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.

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).

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.

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.