Urinary Tract Infection-Related Mortality Trends in Adults Aged ≥ 25 Years in the United States: A CDC WONDER Analysis from 1999 to 2023

Urinary Tract Infection-Related Mortality Trends in Adults Aged ≥ 25 Years in the United States: A CDC WONDER Analysis from 1999 to 2023 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Urinary Tract Infection-Related Mortality Trends in Adults Aged ≥ 25 Years in the United States: A CDC WONDER Analysis from 1999 to 2023 Muhammad Ali, Noreen Haidar Khan, Ahmed Hassan, Sadia Ghafur, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7811606/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Urinary tract infections (UTI) are prevalent among adults in the United States, yet their demographic and regional mortality trends are unexplored. Uncovering national trends in UTI-related mortality among adults can highlight demographic and regional disparities, guiding research efforts aimed at improving clinical care and promoting better patient outcomes. This descriptive analysis reveals mortality trends and disparities among U.S. adults aged ≥ 25 years with UTI from 1999 to 2023. Methods The Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) Multiple Cause-of-Death dataset (1999–2023) was analyzed for mortality trends in adults aged ≥ 25 years using ICD-10 codes for UTI. Crude mortality rates (CMRs) and age-adjusted mortality rates (AAMRs) per 100,000 were extracted by year, sex/gender, age, race/ethnicity, census region, state, and urban–rural divisions. Annual percent change (APC) and average annual percent change (AAPC) in AAMRs were calculated using the permutation test and the parametric method via Jointpoint regression software with corresponding 95% confidence intervals (95% CI). Results A total of 1,037,471 UTI-related deaths occurred among U.S. adults from 1999 to 2023, mainly in medical facilities (61.82%). Initially, AAMRs decreased from 20.04 in 1999 to 16.86 in 2018 (APC: -0.77; 95% CI: -1.21 to -0.45), followed by increasing rates until 19.38 in 2023 (APC: 3.57; 95% CI: 1.57 to 8.02). The highest mortality burden in terms of average AAMR was noted among older adults, women, non-Hispanic (NH) Black/African Americans, residents of the Southern census region, Tennessee, Oklahoma, and those in rural areas. Leading causes of death among UTI decedents shifted during the COVID-19 pandemic, with COVID-19 emerging as a major contributing cause. Conclusion UTI-related mortality among U.S. adults aged ≥ 25 years showed shifting trends and marked demographic and regional disparities. Older adults, women, NH Black/African Americans, rural residents, and those in the Southern Regions and States bore the greatest burden. Leading causes of UTI-associated deaths shifted during the pandemic, with COVID-19 emerging as a significant factor. These findings illustrate the urgency for targeted interventions and informed healthcare policies to address UTI-related mortality burden, especially in at-risk communities. Urinary Tract Infections (UTI) Mortality Trends CDC Wonder Population Health Healthcare Epidemiology Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 1.0 BACKGROUND Urinary tract infections (UTIs) remain prevalent as one of the most common bacterial infections worldwide, ranging from mild lower urinary tract infections, such as cystitis, to severe and potentially fatal urosepsis if left untreated [ 1 ]. Although the majority of UTIs are treated effectively with appropriate antimicrobial therapy, complicated UTIs, especially in high-risk groups such as geriatrics, the immunocompromised, and those with indwelling urinary catheters, have substantially increased morbidity and mortality [ 2 ]. Mortality from UTI is often a result of systemic complications downstream of the localized urinary infection, such as septic shock, multiorgan failure, and worsening underlying comorbidities [ 3 ]. Recent research reports in-hospital mortality rates between 2.8% and 3.4%, mainly attributed to complicated UTIs, and catheter-associated UTIs (CAUTI). These also account for majority of adverse outcomes, such as prolonged length of in-hospital stay, and increased rates of in-hospital mortality [ 2 ]. The management of UTI is further complicated by increasing levels of antimicrobial resistance, as extended-spectrum beta-lactamase producing bacteria such as Escherichia coli and Klebsiella pneumoniae double the risk of death compared to the drug-susceptible comparison. [ 5 ]. Early surveillance in the United States (U.S) shows concerning resistance rates to common empiric therapy, with 38.5% resistance to ampicillin and 18% to trimethoprim-sulfamethoxazole [ 5 ]. There is significant economic burden associated with UTIs. From 2006 to 2009, there were over 10 million emergency department visits associated with UTIs, resulting in more than $ 2 billion (U.S. Dollars) in direct costs [ 1 ]. UTIs also disproportionately impact the elderly population, potentially due to age-related immune health decline, higher number of comorbidities, and high rates of catheter usage. In nursing homes and long-term care settings, infections are often polymicrobial and have high rates of associated catheter bacteriuria, which can result in urosepsis [ 6 ]. UTIs can ascend from the urethra to the bladder and kidneys while disrupting the mucosal immune defenses; and in extreme cases, severe bacteremia may develop [ 3 ]. The procedure of catheterization heightens these risks by allowing biofilm formation and long-term bacterial colonization, usually by multidrug-resistant organisms [ 7 ]. Additionally, from 2008 to 2017, outpatient visits and telemedicine encounters for UTIs increased, particularly in older adults. However, urine culture confirmations reduced during this time, while antibiotic prescriptions remained high, raising concerns about overdiagnosis, inappropriate antibiotic prescribing, and future resistance-associated mortality [ 4 , 8 ]. Despite the prevalence of UTIs, comprehensive stratified analyses of mortality trends among a wide range of age groups within the adult population in the U.S are limited. Our descriptive retrospective analysis describes mortality patterns among U.S. adults aged ≥ 25 years with a UTI from 1999 to 2023. Evaluating demographic and regional trends and disparities in UTI-related mortality helps offer guidance on public health policy implications, promoting the development of targeted interventions, and enhancing health equity for at-risk communities. 2.0 METHODS 2.1 Study Setting and Population This population-based, retrospective analysis evaluates UTI–related mortality among adult U.S residents aged ≥ 25 years from 1999 to 2023. Mortality data were accessed from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) using the Multiple Cause-of-Death dataset [ 9 ]. UTI-related deaths were identified using the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) [ 10 ]. Specified ICD-10 codes used for UTI, and the leading causes of UTI-associated deaths are listed in Supplemental Table 1. The Multiple Cause-of-Death dataset of death certificates was studied to select UTI-related deaths, which were determined to be those with UTI reported anywhere on the death certificate, either as a contributing or underlying cause of death (UCD). A sensitivity analysis was also conducted using UTI as the UCD. To examine the impact of COVID-19 on UTI-associated mortality, an additional analysis was conducted, where COVID-19 (U07.1) was listed as the UCD, and UTI was listed as a contributor from 2020 to 2023. The impact of COVID-19 was further assessed by extracting state-level data and the leading UTI-associated causes of death in a pre-COVID-19 time period (1999–2019) and another COVID-19 time period (2020–2023). Since a publicly available de-identified government-issued public use dataset was utilized, institutional review board approval was not required. This study follows the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines for observational studies [ 11 ]. 2.2 Data Extraction Results were stratified by year, place of death, age group, sex/gender, race/ethnicity, state, urban-rural classification, U.S. census region, and the leading underlying causes of UTI-associated deaths. Location of death was defined as medical facilities (inpatient, outpatient, emergency room, death on arrival, or status unknown), the decedent’s home, hospice, nursing home/long-term care facility, and place of death unknown/other. Age groups were defined as young adults (25–44 years), middle-aged adults (45–64 years), and older adults (≥ 65 years) to capture variation in UTI-related mortality risk across a broad spectrum of adulthood. Race/ethnicity was grouped into non-Hispanic (NH) White, NH Black/African American, Hispanic/Latino, NH Asian/Pacific Islander, and NH American Indian/Alaska Native. This information relies on reported data on death certificates and has been used in previous analyses of the CDC WONDER database [ 12 ]. The National Center for Health Statistics Urban-Rural Classification was used to classify the population into urban (large metropolitan area [population ≥ 1 million], medium/small metropolitan area [population 50,000-999,999]) and rural (population < 50,000) counties per the 2013 U.S. census classification [ 13 ]. U.S. census regions were grouped into the Northeast, the Midwest, the South, and the West according to the U.S. Census Bureau definitions [ 14 ]. 2.3 Statistical Analysis We computed the crude mortality rates (CMRs) and age-adjusted mortality rates (AAMRs) per 100,000 population by year, sex/gender, race/ethnicity, U.S. census region, state, and 2013 urbanization status with 95% confidence intervals to analyze national trends in UTI-related mortality among the adult population. The 2000 US population served as the baseline for AAMR standardization [ 15 ]. The number of deaths from UTI was divided by the corresponding US population for that year to determine the CMR. To determine national annual mortality trends, the Joinpoint regression program (Joinpoint V 5.2.0.0, National Cancer Institute) was used to determine annual percent change (APC) and average annual percent change (AAPC) in AAMRs via permutation test and the parametric method with corresponding 95% confidence intervals (95% CI) [ 16 ]. The Joinpoint Regression Model detects statistically significant changes by fitting log-linear regression models whenever temporal variation occurs. APCs were thought to increase or decrease if the slope describing the shift in mortality differed from zero using 2-tailed t-testing, with a value of p < 0.05 determining statistical significance. 3.0 RESULTS A total of 1,037,471 UTI-related deaths occurred among adults aged ≥ 25 years from 1999 to 2023 in the United States. Most deaths occurred in medical facilities (61.82%), followed by nursing home/long-term care facilities (21.83%), the decedent’s home (8.97%), hospices (4.72%), and other/place of death unknown (2.66%) (Fig. 1 ; Supplemental Table 2). 3.1 Annual Trends for UTI-Related AAMR The average Overall AAMR from 1999 to 2023 was 18.70. Overall AAMRs initially decreased from 20.04 in 1999 to 16.86 in 2018 (APC: -0.77; 95% CI: -1.21 to -0.45), followed by increasing rates until 19.38 in 2023 (APC: 3.57; 95% CI: 1.57 to 8.02). In summary, overall AAMRs remained statistically stable from 1999 to 2023 in terms of AAPC (Fig. 2 ; Supplemental Tables 3 and 4). 3.2 Annual Trends for UTI-Related AAMR Stratified by Sex Women had a greater number of deaths (659,018) compared to men (378,453), as well as a higher average AAMR (average AAMR women: 19.57, average AAMR men: 17.44). AAMRs for women initially decreased from 20.40 in 1999 to 16.89 in 2019 (APC: -0.54; 95% CI: -1.00 to -0.25), followed by increasing rates until 20.18 in 2023 (APC: 4.03; 95% CI: 1.25 to 9.96). Men had their AAMRs remain statistically stable throughout the years in terms of APC. Both women and men had their AAMRs remain statistically stable in terms of AAPC from 1999 to 2023 (Fig. 2 ; Supplemental Tables 2,3, and 4). 3.3 Annual trends for UTI-Related AAMR Stratified by Race Non-Hispanic (NH) Whites had the greatest number of deaths (842,945), followed by NH Black/African Americans (109,063), Hispanic/Latinos (56,690), NH Asian/Pacific Islanders (19,802), and NH American Indian/Alaska Natives (5,966). NH Black/African Americans had the highest average AAMR (23.68), followed by NH American Indian/Alaska Natives (21.81), NH White individuals (18.83), Hispanic/Latinos (14.65), and NH Asian/Pacific Islanders (10.13). NH Black/African Americans initially had their AAMRs decrease from 30.43 in 1999 to 18.70 in 2018 (APC: -2.67; 95% CI: -3.31 to -1.96), followed by statistically stable rates afterwards until 2023. NH American Indian/Alaska Natives initially had their AAMRs increase from 16.53 in 1999 to 25.46 in 2011 (APC: 2.21; 95% CI: 0.84 to 5.02), followed by decreasing rates to 20.03 in 2018 (APC: -3.33; 95% CI: -10.89 to -0.76). Mortality rates then increased afterwards from 2018 to 28.91 in 2021 (APC: 13.88; 95% CI: 6.40 to 19.23), followed finally by decreasing rates until 22.92 in 2023 (APC: -9.64; 95% CI: -16.68 to -0.60). AAMRs for NH Whites initially decreased from 19.38 in 1999 to 17.54 in 2018 (APC: -0.39; 95% CI: -0.80 to -0.08), followed by increasing rates until 20.44 in 2023 (APC: 3.93; 95% CI: 1.97 to 8.22). AAMRs for Hispanic/Latinos similarly initially decreased from 16.53 in 1999 to 12.55 in 2018 (APC: -1.32; 95% CI: -2.14 to -0.79), followed by increasing rates until 14.72 in 2023 (APC: 3.86; 95% CI: 1.21 to 10.59). AAMRs for NH Asian/Pacific Islanders were initially statistically stable from 1999 to 2008, followed by decreasing mortality rates from 12.14 in 2008 to 7.50 in 2018 (APC: -3.81; 95% CI: -5.61 to -2.90), and lastly increasing rates until 9.34 in 2023 (APC: 4.39; 95% CI: 2.26 to 7.48). In summary, AAMRs for NH American Indian/Alaska Natives and NH Whites both had increasing rates from 1999 to 2023 (AAPC NH American Indian/Alaska Native: 0.89; 95% CI: 0.29 to 1.70, AAPC White: 0.49; 95% CI: 0.20 to 0.78). AAMRs for NH Black/African Americans had decreasing rates (AAPC: -1.49; 95% CI: -1.93 to -1.02), while NH Asian/Pacific Islanders and Hispanic/Latinos had statistically stable rates in terms of AAPC from 1999 to 2023 (Fig. 3 ; Supplemental Tables 2, 4, and 5). 3.4 Annual Trends for UTI-Related AAMR Stratified by Age Group The number of deaths increased with age as older adults had the highest number of deaths (939,283), followed by middle-aged adults (86,593) and young adults (11,595). Similarly, average AAMRs also increased with age, as older adults had the highest average AAMR (87.16), followed by middle-aged adults (4.08) and younger adults (0.58). Older adults initially had their AAMRs decrease from 95.76 in 1999 to 74.16 in 2019 (APC: -0.93; 95% CI: -1.30 to -0.65), followed by increasing mortality rates until 88.12 in 2023 (APC: 4.38; 95% CI: 1.77 to 10.01). AAMRs for middle-aged adults initially decreased from 3.21 in 1999 to 4.39 in 2018 (APC: 1.65; 95% CI: 1.17 to 2.04) and to 5.99 in 2021 (APC: 10.98; 95% CI: 7.03 to 13.08). Mortality rates decreased afterwards until 2023. AAMRs for younger adults were initially statistically stable from 1999 to 2018, followed by increasing mortality rates from 0.57 in 2018 to 0.78 in 2023 (APC: 7.84; 95% CI: 3.68 to 18.22). In summary, AAMRs for younger adults and middle-aged adults increased from 1999 to 2023 (AAPC younger adults: 2.83; 95% CI: 2.12 to 3.47, AAPC middle-aged adults: 2.13; 95% CI: 1.68 to 2.43). AAMRs for older adults remained statistically stable in terms of AAPC from 1999 to 2023 (Fig. 4 ; Supplemental Tables 2, 4, and 6). 3.5 Annual Trends for UTI-Related AAMR Stratified by Urbanization (1999–2020) From 1999 to 2020, urban areas had a greater number of deaths (695,875) compared to rural areas (180,436), while the average AAMR was higher in rural areas than in urban areas (average AAMR rural: 21.35, average AAMR urban: 17.90). Urban areas had their AAMRs decrease from 19.75 in 1999 to 18.07 in 2023 (AAPC: -0.59; 95% CI: -1.03 to -0.32). There were no statistically significant increases or decreases throughout the years concerning APCs for urban or rural areas, and similarly, statistically significant AAPC changes from 1999 to 2020 for rural areas (Fig. 5 ; Supplemental Tables 2, 4, and 7). 3.6 Annual trends for UTI-Related AAMR Stratified by U.S. Census Region The South had the greatest number of deaths (412,511), followed by the Midwest (223,820), the West (220,108), and the Northeast (181,032). The highest average AAMR was noted in the South (20.75), followed by the West (18.66), the Midwest (17.69), and the Northeast (16.18). The South had its AAMRs initially decrease from 22.87 in 1999 to 18.81 in 2018 (AAPC: -0.99; 95% CI: -1.38 to -0.66), followed by statistically stable rates until 2023. AAMRs for the West were initially statistically stable from 1999 to 2008, followed by decreasing mortality rates from 19.48 in 2008 to 15.54 in 2019 (APC: -1.47; 95% CI: -4.49 to -0.88) and finally increasing rates until 19.01 in 2023 (APC: 5.15; 95% CI: 2.57 to 9.72). The Midwest had its AAMRs initially decrease from 18.88 in 1999 to 16.06 in 2018 (APC: -0.61; 95% CI: -1.72 to -0.20), followed by increasing mortality rates until 18.03 in 2023 (APC: 3.18; 95% CI: 0.45 to 9.90). AAMRs for the Northeast were initially statistically stable from 1999 to 2011, followed by decreasing mortality rates from 17.12 in 2011 to 14.12 in 2018 (APC: -2.41; 95% CI: -6.07 to -1.20), and finally by increasing rates until 16.22 in 2023 (APC: 4.03; 95% CI: 1.90 to 7.93). In summary, AAMRs for all U.S. census regions remained statistically stable from 1999 to 2023, as indicated by AAPCs (Fig. 6 ; Supplemental Tables 2, 4, and 8). 3.7 UTI-Related Deaths and AAMR Stratified by State From 1999 to 2023, California had the highest number of deaths at 118,860, accounting for 11.46% of statewide deaths, while Alaska had the lowest number of deaths at 1,080, which accounted for 0.10%. States in the top 90th percentile of deaths included California, Florida, New York, Pennsylvania, and Texas. In contrast, states in the bottom 10th percentile of deaths were Alaska, North Dakota, Vermont, Wyoming, and the District of Columbia. From 1999 to 2019, AAMRs ranged from 10.40 in Hawaii to 29.18 in Tennessee. States within the top 90th percentile of AAMR in this time frame included Mississippi, Oklahoma, South Carolina, Tennessee, and West Virginia. States in the bottom 10th percentile of AAMRs were Arizona, Florida, Hawaii, Minnesota, and Nevada. From 2020 to 2023, AAMRs extended from 9.46 in Hawaii to 47.49 in Oklahoma. States in the top 90th percentile of AAMR in this time period included Kentucky, Mississippi, Oklahoma, South Dakota, and West Virginia. States in the bottom 10th percentile of AAMR were Arizona, Connecticut, Hawaii, Maine, and New York (Supplemental Table 9, Supplemental Figs. 1,2, and 3). 3.8 Leading Underlying Causes of UTI-Associated Deaths by Number of Deaths and AAMR From 1999 to 2019, the top 5 leading underlying causes of UTI-associated death included diseases of the heart, malignant neoplasms, cerebrovascular diseases, Alzheimer’s disease, and influenza and pneumonia. Diseases of the heart caused 79,718 deaths and had an AAMR of 1.77. Malignant neoplasms resulted in 63,767 deaths and had an AAMR of 1.43. Cerebrovascular diseases resulted in 42,428 deaths with an AAMR of 0.94. Alzheimer’s disease led to 41,022 deaths with an AAMR of 0.91. Influenza and pneumonia caused 23,080 deaths along with an AAMR of 0.50. From 2020 to 2023, the top 5 leading underlying causes of deaths were malignant neoplasms, diseases of the heart, COVID-19, cerebrovascular disease, and Alzheimer's disease. Malignant neoplasms caused 19,379 deaths and had an AAMR of 1.76. Diseases of the heart resulted in 17,345 deaths and had an AAMR of 1.64. COVID-19 caused 11,519 deaths along with an AAMR of 1.09. Cerebrovascular disease resulted in 10,306 deaths and had an AAMR of 0.95. Alzheimer’s disease led to 8,791 deaths with an AAMR of 0.84 (Supplemental Tables 10 and 11; Supplemental Figs. 4, 5, 6, and 7). 3.9 Annual Trends in AAMR when UTI is Listed as UCD When UTI was listed as the UCD as part of a sensitivity analysis, 325,917 deaths occurred with an average AAMR of 6.01. AAMRs initially were statistically stable from 1999 to 2006, 2006 to 2009, and 2009 to 2019. Mortality rates then increased from 4.46 in 2019 to 5.15 in 2023 (APC: 3.38; 95% CI: 0.13 to 9.39). In summary, AAMRs decreased from 8.17 in 1999 to 5.15 in 2023 (AAPC: -1.56; 95% CI: -2.01 to -1.17) (Fig. 7 ; Supplemental Table 12). 3.10 Annual Trends in AAMR in COVID-related mortality in adults with UTI (2020–2023) COVID-19-related mortality in adults with UTI resulted in 11,519 deaths and had an average AAMR of 1.08 from 2020 to 2023. AAMRs were statistically stable from 2020 until 2023 (Fig. 8 ; Supplemental Table 13). 4.0 DISCUSSION Our 25-year analysis of trends in mortality data for UTI in adults from CDC WONDER denotes several important findings. Firstly, we observed that overall AAMR was divided in a bi-phasic manner. Secondly, women exhibited a higher average AAMR than men. Stratifying by race/ethnicity, we observed the highest AAMR in NH Black/African Americans, followed by NH American Indian/Alaska Natives, NH Whites, Hispanic/Latinos, and finally NH Asian/Pacific Islanders. Additionally, the mortality burden was highest among older adults compared to other age groups in terms of total deaths and AAMR. Regionally, urban areas reported greater total deaths, despite rural areas exhibiting a higher average AAMR. Mortality was highest in the Southern Region of the United States, followed by the West, the Midwest, and the Northeast. In accordance with the highest number of deaths, states in the top 90th percentile of deaths included California, Florida, New York, Pennsylvania, and Texas; in contrast, states in the bottom 10th percentile of deaths were Alaska, North Dakota, Vermont, Wyoming, and the District of Columbia. Between 1999 and 2019, the leading causes of death in adults with UTI were diseases of the heart, malignant neoplasms, cerebrovascular diseases, Alzheimer’s disease, and influenza and pneumonia. Between 2020 and 2023, the leading causes shifted to malignant neoplasms, diseases of the heart, COVID-19, cerebrovascular disease, and Alzheimer's disease. We also observed an overall decrease in AAMR when UTI was listed as a leading cause of death. Lastly, the annual trend in AAMR in COVID-related mortality in adults with UTI was statistically stable throughout the study period. Overall, these findings are pertinent and carry significant implications for future healthcare policies. The overall AAMR trend was divided into two distinct phases, with a decrease in AAMR observed from 1999 to 2018. This trend can be attributed to a plethora of reasons. Firstly, previous studies show that UTIs are one of the leading causes of sepsis in hospitalized patients [ 17 ]. The Introduction of National and International initiatives, such as the Surviving Sepsis Campaign (SSC), led to reduced deaths from infections that may progress to sepsis/urosepsis [ 18 ]. This has been documented despite the increasing incidence of sepsis [ 19 ]. Another factor that may be contributing to this trend could be the improved prevention of CAUTI and reduced catheter use [ 20 ]. Nurse-led removal protocols and programs limiting unnecessary indwelling catheters cut the number and severity of healthcare-associated UTIs [ 21 ]. During the remainder of the study period till 2023, we noticed an increase in AAMR. This may be attributed to the disruption of healthcare services due to the COVID-19 pandemic [ 22 ]. Similarly, rising antimicrobial resistance, particularly in Gram-negative pathogens - as they are the predominant causative agents - indicates that empiric treatment is more likely to fail and may require more expensive/aggressive antimicrobial therapy, which may not be accessible to all patients or medical centers [ 23 ]. It is important to mention that these explanations are purely speculative, and there is a need for more granular and mechanistic studies to establish causative factors behind this mortality pattern. Evaluation of AAMR in UTI-related mortality demonstrated that women exhibit an overall higher mortality than men. The reasons for this may be multifactorial. Women have a higher incidence of UTI as compared to men, mainly due to female lower urinary tract anatomy and its proximity to the reproductive organs [ 24 ]. Compared to men, women have a shorter urethra, which reduces the distance for bacterial ingress. Similarly, the proximity of the anus allows colonization of the distal urinary tract and reproductive organs by Escherichia coli, Enterococcus faecalis, and the Streptococcus species [ 24 ]. Post menopausal vaginas are more susceptible to colonization by other bacteria due to glycogen deficiency and decreasing estrogen levels, which contribute to a reduction in lactic acid bacteria and vaginal atrophy [ 24 ]. An increasing number of Cesarean sections and perioperative catheterizations is yet another important risk factor for UTIs in pregnant women [ 24 ]. However, further research is required to evaluate potential disparities in UTI treatment between men and women. We observed significant variations in mortality rates in Ethnic groups, mirroring the racial inequalities in the United States. Minority Racial groups, such as the NH Black/African Americans and NH American Indian/Alaska Natives, had the highest AAMRs compared to other racial groups. It is a well-known fact that NH Black/African American patients have higher rates of hypertension, diabetes, and chronic kidney disease, which are strong risk factors for severe UTIs and lead to worse outcomes [ 25 ]. Another contributing factor may be that racial minorities like Blacks and Native Americans are less likely to be insured compared to other groups [ 26 ]. This lack of insurance coverage means that these subpopulations are less likely to afford treatments and more likely to receive care in sub-optimal settings. In contrast, Asian Americans, who have a higher median household income and educational attainment than national averages showed lower AAMR [ 27 ]. The higher income in this subpopulation may ensure access to timely care, better health literacy, and earlier treatment of infections. Lastly, many Asian Americans are first-generation immigrants; these immigrant populations are suggested to have a health advantage (Healthy Immigrant Effect) over domestic-born residents [ 28 ]. Trend-wise, the overall AAMR for both NH Whites and NH American Indian/Alaska Natives increased, while the NH Black/African Americans had a decreasing AAMR during the study period. This steep decline among NH Black/African Americans from a very high baseline may reflect a greater potential for improvement as broader public health initiatives (e.g., SSC and CAUTI prevention) began to address the severe systemic gaps in care that initially contributed to this population's disproportionate burden. Our analysis of varying age groups showed that the AAMR was highest among older adults. Older adults have limited physiological reserve, such as immunosenescence and impaired renal function [ 6 ]. The aging process leads to frailty, which is defined as a state of vulnerability due to poor resolution of homeostasis after a stressor event such as systemic stress imposed by UTI [ 29 , 30 ]. Worryingly, AAMRs among young and middle-aged adults increased throughout the study period. This may be attributed to risky sexual behaviors such as having multiple partners and inconsistent condom use, which can introduce bacteria to the urinary tract, thus increasing the risk of UTI. Similarly, inadequate personal hygiene practices can further facilitate bacterial colonization and infection [ 31 , 32 ]. Recognizing this heightened vulnerability in this subgroup underscores the need for targeted public health strategies and better resource allocation to reduce mortality in older adults. Geographically, the AAMR showed variations, with the highest AAMR observed in the South and the lowest AAMR observed in the Northeastern region of the United States. This higher AAMR in the south can be attributed to a variety of socioeconomic, demographic, and environmental factors. It is well-documented that individuals from the South are more likely to experience medical financial hardships from a lack of insurance coverage [ 33 ]. Ultimately, individuals in these regions are less likely to access routine healthcare services. This delay can result in poor UTI management, leading to complications and ultimately mortality. Another potential contributing factor may be the higher prevalence of comorbidities in these regions, which increases the risk of complications [ 34 ]. Among States, the AAMR was divided into two time periods (pre-COVID-19 and COVID-19 time frames). From 1999 to 2019 (pre-COVID-19 time frame), the states in the top 90th percentile included Mississippi, Oklahoma, South Carolina, Tennessee, and West Virginia. Meanwhile, States in the bottom 10th percentile of AAMRs were Arizona, Florida, Hawaii, Minnesota, and Nevada. From 2020 to 2023 (COVID-19 time frame), the states in the top 90th percentile included Kentucky, Mississippi, Oklahoma, South Dakota, and West Virginia. States in the bottom 10th percentile of AAMR were Arizona, Connecticut, Hawaii, Maine, and New York. Most states in the top 90th percentile across both time frames are geographically located in the Southern region of the United States, and this is consistent with our above discussion. Stratification by urbanization showed that the rural areas exhibited a higher AAMR, even though the number of deaths was higher in urban areas. These findings demonstrate that socioeconomic status is an essential factor in UTI-related outcomes, including mortality. In our analysis of UTI and associated causes of death, we noticed that during the pre-COVID-19 time frame, the leading associated causes of death were diseases of the heart, malignant neoplasms, cerebrovascular diseases, Alzheimer’s disease, and influenza and pneumonia. There was a slight variation in this trend during the COVID-19 period, with malignant neoplasms displacing diseases of the heart as the leading underlying cause of death, followed by diseases of the heart, COVID-19, cerebrovascular disease, and Alzheimer's disease. This displacement could likely be due to the impact of COVID-19 on cancer care, leading to delays in identifying new cancers and delivery of treatment, thus resulting in a higher mortality rate [ 35 ]. Between 2019 and 2023, a universal increase in UTI-related mortality was observed across all demographics. This period coincides with the COVID-19 pandemic. Hospitals with high COVID-19 admission rates reported increased inpatient occupancy and length of stays and a decline in hospital quality [ 36 ]. These factors lead to delayed diagnosis or treatment, contributing to elevated mortality. The extension of in-hospital stays during the COVID-19 pandemic likely contributed to a rise in CAUTI, as prolonged hospitalizations often involved extended use of indwelling catheters, which are major risk factors for UTI [ 37 ]. These findings have crucial implications for public health policies. They underscore the need for comprehensive strategies aimed at preventing and managing UTIs. This includes the integration of advancements in early diagnostics methods and timely clinical interventions. Furthermore, we need to address disparities in healthcare access, support community-based initiatives, and provide culturally appropriate health education, which may contribute to reducing racial and regional differences in mortality. 4.1 Limitations: Several limitations need to be considered. This data is based on national death certificate data and is thus purely observational, preventing causal inferences. This temporal ambiguity limits causal interference and impacts clinical interpretation. Secondly, the data is subject to underreporting or misclassification, which may lead to the omission of UTI as a cause of death, due to known inconsistencies in diagnostic coding practices. This may elevate or diminish mortality rates, which may distort our interpretation. Mortality data tends to lack clinical granularity, such as information on comorbidities and treatment history, making it difficult to establish whether the mortality was primarily caused by UTI or other clinical factors. Lastly, extracting AAMRs for urbanization was only possible using CDC WONDER from 1999 to 2020. 5.0 Conclusion Our 25-year analysis of UTI mortality trends in adults aged 25 and older revealed notable disparities by sex, race, age, and geography. Overall, AAMR was divided into two distinct phases. Higher AAMR was observed in Women, adults aged 65 years or older, NH Blacks, Rural areas, and the Southern Region of the United States. Leading causes of death in UTI patients shifted during the COVID-19 pandemic, with malignant neoplasms surpassing heart disease, and COVID-19 emerging as a significant contributor. These findings highlight the need for targeted public health interventions and informed healthcare policies to address demographic and regional disparities in UTI-related mortality. Abbreviations AAMR Age–adjusted Mortality Rate AAPC Average Annual Percent Change APC Annual Percent Change CAUTI Catheter–Associated Urinary Tract Infection CDC WONDER Centers for Disease Control and Prevention Wide–Ranging Online Data for Epidemiologic Research CMR Crude Mortality Rate ICD 10–International Statistical Classification of Disease and Related Health Problems, 10th Revision NH non–Hispanic SSC Surviving Sepsis Campaign U.S United States UCD Underlying Cause of Death UTI Urinary Tract Infection Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Funding Not applicable. Author Contribution **MA** : conceptualization, project administration, supervision, validation, investigation, methodology, writing, writing – original draft, writing – review and editing; **NHK** : investigation, methodology, writing – original draft, writing – review and editing; **AH** : investigation, methodology, writing – original draft, writing – review and editing; **SG** : investigation, methodology, writing – original draft, writing – review and editing; **HK** : investigation, methodology, writing – original draft, writing – review and editing; **MSA** : investigation, methodology, writing – original draft, writing – review and editing; **IA** : methodology, writing – original draft, writing – review and editing; **AR** : investigation, methodology, writing – original draft, writing – review and editing; **AN** : investigation, methodology, writing – original draft, writing – review and editing; **KAK** : writing – review and editing; **MAS** : writing – review and editing; **MAJ** : writing – review and editing; **FA** : writing – review and editing. All authors read and approved the final manuscript. Acknowledgements Not applicable. Data Availability The datasets generated and/or analysed during the current study is publicly available, de-identified data from the CDC WONDER Multiple Cause-of-Death database. Available at: [https://wonder.cdc.gov/mcd.html](https:/wonder.cdc.gov/mcd.html) References Puca E. Urinary tract infection in adults. Clin Microbiol. 2014;3(6):100–20. 10.4172/2327-5073.1000e120 . Zilberberg MD, Nathanson BH, Sulham K, Fan W, Shorr AF. Descriptive epidemiology and outcomes of hospitalizations with complicated urinary tract infections: results from the U.S. nationwide inpatient sample. BMC Infect Dis. 2022;22(1):476. 10.1186/s12879-022-07383-9 . Daniels KR, Lee GC, Frei CR. Trends in catheter-associated urinary tract infections among a national cohort of hospitalized adults, 2001–2010. Am J Infect Control. 2014;42(1):17–22. 10.1016/j.ajic.2013.06.021 . Yadav K, Weissman JS, Fine AM, et al. 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11:58:28","extension":"html","order_by":21,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":120070,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7811606/v1/4fd97e975cc4e0a0e8c721ba.html"},{"id":96285592,"identity":"2d7626f0-ee63-413e-bfa5-9685c3b5e445","added_by":"auto","created_at":"2025-11-19 11:58:27","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":416692,"visible":true,"origin":"","legend":"\u003cp\u003ePercent Total of UTI-Related Deaths by Location of Death, 1999 to 2023.\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-7811606/v1/b7b117f3e4cd622d4eb57636.png"},{"id":96285594,"identity":"942b9022-d86b-4ee9-ac48-59a1dc071841","added_by":"auto","created_at":"2025-11-19 11:58:27","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":76577,"visible":true,"origin":"","legend":"\u003cp\u003eTrends in UTI-Related Age-Adjusted Mortality Rate, Stratified by Sex, 1999 to 2023.\u003c/p\u003e\n\u003cp\u003e*Indicates APC is significantly different from 0\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-7811606/v1/959cb67caa2d5794e9b0e97b.png"},{"id":96285598,"identity":"091b3d34-a493-4d4d-a9a0-733de8ed2839","added_by":"auto","created_at":"2025-11-19 11:58:27","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":137155,"visible":true,"origin":"","legend":"\u003cp\u003eTrends in UTI-Related Age-Adjusted Mortality Rate, Stratified by Race, 1999 to 2023.\u003c/p\u003e\n\u003cp\u003eNH = non-Hispanic\u003c/p\u003e\n\u003cp\u003e*Indicates APC is significantly different from 0\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-7811606/v1/afb8a94f59891634d0fe6970.png"},{"id":96364981,"identity":"3f071c83-76a5-4d31-8b9c-1f70e1df1bc8","added_by":"auto","created_at":"2025-11-20 10:09:52","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":79817,"visible":true,"origin":"","legend":"\u003cp\u003eTrends in UTI-related Age-Adjusted Mortality Rate, Stratified by Age Group, 1999 to 2023.\u003c/p\u003e\n\u003cp\u003e*Indicates APC is significantly different from 0\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-7811606/v1/55b8c02e79cdf89385c78569.png"},{"id":96285603,"identity":"a618b18e-2afa-4b7b-a358-f6e839c69c86","added_by":"auto","created_at":"2025-11-19 11:58:27","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":54766,"visible":true,"origin":"","legend":"\u003cp\u003eTrends in UTI-Related Age-Adjusted Mortality Rate, Stratified by Urbanization, 1999 to 2020.\u003c/p\u003e\n\u003cp\u003e*Indicates APC is significantly different from 0\u003c/p\u003e","description":"","filename":"image5.png","url":"https://assets-eu.researchsquare.com/files/rs-7811606/v1/fa71581a69c5bf9942bba05f.png"},{"id":96363937,"identity":"7d89dc0d-2b88-46b0-856e-5d887c334b63","added_by":"auto","created_at":"2025-11-20 10:08:28","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":107513,"visible":true,"origin":"","legend":"\u003cp\u003eTrends in UTI-related Age-Adjusted Mortality Rate, Stratified by Census Region, 1999 to 2023.\u003c/p\u003e\n\u003cp\u003e*Indicates APC is significantly different from 0\u003c/p\u003e","description":"","filename":"image6.png","url":"https://assets-eu.researchsquare.com/files/rs-7811606/v1/a77a4b3354f3b6d62a83c00d.png"},{"id":96364958,"identity":"08c181c0-99b2-4fcf-b2e9-8ff118d3ed2b","added_by":"auto","created_at":"2025-11-20 10:09:51","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":44170,"visible":true,"origin":"","legend":"\u003cp\u003eAge-Adjusted Mortality Rate when UTI is the Underlying Cause of Death, 1999 to 2023.\u003c/p\u003e\n\u003cp\u003e*Indicates APC is significantly different from 0\u003c/p\u003e","description":"","filename":"image7.png","url":"https://assets-eu.researchsquare.com/files/rs-7811606/v1/001ba758ae55545a2ec4005c.png"},{"id":96285595,"identity":"afaa9ea3-2814-41c1-87ec-acad97f22646","added_by":"auto","created_at":"2025-11-19 11:58:27","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":32490,"visible":true,"origin":"","legend":"\u003cp\u003eAge-Adjusted Mortality Rate when COVID-19 is the Underlying Cause of Death and UTI is a Contributor, 2020 to 2023.\u003c/p\u003e","description":"","filename":"image8.png","url":"https://assets-eu.researchsquare.com/files/rs-7811606/v1/547e0d034728c7d1f3f4189f.png"},{"id":106971794,"identity":"e8bffddc-541d-44aa-81a2-89157b3c2ad9","added_by":"auto","created_at":"2026-04-15 10:21:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1792793,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7811606/v1/33edee4e-3534-4d97-9723-06ed48b07994.pdf"},{"id":96285623,"identity":"abd169c9-3570-4182-9842-26f893dde1a2","added_by":"auto","created_at":"2025-11-19 11:58:28","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":10866428,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary File 1. Docx\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSupplementary Materials\u003c/p\u003e\n\u003cp\u003eContains supplemental tables and supplemental figures referenced in the manuscript as an additional file\u003c/p\u003e","description":"","filename":"SupplementaryFile1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7811606/v1/7375605769aba44d28550157.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Urinary Tract Infection-Related Mortality Trends in Adults Aged ≥ 25 Years in the United States: A CDC WONDER Analysis from 1999 to 2023","fulltext":[{"header":"1.0 BACKGROUND","content":"\u003cp\u003eUrinary tract infections (UTIs) remain prevalent as one of the most common bacterial infections worldwide, ranging from mild lower urinary tract infections, such as cystitis, to severe and potentially fatal urosepsis if left untreated [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Although the majority of UTIs are treated effectively with appropriate antimicrobial therapy, complicated UTIs, especially in high-risk groups such as geriatrics, the immunocompromised, and those with indwelling urinary catheters, have substantially increased morbidity and mortality [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Mortality from UTI is often a result of systemic complications downstream of the localized urinary infection, such as septic shock, multiorgan failure, and worsening underlying comorbidities [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eRecent research reports in-hospital mortality rates between 2.8% and 3.4%, mainly attributed to complicated UTIs, and catheter-associated UTIs (CAUTI). These also account for majority of adverse outcomes, such as prolonged length of in-hospital stay, and increased rates of in-hospital mortality [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The management of UTI is further complicated by increasing levels of antimicrobial resistance, as extended-spectrum beta-lactamase producing bacteria such as Escherichia coli and Klebsiella pneumoniae double the risk of death compared to the drug-susceptible comparison. [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Early surveillance in the United States (U.S) shows concerning resistance rates to common empiric therapy, with 38.5% resistance to ampicillin and 18% to trimethoprim-sulfamethoxazole [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. There is significant economic burden associated with UTIs.\u003c/p\u003e\u003cp\u003eFrom 2006 to 2009, there were over 10\u0026nbsp;million emergency department visits associated with UTIs, resulting in more than \u003cspan\u003e$\u003c/span\u003e2\u0026nbsp;billion (U.S. Dollars) in direct costs [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. UTIs also disproportionately impact the elderly population, potentially due to age-related immune health decline, higher number of comorbidities, and high rates of catheter usage. In nursing homes and long-term care settings, infections are often polymicrobial and have high rates of associated catheter bacteriuria, which can result in urosepsis [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. UTIs can ascend from the urethra to the bladder and kidneys while disrupting the mucosal immune defenses; and in extreme cases, severe bacteremia may develop [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The procedure of catheterization heightens these risks by allowing biofilm formation and long-term bacterial colonization, usually by multidrug-resistant organisms [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Additionally, from 2008 to 2017, outpatient visits and telemedicine encounters for UTIs increased, particularly in older adults. However, urine culture confirmations reduced during this time, while antibiotic prescriptions remained high, raising concerns about overdiagnosis, inappropriate antibiotic prescribing, and future resistance-associated mortality [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eDespite the prevalence of UTIs, comprehensive stratified analyses of mortality trends among a wide range of age groups within the adult population in the U.S are limited. Our descriptive retrospective analysis describes mortality patterns among U.S. adults aged\u0026thinsp;\u0026ge;\u0026thinsp;25 years with a UTI from 1999 to 2023. Evaluating demographic and regional trends and disparities in UTI-related mortality helps offer guidance on public health policy implications, promoting the development of targeted interventions, and enhancing health equity for at-risk communities.\u003c/p\u003e"},{"header":"2.0 METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Study Setting and Population\u003c/h2\u003e\u003cp\u003eThis population-based, retrospective analysis evaluates UTI\u0026ndash;related mortality among adult U.S residents aged\u0026thinsp;\u0026ge;\u0026thinsp;25 years from 1999 to 2023. Mortality data were accessed from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) using the Multiple Cause-of-Death dataset [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. UTI-related deaths were identified using the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Specified ICD-10 codes used for UTI, and the leading causes of UTI-associated deaths are listed in Supplemental Table\u0026nbsp;1.\u003c/p\u003e\u003cp\u003eThe Multiple Cause-of-Death dataset of death certificates was studied to select UTI-related deaths, which were determined to be those with UTI reported anywhere on the death certificate, either as a contributing or underlying cause of death (UCD). A sensitivity analysis was also conducted using UTI as the UCD. To examine the impact of COVID-19 on UTI-associated mortality, an additional analysis was conducted, where COVID-19 (U07.1) was listed as the UCD, and UTI was listed as a contributor from 2020 to 2023. The impact of COVID-19 was further assessed by extracting state-level data and the leading UTI-associated causes of death in a pre-COVID-19 time period (1999\u0026ndash;2019) and another COVID-19 time period (2020\u0026ndash;2023). Since a publicly available de-identified government-issued public use dataset was utilized, institutional review board approval was not required. This study follows the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines for observational studies [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Data Extraction\u003c/h2\u003e\u003cp\u003eResults were stratified by year, place of death, age group, sex/gender, race/ethnicity, state, urban-rural classification, U.S. census region, and the leading underlying causes of UTI-associated deaths. Location of death was defined as medical facilities (inpatient, outpatient, emergency room, death on arrival, or status unknown), the decedent\u0026rsquo;s home, hospice, nursing home/long-term care facility, and place of death unknown/other. Age groups were defined as young adults (25\u0026ndash;44 years), middle-aged adults (45\u0026ndash;64 years), and older adults (\u0026ge;\u0026thinsp;65 years) to capture variation in UTI-related mortality risk across a broad spectrum of adulthood. Race/ethnicity was grouped into non-Hispanic (NH) White, NH Black/African American, Hispanic/Latino, NH Asian/Pacific Islander, and NH American Indian/Alaska Native. This information relies on reported data on death certificates and has been used in previous analyses of the CDC WONDER database [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The National Center for Health Statistics Urban-Rural Classification was used to classify the population into urban (large metropolitan area [population\u0026thinsp;\u0026ge;\u0026thinsp;1 million], medium/small metropolitan area [population 50,000-999,999]) and rural (population\u0026thinsp;\u0026lt;\u0026thinsp;50,000) counties per the 2013 U.S. census classification [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. U.S. census regions were grouped into the Northeast, the Midwest, the South, and the West according to the U.S. Census Bureau definitions [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Statistical Analysis\u003c/h2\u003e\u003cp\u003eWe computed the crude mortality rates (CMRs) and age-adjusted mortality rates (AAMRs) per 100,000 population by year, sex/gender, race/ethnicity, U.S. census region, state, and 2013 urbanization status with 95% confidence intervals to analyze national trends in UTI-related mortality among the adult population. The 2000 US population served as the baseline for AAMR standardization [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The number of deaths from UTI was divided by the corresponding US population for that year to determine the CMR. To determine national annual mortality trends, the Joinpoint regression program (Joinpoint V 5.2.0.0, National Cancer Institute) was used to determine annual percent change (APC) and average annual percent change (AAPC) in AAMRs via permutation test and the parametric method with corresponding 95% confidence intervals (95% CI) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The Joinpoint Regression Model detects statistically significant changes by fitting log-linear regression models whenever temporal variation occurs. APCs were thought to increase or decrease if the slope describing the shift in mortality differed from zero using 2-tailed t-testing, with a value of p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 determining statistical significance.\u003c/p\u003e\u003c/div\u003e"},{"header":"3.0 RESULTS","content":"\u003cp\u003eA total of 1,037,471 UTI-related deaths occurred among adults aged\u0026thinsp;\u0026ge;\u0026thinsp;25 years from 1999 to 2023 in the United States. Most deaths occurred in medical facilities (61.82%), followed by nursing home/long-term care facilities (21.83%), the decedent\u0026rsquo;s home (8.97%), hospices (4.72%), and other/place of death unknown (2.66%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e; Supplemental Table\u0026nbsp;2).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e3.1 Annual Trends for UTI-Related AAMR\u003c/h2\u003e\u003cp\u003eThe average Overall AAMR from 1999 to 2023 was 18.70. Overall AAMRs initially decreased from 20.04 in 1999 to 16.86 in 2018 (APC: -0.77; 95% CI: -1.21 to -0.45), followed by increasing rates until 19.38 in 2023 (APC: 3.57; 95% CI: 1.57 to 8.02). In summary, overall AAMRs remained statistically stable from 1999 to 2023 in terms of AAPC (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e; Supplemental Tables\u0026nbsp;3 and 4).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e3.2 Annual Trends for UTI-Related AAMR Stratified by Sex\u003c/h2\u003e\u003cp\u003eWomen had a greater number of deaths (659,018) compared to men (378,453), as well as a higher average AAMR (average AAMR women: 19.57, average AAMR men: 17.44).\u003c/p\u003e\u003cp\u003eAAMRs for women initially decreased from 20.40 in 1999 to 16.89 in 2019 (APC: -0.54; 95% CI: -1.00 to -0.25), followed by increasing rates until 20.18 in 2023 (APC: 4.03; 95% CI: 1.25 to 9.96). Men had their AAMRs remain statistically stable throughout the years in terms of APC. Both women and men had their AAMRs remain statistically stable in terms of AAPC from 1999 to 2023 (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e; Supplemental Tables\u0026nbsp;2,3, and 4).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e3.3 Annual trends for UTI-Related AAMR Stratified by Race\u003c/h2\u003e\u003cp\u003eNon-Hispanic (NH) Whites had the greatest number of deaths (842,945), followed by NH Black/African Americans (109,063), Hispanic/Latinos (56,690), NH Asian/Pacific Islanders (19,802), and NH American Indian/Alaska Natives (5,966). NH Black/African Americans had the highest average AAMR (23.68), followed by NH American Indian/Alaska Natives (21.81), NH White individuals (18.83), Hispanic/Latinos (14.65), and NH Asian/Pacific Islanders (10.13).\u003c/p\u003e\u003cp\u003eNH Black/African Americans initially had their AAMRs decrease from 30.43 in 1999 to 18.70 in 2018 (APC: -2.67; 95% CI: -3.31 to -1.96), followed by statistically stable rates afterwards until 2023. NH American Indian/Alaska Natives initially had their AAMRs increase from 16.53 in 1999 to 25.46 in 2011 (APC: 2.21; 95% CI: 0.84 to 5.02), followed by decreasing rates to 20.03 in 2018 (APC: -3.33; 95% CI: -10.89 to -0.76). Mortality rates then increased afterwards from 2018 to 28.91 in 2021 (APC: 13.88; 95% CI: 6.40 to 19.23), followed finally by decreasing rates until 22.92 in 2023 (APC: -9.64; 95% CI: -16.68 to -0.60). AAMRs for NH Whites initially decreased from 19.38 in 1999 to 17.54 in 2018 (APC: -0.39; 95% CI: -0.80 to -0.08), followed by increasing rates until 20.44 in 2023 (APC: 3.93; 95% CI: 1.97 to 8.22). AAMRs for Hispanic/Latinos similarly initially decreased from 16.53 in 1999 to 12.55 in 2018 (APC: -1.32; 95% CI: -2.14 to -0.79), followed by increasing rates until 14.72 in 2023 (APC: 3.86; 95% CI: 1.21 to 10.59). AAMRs for NH Asian/Pacific Islanders were initially statistically stable from 1999 to 2008, followed by decreasing mortality rates from 12.14 in 2008 to 7.50 in 2018 (APC: -3.81; 95% CI: -5.61 to -2.90), and lastly increasing rates until 9.34 in 2023 (APC: 4.39; 95% CI: 2.26 to 7.48).\u003c/p\u003e\u003cp\u003eIn summary, AAMRs for NH American Indian/Alaska Natives and NH Whites both had increasing rates from 1999 to 2023 (AAPC NH American Indian/Alaska Native: 0.89; 95% CI: 0.29 to 1.70, AAPC White: 0.49; 95% CI: 0.20 to 0.78). AAMRs for NH Black/African Americans had decreasing rates (AAPC: -1.49; 95% CI: -1.93 to -1.02), while NH Asian/Pacific Islanders and Hispanic/Latinos had statistically stable rates in terms of AAPC from 1999 to 2023 (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e; Supplemental Tables\u0026nbsp;2, 4, and 5).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e3.4 Annual Trends for UTI-Related AAMR Stratified by Age Group\u003c/h2\u003e\u003cp\u003eThe number of deaths increased with age as older adults had the highest number of deaths (939,283), followed by middle-aged adults (86,593) and young adults (11,595). Similarly, average AAMRs also increased with age, as older adults had the highest average AAMR (87.16), followed by middle-aged adults (4.08) and younger adults (0.58).\u003c/p\u003e\u003cp\u003eOlder adults initially had their AAMRs decrease from 95.76 in 1999 to 74.16 in 2019 (APC: -0.93; 95% CI: -1.30 to -0.65), followed by increasing mortality rates until 88.12 in 2023 (APC: 4.38; 95% CI: 1.77 to 10.01). AAMRs for middle-aged adults initially decreased from 3.21 in 1999 to 4.39 in 2018 (APC: 1.65; 95% CI: 1.17 to 2.04) and to 5.99 in 2021 (APC: 10.98; 95% CI: 7.03 to 13.08). Mortality rates decreased afterwards until 2023. AAMRs for younger adults were initially statistically stable from 1999 to 2018, followed by increasing mortality rates from 0.57 in 2018 to 0.78 in 2023 (APC: 7.84; 95% CI: 3.68 to 18.22).\u003c/p\u003e\u003cp\u003eIn summary, AAMRs for younger adults and middle-aged adults increased from 1999 to 2023 (AAPC younger adults: 2.83; 95% CI: 2.12 to 3.47, AAPC middle-aged adults: 2.13; 95% CI: 1.68 to 2.43). AAMRs for older adults remained statistically stable in terms of AAPC from 1999 to 2023 (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e; Supplemental Tables\u0026nbsp;2, 4, and 6).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e3.5 Annual Trends for UTI-Related AAMR Stratified by Urbanization (1999\u0026ndash;2020)\u003c/h2\u003e\u003cp\u003eFrom 1999 to 2020, urban areas had a greater number of deaths (695,875) compared to rural areas (180,436), while the average AAMR was higher in rural areas than in urban areas (average AAMR rural: 21.35, average AAMR urban: 17.90).\u003c/p\u003e\u003cp\u003eUrban areas had their AAMRs decrease from 19.75 in 1999 to 18.07 in 2023 (AAPC: -0.59; 95% CI: -1.03 to -0.32). There were no statistically significant increases or decreases throughout the years concerning APCs for urban or rural areas, and similarly, statistically significant AAPC changes from 1999 to 2020 for rural areas (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e; Supplemental Tables\u0026nbsp;2, 4, and 7).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e3.6 Annual trends for UTI-Related AAMR Stratified by U.S. Census Region\u003c/h2\u003e\u003cp\u003eThe South had the greatest number of deaths (412,511), followed by the Midwest (223,820), the West (220,108), and the Northeast (181,032). The highest average AAMR was noted in the South (20.75), followed by the West (18.66), the Midwest (17.69), and the Northeast (16.18).\u003c/p\u003e\u003cp\u003eThe South had its AAMRs initially decrease from 22.87 in 1999 to 18.81 in 2018 (AAPC: -0.99; 95% CI: -1.38 to -0.66), followed by statistically stable rates until 2023. AAMRs for the West were initially statistically stable from 1999 to 2008, followed by decreasing mortality rates from 19.48 in 2008 to 15.54 in 2019 (APC: -1.47; 95% CI: -4.49 to -0.88) and finally increasing rates until 19.01 in 2023 (APC: 5.15; 95% CI: 2.57 to 9.72). The Midwest had its AAMRs initially decrease from 18.88 in 1999 to 16.06 in 2018 (APC: -0.61; 95% CI: -1.72 to -0.20), followed by increasing mortality rates until 18.03 in 2023 (APC: 3.18; 95% CI: 0.45 to 9.90). AAMRs for the Northeast were initially statistically stable from 1999 to 2011, followed by decreasing mortality rates from 17.12 in 2011 to 14.12 in 2018 (APC: -2.41; 95% CI: -6.07 to -1.20), and finally by increasing rates until 16.22 in 2023 (APC: 4.03; 95% CI: 1.90 to 7.93).\u003c/p\u003e\u003cp\u003eIn summary, AAMRs for all U.S. census regions remained statistically stable from 1999 to 2023, as indicated by AAPCs (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e; Supplemental Tables\u0026nbsp;2, 4, and 8).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003e3.7 UTI-Related Deaths and AAMR Stratified by State\u003c/h2\u003e\u003cp\u003eFrom 1999 to 2023, California had the highest number of deaths at 118,860, accounting for 11.46% of statewide deaths, while Alaska had the lowest number of deaths at 1,080, which accounted for 0.10%. States in the top 90th percentile of deaths included California, Florida, New York, Pennsylvania, and Texas. In contrast, states in the bottom 10th percentile of deaths were Alaska, North Dakota, Vermont, Wyoming, and the District of Columbia. From 1999 to 2019, AAMRs ranged from 10.40 in Hawaii to 29.18 in Tennessee. States within the top 90th percentile of AAMR in this time frame included Mississippi, Oklahoma, South Carolina, Tennessee, and West Virginia. States in the bottom 10th percentile of AAMRs were Arizona, Florida, Hawaii, Minnesota, and Nevada. From 2020 to 2023, AAMRs extended from 9.46 in Hawaii to 47.49 in Oklahoma. States in the top 90th percentile of AAMR in this time period included Kentucky, Mississippi, Oklahoma, South Dakota, and West Virginia. States in the bottom 10th percentile of AAMR were Arizona, Connecticut, Hawaii, Maine, and New York (Supplemental Table\u0026nbsp;9, Supplemental Figs.\u0026nbsp;1,2, and 3).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003e3.8 Leading Underlying Causes of UTI-Associated Deaths by Number of Deaths and AAMR\u003c/h2\u003e\u003cp\u003eFrom 1999 to 2019, the top 5 leading underlying causes of UTI-associated death included diseases of the heart, malignant neoplasms, cerebrovascular diseases, Alzheimer\u0026rsquo;s disease, and influenza and pneumonia. Diseases of the heart caused 79,718 deaths and had an AAMR of 1.77. Malignant neoplasms resulted in 63,767 deaths and had an AAMR of 1.43. Cerebrovascular diseases resulted in 42,428 deaths with an AAMR of 0.94. Alzheimer\u0026rsquo;s disease led to 41,022 deaths with an AAMR of 0.91. Influenza and pneumonia caused 23,080 deaths along with an AAMR of 0.50. From 2020 to 2023, the top 5 leading underlying causes of deaths were malignant neoplasms, diseases of the heart, COVID-19, cerebrovascular disease, and Alzheimer's disease. Malignant neoplasms caused 19,379 deaths and had an AAMR of 1.76. Diseases of the heart resulted in 17,345 deaths and had an AAMR of 1.64. COVID-19 caused 11,519 deaths along with an AAMR of 1.09. Cerebrovascular disease resulted in 10,306 deaths and had an AAMR of 0.95. Alzheimer\u0026rsquo;s disease led to 8,791 deaths with an AAMR of 0.84 (Supplemental Tables\u0026nbsp;10 and 11; Supplemental Figs.\u0026nbsp;4, 5, 6, and 7).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003e3.9 Annual Trends in AAMR when UTI is Listed as UCD\u003c/h2\u003e\u003cp\u003eWhen UTI was listed as the UCD as part of a sensitivity analysis, 325,917 deaths occurred with an average AAMR of 6.01. AAMRs initially were statistically stable from 1999 to 2006, 2006 to 2009, and 2009 to 2019. Mortality rates then increased from 4.46 in 2019 to 5.15 in 2023 (APC: 3.38; 95% CI: 0.13 to 9.39).\u003c/p\u003e\u003cp\u003eIn summary, AAMRs decreased from 8.17 in 1999 to 5.15 in 2023 (AAPC: -1.56; 95% CI: -2.01 to -1.17) (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e; Supplemental Table\u0026nbsp;12).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003e3.10 Annual Trends in AAMR in COVID-related mortality in adults with UTI (2020\u0026ndash;2023)\u003c/h2\u003e\u003cp\u003eCOVID-19-related mortality in adults with UTI resulted in 11,519 deaths and had an average AAMR of 1.08 from 2020 to 2023. AAMRs were statistically stable from 2020 until 2023 (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003e; Supplemental Table\u0026nbsp;13).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"4.0 DISCUSSION","content":"\u003cp\u003eOur 25-year analysis of trends in mortality data for UTI in adults from CDC WONDER denotes several important findings. Firstly, we observed that overall AAMR was divided in a bi-phasic manner. Secondly, women exhibited a higher average AAMR than men. Stratifying by race/ethnicity, we observed the highest AAMR in NH Black/African Americans, followed by NH American Indian/Alaska Natives, NH Whites, Hispanic/Latinos, and finally NH Asian/Pacific Islanders. Additionally, the mortality burden was highest among older adults compared to other age groups in terms of total deaths and AAMR. Regionally, urban areas reported greater total deaths, despite rural areas exhibiting a higher average AAMR. Mortality was highest in the Southern Region of the United States, followed by the West, the Midwest, and the Northeast. In accordance with the highest number of deaths, states in the top 90th percentile of deaths included California, Florida, New York, Pennsylvania, and Texas; in contrast, states in the bottom 10th percentile of deaths were Alaska, North Dakota, Vermont, Wyoming, and the District of Columbia. Between 1999 and 2019, the leading causes of death in adults with UTI were diseases of the heart, malignant neoplasms, cerebrovascular diseases, Alzheimer\u0026rsquo;s disease, and influenza and pneumonia. Between 2020 and 2023, the leading causes shifted to malignant neoplasms, diseases of the heart, COVID-19, cerebrovascular disease, and Alzheimer's disease. We also observed an overall decrease in AAMR when UTI was listed as a leading cause of death. Lastly, the annual trend in AAMR in COVID-related mortality in adults with UTI was statistically stable throughout the study period. Overall, these findings are pertinent and carry significant implications for future healthcare policies.\u003c/p\u003e\u003cp\u003eThe overall AAMR trend was divided into two distinct phases, with a decrease in AAMR observed from 1999 to 2018. This trend can be attributed to a plethora of reasons. Firstly, previous studies show that UTIs are one of the leading causes of sepsis in hospitalized patients [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The Introduction of National and International initiatives, such as the Surviving Sepsis Campaign (SSC), led to reduced deaths from infections that may progress to sepsis/urosepsis [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. This has been documented despite the increasing incidence of sepsis [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Another factor that may be contributing to this trend could be the improved prevention of CAUTI and reduced catheter use [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Nurse-led removal protocols and programs limiting unnecessary indwelling catheters cut the number and severity of healthcare-associated UTIs [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. During the remainder of the study period till 2023, we noticed an increase in AAMR. This may be attributed to the disruption of healthcare services due to the COVID-19 pandemic [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Similarly, rising antimicrobial resistance, particularly in Gram-negative pathogens - as they are the predominant causative agents - indicates that empiric treatment is more likely to fail and may require more expensive/aggressive antimicrobial therapy, which may not be accessible to all patients or medical centers [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. It is important to mention that these explanations are purely speculative, and there is a need for more granular and mechanistic studies to establish causative factors behind this mortality pattern.\u003c/p\u003e\u003cp\u003eEvaluation of AAMR in UTI-related mortality demonstrated that women exhibit an overall higher mortality than men. The reasons for this may be multifactorial. Women have a higher incidence of UTI as compared to men, mainly due to female lower urinary tract anatomy and its proximity to the reproductive organs [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Compared to men, women have a shorter urethra, which reduces the distance for bacterial ingress. Similarly, the proximity of the anus allows colonization of the distal urinary tract and reproductive organs by Escherichia coli, Enterococcus faecalis, and the Streptococcus species [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Post menopausal vaginas are more susceptible to colonization by other bacteria due to glycogen deficiency and decreasing estrogen levels, which contribute to a reduction in lactic acid bacteria and vaginal atrophy [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. An increasing number of Cesarean sections and perioperative catheterizations is yet another important risk factor for UTIs in pregnant women [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. However, further research is required to evaluate potential disparities in UTI treatment between men and women.\u003c/p\u003e\u003cp\u003eWe observed significant variations in mortality rates in Ethnic groups, mirroring the racial inequalities in the United States. Minority Racial groups, such as the NH Black/African Americans and NH American Indian/Alaska Natives, had the highest AAMRs compared to other racial groups. It is a well-known fact that NH Black/African American patients have higher rates of hypertension, diabetes, and chronic kidney disease, which are strong risk factors for severe UTIs and lead to worse outcomes [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Another contributing factor may be that racial minorities like Blacks and Native Americans are less likely to be insured compared to other groups [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. This lack of insurance coverage means that these subpopulations are less likely to afford treatments and more likely to receive care in sub-optimal settings. In contrast, Asian Americans, who have a higher median household income and educational attainment than national averages showed lower AAMR [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. The higher income in this subpopulation may ensure access to timely care, better health literacy, and earlier treatment of infections. Lastly, many Asian Americans are first-generation immigrants; these immigrant populations are suggested to have a health advantage (Healthy Immigrant Effect) over domestic-born residents [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Trend-wise, the overall AAMR for both NH Whites and NH American Indian/Alaska Natives increased, while the NH Black/African Americans had a decreasing AAMR during the study period. This steep decline among NH Black/African Americans from a very high baseline may reflect a greater potential for improvement as broader public health initiatives (e.g., SSC and CAUTI prevention) began to address the severe systemic gaps in care that initially contributed to this population's disproportionate burden.\u003c/p\u003e\u003cp\u003eOur analysis of varying age groups showed that the AAMR was highest among older adults. Older adults have limited physiological reserve, such as immunosenescence and impaired renal function [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The aging process leads to frailty, which is defined as a state of vulnerability due to poor resolution of homeostasis after a stressor event such as systemic stress imposed by UTI [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Worryingly, AAMRs among young and middle-aged adults increased throughout the study period. This may be attributed to risky sexual behaviors such as having multiple partners and inconsistent condom use, which can introduce bacteria to the urinary tract, thus increasing the risk of UTI. Similarly, inadequate personal hygiene practices can further facilitate bacterial colonization and infection [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Recognizing this heightened vulnerability in this subgroup underscores the need for targeted public health strategies and better resource allocation to reduce mortality in older adults.\u003c/p\u003e\u003cp\u003eGeographically, the AAMR showed variations, with the highest AAMR observed in the South and the lowest AAMR observed in the Northeastern region of the United States. This higher AAMR in the south can be attributed to a variety of socioeconomic, demographic, and environmental factors. It is well-documented that individuals from the South are more likely to experience medical financial hardships from a lack of insurance coverage [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Ultimately, individuals in these regions are less likely to access routine healthcare services. This delay can result in poor UTI management, leading to complications and ultimately mortality. Another potential contributing factor may be the higher prevalence of comorbidities in these regions, which increases the risk of complications [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Among States, the AAMR was divided into two time periods (pre-COVID-19 and COVID-19 time frames). From 1999 to 2019 (pre-COVID-19 time frame), the states in the top 90th percentile included Mississippi, Oklahoma, South Carolina, Tennessee, and West Virginia. Meanwhile, States in the bottom 10th percentile of AAMRs were Arizona, Florida, Hawaii, Minnesota, and Nevada. From 2020 to 2023 (COVID-19 time frame), the states in the top 90th percentile included Kentucky, Mississippi, Oklahoma, South Dakota, and West Virginia. States in the bottom 10th percentile of AAMR were Arizona, Connecticut, Hawaii, Maine, and New York. Most states in the top 90th percentile across both time frames are geographically located in the Southern region of the United States, and this is consistent with our above discussion. Stratification by urbanization showed that the rural areas exhibited a higher AAMR, even though the number of deaths was higher in urban areas. These findings demonstrate that socioeconomic status is an essential factor in UTI-related outcomes, including mortality.\u003c/p\u003e\u003cp\u003eIn our analysis of UTI and associated causes of death, we noticed that during the pre-COVID-19 time frame, the leading associated causes of death were diseases of the heart, malignant neoplasms, cerebrovascular diseases, Alzheimer\u0026rsquo;s disease, and influenza and pneumonia. There was a slight variation in this trend during the COVID-19 period, with malignant neoplasms displacing diseases of the heart as the leading underlying cause of death, followed by diseases of the heart, COVID-19, cerebrovascular disease, and Alzheimer's disease. This displacement could likely be due to the impact of COVID-19 on cancer care, leading to delays in identifying new cancers and delivery of treatment, thus resulting in a higher mortality rate [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eBetween 2019 and 2023, a universal increase in UTI-related mortality was observed across all demographics. This period coincides with the COVID-19 pandemic. Hospitals with high COVID-19 admission rates reported increased inpatient occupancy and length of stays and a decline in hospital quality [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. These factors lead to delayed diagnosis or treatment, contributing to elevated mortality. The extension of in-hospital stays during the COVID-19 pandemic likely contributed to a rise in CAUTI, as prolonged hospitalizations often involved extended use of indwelling catheters, which are major risk factors for UTI [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThese findings have crucial implications for public health policies. They underscore the need for comprehensive strategies aimed at preventing and managing UTIs. This includes the integration of advancements in early diagnostics methods and timely clinical interventions. Furthermore, we need to address disparities in healthcare access, support community-based initiatives, and provide culturally appropriate health education, which may contribute to reducing racial and regional differences in mortality.\u003c/p\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003e4.1 Limitations:\u003c/h2\u003e\u003cp\u003eSeveral limitations need to be considered. This data is based on national death certificate data and is thus purely observational, preventing causal inferences. This temporal ambiguity limits causal interference and impacts clinical interpretation. Secondly, the data is subject to underreporting or misclassification, which may lead to the omission of UTI as a cause of death, due to known inconsistencies in diagnostic coding practices. This may elevate or diminish mortality rates, which may distort our interpretation. Mortality data tends to lack clinical granularity, such as information on comorbidities and treatment history, making it difficult to establish whether the mortality was primarily caused by UTI or other clinical factors. Lastly, extracting AAMRs for urbanization was only possible using CDC WONDER from 1999 to 2020.\u003c/p\u003e\u003c/div\u003e"},{"header":"5.0 Conclusion","content":"\u003cp\u003eOur 25-year analysis of UTI mortality trends in adults aged 25 and older revealed notable disparities by sex, race, age, and geography. Overall, AAMR was divided into two distinct phases. Higher AAMR was observed in Women, adults aged 65 years or older, NH Blacks, Rural areas, and the Southern Region of the United States. Leading causes of death in UTI patients shifted during the COVID-19 pandemic, with malignant neoplasms surpassing heart disease, and COVID-19 emerging as a significant contributor. These findings highlight the need for targeted public health interventions and informed healthcare policies to address demographic and regional disparities in UTI-related mortality.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAAMR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAge\u0026ndash;adjusted Mortality Rate\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAAPC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAverage Annual Percent Change\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAPC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAnnual Percent Change\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCAUTI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eCatheter\u0026ndash;Associated Urinary Tract Infection\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCDC WONDER\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eCenters for Disease Control and Prevention Wide\u0026ndash;Ranging Online Data for Epidemiologic Research\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCMR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eCrude Mortality Rate\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eICD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003e10\u0026ndash;International Statistical Classification of Disease and Related Health Problems, 10th Revision\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNH\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003enon\u0026ndash;Hispanic\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSSC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eSurviving Sepsis Campaign\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eU.S\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eUnited States\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eUCD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eUnderlying Cause of Death\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eUTI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eUrinary Tract Infection\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eCompeting interests\u003c/h2\u003e\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003e**MA** : conceptualization, project administration, supervision, validation, investigation, methodology, writing, writing \u0026ndash; original draft, writing \u0026ndash; review and editing; **NHK** : investigation, methodology, writing \u0026ndash; original draft, writing \u0026ndash; review and editing; **AH** : investigation, methodology, writing \u0026ndash; original draft, writing \u0026ndash; review and editing; **SG** : investigation, methodology, writing \u0026ndash; original draft, writing \u0026ndash; review and editing; **HK** : investigation, methodology, writing \u0026ndash; original draft, writing \u0026ndash; review and editing; **MSA** : investigation, methodology, writing \u0026ndash; original draft, writing \u0026ndash; review and editing; **IA** : methodology, writing \u0026ndash; original draft, writing \u0026ndash; review and editing; **AR** : investigation, methodology, writing \u0026ndash; original draft, writing \u0026ndash; review and editing; **AN** : investigation, methodology, writing \u0026ndash; original draft, writing \u0026ndash; review and editing; **KAK** : writing \u0026ndash; review and editing; **MAS** : writing \u0026ndash; review and editing; **MAJ** : writing \u0026ndash; review and editing; **FA** : writing \u0026ndash; review and editing. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated and/or analysed during the current study is publicly available, de-identified data from the CDC WONDER Multiple Cause-of-Death database. Available at: [https://wonder.cdc.gov/mcd.html](https:/wonder.cdc.gov/mcd.html)\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePuca E. Urinary tract infection in adults. Clin Microbiol. 2014;3(6):100\u0026ndash;20. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.4172/2327-5073.1000e120\u003c/span\u003e\u003cspan address=\"10.4172/2327-5073.1000e120\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZilberberg MD, Nathanson BH, Sulham K, Fan W, Shorr AF. 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Am J Infect Control. 2024;52(2):147\u0026ndash;51. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ajic.2023.05.014\u003c/span\u003e\u003cspan address=\"10.1016/j.ajic.2023.05.014\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Urinary Tract Infections (UTI), Mortality Trends, CDC Wonder, Population Health, Healthcare Epidemiology","lastPublishedDoi":"10.21203/rs.3.rs-7811606/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7811606/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eUrinary tract infections (UTI) are prevalent among adults in the United States, yet their demographic and regional mortality trends are unexplored. Uncovering national trends in UTI-related mortality among adults can highlight demographic and regional disparities, guiding research efforts aimed at improving clinical care and promoting better patient outcomes. This descriptive analysis reveals mortality trends and disparities among U.S. adults aged\u0026thinsp;\u0026ge;\u0026thinsp;25 years with UTI from 1999 to 2023.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThe Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) Multiple Cause-of-Death dataset (1999\u0026ndash;2023) was analyzed for mortality trends in adults aged\u0026thinsp;\u0026ge;\u0026thinsp;25 years using ICD-10 codes for UTI. Crude mortality rates (CMRs) and age-adjusted mortality rates (AAMRs) per 100,000 were extracted by year, sex/gender, age, race/ethnicity, census region, state, and urban\u0026ndash;rural divisions. Annual percent change (APC) and average annual percent change (AAPC) in AAMRs were calculated using the permutation test and the parametric method via Jointpoint regression software with corresponding 95% confidence intervals (95% CI).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eA total of 1,037,471 UTI-related deaths occurred among U.S. adults from 1999 to 2023, mainly in medical facilities (61.82%). Initially, AAMRs decreased from 20.04 in 1999 to 16.86 in 2018 (APC: -0.77; 95% CI: -1.21 to -0.45), followed by increasing rates until 19.38 in 2023 (APC: 3.57; 95% CI: 1.57 to 8.02). The highest mortality burden in terms of average AAMR was noted among older adults, women, non-Hispanic (NH) Black/African Americans, residents of the Southern census region, Tennessee, Oklahoma, and those in rural areas. Leading causes of death among UTI decedents shifted during the COVID-19 pandemic, with COVID-19 emerging as a major contributing cause.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eUTI-related mortality among U.S. adults aged\u0026thinsp;\u0026ge;\u0026thinsp;25 years showed shifting trends and marked demographic and regional disparities. Older adults, women, NH Black/African Americans, rural residents, and those in the Southern Regions and States bore the greatest burden. Leading causes of UTI-associated deaths shifted during the pandemic, with COVID-19 emerging as a significant factor. These findings illustrate the urgency for targeted interventions and informed healthcare policies to address UTI-related mortality burden, especially in at-risk communities.\u003c/p\u003e","manuscriptTitle":"Urinary Tract Infection-Related Mortality Trends in Adults Aged ≥ 25 Years in the United States: A CDC WONDER Analysis from 1999 to 2023","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-19 11:58:22","doi":"10.21203/rs.3.rs-7811606/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"31daf749-6ac1-4097-93a8-387f3e585ed1","owner":[],"postedDate":"November 19th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-15T10:05:28+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-19 11:58:22","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7811606","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7811606","identity":"rs-7811606","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}