Society of America guidelines [5]. Multivariate regression with generalized linear models was used to compare strata for the following outcomes of interest: activity impairment, HRQoL, total uUTI-related costs (direct and out-of-pocket), WPAI measures (absenteeism, presenteeism, overall work impairment, impact on daily activities). Covariates were chosen via a stepwise selection process using SAS PROC HPGENSELECT (SAS Institute Inc., NC, USA) on the full cohort sample. For number of therapies, results were adjusted for age, race/ethnicity, employment, and use of any second-line antibiotic. For appropriateness of therapy, adjustments were made for age, race/ethnicity, employment, region, and any physician-ordered urine testing.
PCS and MCS were compared to the general US population average (Optum Inc., MN, USA) and categorized as "Same or Better" than the general population, "Below" the general population or "Well below" the general population, defined as scores lower by � 5 points (the minimum clinically important difference for PCS and MCS) [15].
Propensity score matching (1:1) was used to assess uUTI burden in the study cohort compared with a matched US population from the National Health and Wellness Survey (NHWS) 2020. The NHWS is a self-administered, internet-based survey of a nationwide sample of adults (aged � 18 years) stratified by age, gender, and racial/ethnic groups to represent the demographic composition of the US adult population [16]. This analysis was performed to address the potential impact that the COVID-19 pandemic may have had on study measure responses (such as activities involving social contact) and was used to assess the incremental burden associated with uUTI when compared to a matched population that were also survey participants during a similar time period in 2020.
This study was originally scoped to include 850 participants meeting all eligibility criteria. The final study sample used for analysis included 375 respondents. Precision analysis estimates for descriptive statistics show that at a 95% confidence interval (CI) the associated margin of error (MOE) for the minimum sample size of 385 is ±5%. At a 99% CI the associated MOE for a sample size of 339 is ±7%. Power calculations for linear multiple regression modelling (including composite AIA score, HRQoL MCS/PCS scores, etc.) indicate that a sample size of 160 was required to reach a power of 80% (α = 0.05) for an effect size of 5%. The current study sample size with a minimum of 375 is powered at 99% (α = 0.05) to detect a 5% effect size when performing linear multiple regression modelling.

Ethics
Ethical approval of the study protocol was provided by Pearl IRB LLC (Indianapolis, USA; reference #20-KANT-222). Participants provided written informed consent (via an online consent form) prior to their involvement in the study. No personally identifiable information was collected as part of the study. The study complied with all applicable privacy laws.
Participant demographic data and clinical characteristics are shown in Table 1. Study participants were evenly distributed across all age groups; the majority were white (84.8%), 44.0% were married, 34.1% were in full-time employment, and 41.1% had employer-provided health insurance. Many participants were never smokers (45.9%), and the most common current comorbidities were depression (36.5%), anxiety (32.3%), and hypertension (19.7%). Significant differences in demographic data and clinical characteristics were observed between stratification cohorts (S2 and S3 Tables in S1 File). Participants in rural areas were more likely to report using 2 antibiotics than �3 (31.8% vs. 15.4%; p = 0.018) and participants in urban areas were more likely to report using �3 antibiotics than 2 (38.5% vs. 19.3%; p = 0.018; S2 Table in S1 File). Furthermore, those who received 2 antibiotics were more likely to have current comorbid irritable bowel syndrome (IBS) than those who received 1 antibiotic (18.2% vs. 8.1%; p = 0.009) and were less likely to report current comorbid anxiety than those who received 3 antibiotics (29.5% vs. 50.0%; p = 0.016; S2 Table in S1 File). Participants who received 1 appropriate antibiotic only were more likely to have employer-provided insurance than those who received 1 inappropriate antibiotic only (48.8% vs. 39.3%; p < 0.05; S3 Table in S1 File). Participants in the multiple antibiotics cohort were more likely to have Medicare than the 1 inappropriate antibiotic only cohort (29.3% vs. 23.2%; p < 0.05), and were more likely to be from the Mid-West (54.3% vs. 34.1%; p = 0.001), have a household income of $50,000-74,999 (27.1% vs. 14.6%; p = 0.029), and be currently experiencing IBS than the 1 appropriate antibiotic only cohort (15.7% vs. 6.5%; p = 0.019; S3 Table in S1 File). The mean number of all-cause ER visits in the past 12 months was higher in the multiple antibiotics cohort than in the 1 appropriate antibiotic only cohort (0.7 vs. 0.4; p = 0.015), but a greater proportion of the appropriate

PLOS ONE
The impact of uncomplicated UTI on daily life, healthcare resource use and costs in US women

Health-related quality of life (SF-36)
Most participants (58.7%) had a PCS that was the same as or better than the general population, while for MCS, most participants (52.8%) had scores well below the general population average. Overall PCS, MCS, and SF-6D composite scores were 46.5, 40.0, and 0.63, respectively; these outcomes were significantly worse than those in the matched population (Fig 2). This was most notable for MCS where the uUTI cohort adjusted average score was 40.6 vs. the matched NHWS population adjusted score of 46.9 (Fig 2).
Participants with recurrent uUTI had worse HRQoL than those with non-recurrent uUTI. Mean PCS was 44.2 for patients with recurrent uUTI and 48.2 for those with non-recurrent uUTI (p < 0.0001). Mean SF-6D scores were 0.61 and 0.65 for recurrent and non-recurrent uUTI respectively (p = 0.004). MCS scores were similar between patients with recurrent and non-recurrent uUTI (39.1 and 40.8, respectively [p = 0.185]). Stratification by number of antibiotics used revealed statistically significant differences in the impact of uUTI on PCS and SF-6D (based on use of 1 vs. � 3 therapies); Table 2).

Healthcare resource use
The highest reported type of HRU used for treatment of recent uUTIs were PCP visits (68.8%). There were an average of 1.46 PCP, 0.31 obstetrician/gynecologist (OB/GYN), 0.41 urgent care, and 0.08 ER visits, and 0.01 hospitalizations for participants' most recent uUTI (Table 5).

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The impact of uncomplicated UTI on daily life, healthcare resource use and costs in US women participants who received multiple antibiotics vs. those who received 1 appropriate antibiotic only ($1642 vs. $875, p = 0.002) ( Table 6). Adjusted total direct costs for participants who received � 3 antibiotics for their uUTI were lower than those who received 2 antibiotics ($1041 vs. $2090) and not significantly different to those who received just 1 antibiotic (p = 0.197).

Treatment satisfaction
Treatment satisfaction results can be found in the Supplementary results. Generally, participants with non-recurrent uUTI or who received 1 antibiotic had better treatment satisfaction scores compared with participants with recurrent uUTI or who received > 1 antibiotic, respectively.

Discussion
Among women, uUTIs are a common occurrence [1]. In our study, based on recall, 43% of women had recurrent uUTIs, which was higher than the prevalence reported in the literature, ranging from 20-40% [1,[18][19][20]. Despite this prevalence, the burden of disease on patients is

PLOS ONE
The impact of uncomplicated UTI on daily life, healthcare resource use and costs in US women not well understood. We found that HRQoL scores, particularly MCS, were worse among participants with uUTI than a matched population based on the 2020 NHWS. Similarly, WPAI measures were significantly affected by uUTI compared with the NHWS cohort. These data demonstrate the substantial burden on patients that uUTI represents. Furthermore, we found that survey participants with recurrent uUTI (43.5%) displayed a higher level of activity impairment (shopping, housework/chores and socialising, and WPAI impact on daily activities), worse HRQoL (PCS, SF-6D) and productivity scores (presenteeism, overall work impairment), higher mean total out-of-pocket costs, and higher mean total indirect costs compared with participants with non-recurrent uUTI.

PLOS ONE
The impact of uncomplicated UTI on daily life, healthcare resource use and costs in US women The burden of recurrent UTI from the patient perspective was previously described in a qualitative study of comments on an online forum which demonstrated the substantial and varied impact that repeated infections have on individuals' quality of life [21]. As with our study, these authors found sexual intercourse to be a commonly affected activity [21]. Furthermore, an online survey of women with recurrent UTI in 5 European countries found that 23-55% of participants (depending on country and whether the participants had a current acute UTI or had a UTI in the past 4 weeks) had physical health scores below a US general population comparator, and 55-81% had mental health scores below the comparator [22]. This is consistent with our study where a greater proportion of the cohort had MCS scores below the general population than PCS scores. However, our study has the strength of providing a comparison between recurrent and non-recurrent uUTI, allowing us to demonstrate the additional HRQoL burden that patients with recurrent uUTI have above and beyond that conferred by the infection alone. Additionally, many of the participants in the previous studies would have been ineligible for this study due to signs of complicated UTI. By including just participants with uUTI, we were able to show that even with infections that might conventionally be considered mild, a significant burden is experienced by patients that affects HRQoL.
When stratified by number of oral antibiotics used, participants who received � 3 antibiotics for their most recent uUTI reported worse HRQoL (PCS, SF-6D) than those who received only 1 antibiotic. This could be due to these participants having more severe disease or receiving inappropriate treatment resulting in more prescriptions, thereby resulting in increased patient burden. However, our methodology excluded participants with more severe UTI and asymptomatic bacteriuria, yielding a population with symptomatic uUTI. While we did not exclude participants with concurrent infections, the survey questions were specifically related to their uUTI.
Similarly, when stratified by clinically appropriate oral antibiotic use, participants who received multiple antibiotics had worse HRQoL (PCS, SF-6D) and a higher level of activity

PLOS ONE
The impact of uncomplicated UTI on daily life, healthcare resource use and costs in US women impairment (WPAI impact on daily activities) than those who received 1 appropriate antibiotic, and a greater mean total direct cost than those who received 1 inappropriate antibiotic.
In terms of treatment satisfaction, we found that participants with recurrent uUTIs who received more than 1 antibiotic were less satisfied with treatment than those with non-recurrent uUTIs treated successfully with 1 antibiotic. These data paralleled other endpoints, i.e., recurrent uUTI and more antibiotics were associated with worse outcomes. High levels of satisfaction associated with single antibiotic therapy have been previously reported [23]. The increased direct uUTI-related costs that we observed with the use of multiple vs. single oral antibiotics could be due to inefficient prescribing. Inappropriate prescription of antibiotics based on drug class and duration of therapy has previously been shown to be prevalent in the treatment of uUTI [24]. Our results, however, suggest that ineffective therapies are being prescribed as patients require multiple antibiotics to resolve their uUTIs. Thus, identification of the most appropriate antibiotic therapy may help to optimize direct uUTI-related costs associated with antibiotic treatment. Use of multiple antibiotics can also increase the risk of antimicrobial resistance developing, which is an increasing problem globally [6], and not consistent with antibiotic stewardship practices [25,26]. E. coli, the predominant uropathogen responsible for uUTI [1], is a common causative pathogen for other diseases and a World Health Organization priority pathogen, identified at critical risk of antimicrobial resistance [6].
The most common healthcare resource used by participants to treat their recent uUTI were primary care physician visits followed by urgent care visits and OB/GYN visits. The majority of total direct costs were due to PCP visits and urgent care visits. Compared with the general population, uUTI had significant impacts on absenteeism and presenteeism, resulting in indirect costs that most directly impact employers, specifically those that provide health insurance to employees (70% of matched sample). Insurers that provide coverage for employers and employers who contract insurers for employer-sponsored healthcare plans should account for indirect costs related to uUTI episodes, in addition to the direct treatment costs.
These findings are consistent with earlier work in women with UTI. For example, a prospective survey of women with UTI in England found similar rates of HRU, with 65% of patients who contacted a healthcare professional going to primary care, 4% attending an emergency department and 14% contacting an out-of-hours service [3]. In accordance with our study, an observational study conducted across multiple countries found that anxiety and depression were the most commonly reported comorbidities among women with uUTIs at baseline [27]. Furthermore, the HRQoL scores (PCS and MCS) reported in our study were similar to those reported in a French study of patients with cystitis or other female genital diseases; with a mean PCS of 45.6 and MCS of 41.5 compared with 46.5 and 40.0 in the current study, respectively [28].
A strength of this study is that results are generalizable to adult women in the US diagnosed with uUTI, and as discussed above are similar to results from other regions. There are, however, a number of study limitations. The main limitation relates to the nature of the data. Selfreport for uUTI carries the innate possibility of recall bias which could affect the results, particularly those regarding out-of-pocket costs and recent treatments. Recall bias could also have allowed for the inclusion of a higher proportion of women with recurrent uUTIs. Additionally, we were not able to capture the rationale behind the decisions to prescribe certain antibiotics, and thus second-line therapies that were selected for appropriate reasons would nevertheless have been classed as inappropriate in our study. We also adjusted the recall period for key instrument measures used in the study. Validated versions of SF-36, WPAI and AIA are based on recall periods of the previous 4 weeks, 7 days and 24 hours, respectively; we used up to 60 days and adjustment to a longer look-back period may have affected the accuracy and validity of these instrument outcomes. We altered the lookback period both to standardize the instruments to a single period and to allow us to capture a large enough patient population, where the shorter time periods would have restricted eligible responders to those who had a uUTI in the previous 24 hours. Additionally, the surveys were only conducted in English which limited the diversity of the population available for the study. Total, direct uUTI-related HRU costs were based on imputation using mean estimates per event type from the 2018 Medical Expenditure Panel Survey. This cost imputation, along with the previously mentioned limitation associated with self-reported HRU, may be factors in the finding from the regression analysis that participants who self-reported using 2 antibiotics for their recent uUTI-related treatment had uUTI-related direct costs roughly double that of participants reporting use of � 3 antibiotics for their recent uUTI. As such, these do not represent actual adjudicated costs, and this should be noted when interpreting the results. Additionally, participants were not excluded for having concurrent other infections and may have erroneously self-reported use of antibiotics for uUTI which were actually used for another condition. A further limitation of this survey is that it is only representative of patients willing to participate, perhaps women with recurrent uUTI, and will therefore not capture the disease burden, perceptions, and unmet needs of those not willing to participate.

Conclusions
This study demonstrates that uUTIs are significantly associated with worse patient-reported outcomes such as daily activities, work productivity and mental HRQoL, and that suboptimal treatment (i.e., use of multiple antibiotics) may play a role. Inadequate treatment response, evident by use of multiple antibiotics to treat a uUTI, was associated with an increase in uUTIrelated costs, including productivity loss. While uUTIs are common, their impact on patients should not be underestimated; appropriate treatment is crucial in preventing adverse impacts on quality-of-life and HRU.