Clinical burden of invasive Escherichia coli disease among older adult patients treated in hospitals in the United States

Background Invasive extraintestinal pathogenic Escherichia coli disease (IED) can lead to severe outcomes, particularly among older adults. However, the clinical burden of IED in the U.S. has not been well characterized. Methods IED encounters among patients ≥ 60 years old were identified using the PINC AI™ Healthcare Database (10/01/2015–03/31/2020) by either a positive E. coli culture in blood or another normally sterile body site and ≥ 1 sign of systemic inflammatory response syndrome or signs of sepsis, or a positive E. coli culture in urine with urinary tract infection and signs of sepsis. Medical resource utilization, clinical outcomes, and E. coli isolate characteristics were descriptively reported during the first IED encounter and during the following year (observation period). Results Overall, 19,773 patients with IED were included (mean age: 76.8 years; 67.4% female; 78.5% with signs of sepsis). Most encounters involved community-onset IED (94.3%) and required hospitalization (96.5%; mean duration: 6.9 days), with 32.4% of patients being admitted to the intensive care unit (mean duration: 3.7 days). Most E. coli isolates were resistant to ≥ 1 antibiotic category (61.7%) and 34.4% were resistant to ≥ 3 antibiotic categories. Following their first IED encounter, 34.8% of patients were transferred to a skilled nursing/intermediate care facility, whereas 6.8% had died. During the observation period, 36.8% of patients were rehospitalized, 2.4% had IED recurrence, and in-hospital death increased to 10.9%. Conclusions IED is associated with substantial clinical burden at first encounter with considerable long-term consequences. Findings demonstrate the need for increased IED awareness and highlight potential benefits of prevention. Supplementary Information The online version contains supplementary material available at 10.1186/s12879-023-08479-3.


Background
Escherichia coli (E.coli) are a large and diverse group of bacteria that can be found as part of the normal human intestinal flora.Pathogenic E. coli, both intestinal pathogenic E. coli (InPEC) as well as extraintestinal pathogenic E. coli (ExPEC), comprise E. coli strains that may cause infections with potentially severe complications, including death [1].Indeed, E. coli is a leading cause of community-acquired sepsis, a life-threatening condition that is among the main reasons for hospitalization and death in the U.S. [2][3][4][5][6], particularly among older patients [7].
Pathogenic E. coli can emerge to infect normally sterile body sites and lead to invasive E. coli disease (IED), also known as invasive ExPEC disease, which comprises sepsis (including sepsis due to urinary tract infection [UTI], i.e., urosepsis), bacteremia, peritonitis, meningitis, and other infectious syndromes [2,[8][9][10].A recent metaanalysis reported that the incidence rate for E. coli bacteremia rises progressively beyond 60 years of age, from 110 to 100,000 personyears among adults 60-69-year-old to 319 per 100,000 person-years among those 80 years or older [11].Older patients with E. coli bacteremia are also more likely to have antibiotic-resistant isolates than those aged 18-64 years [12].These findings are of particular importance given that E. coli is the most common pathogen linked to deaths associated with antibiotic resistance [13].Taken together, these studies suggest that older adults may be at greater risk of developing IED and may be more challenging to manage due to the increased likelihood of antibiotic resistance.
Despite its clinical importance, the burden of IED in the U.S., particularly among older adults, is not well characterized.Furthermore, while the epidemiology of IED and patterns of antibiotic resistance have been previously described, including in the U.S. [14], various definitions of IED are used across studies.Therefore, the aim of this study was to describe and characterize the short-term as well as the longer-term outcomes following IED among patients 60 years and older hospitalized in the U.S. using an inclusive definition of IED, which encompassed cases beyond E. coli bacteremia.

Data source
This study used data from the PINC AI™ Healthcare Database (PHD).The data period spanned from October 1, 2015 -March 31, 2020 to include recent data, while focusing on presumed pre-COVID period to reduce risk for over-estimation of the burden due to additional in-hospital health-care services that may have been provided as a result of COVID infections in older patients.The PHD comprises detailed inpatient services from patients admitted to a representative set of > 1,000 U.S. hospitals nationwide and includes admission-level information (e.g., patient characteristics, primary and secondary admitting diagnoses), detailed day-of-service billing information during hospitalizations (e.g., inpatient procedures and medications used by day of stay), and discharge-level data (e.g., length of stay, discharge status) [15].Data are de-identified and comply with the requirements of the Health Insurance Portability and Accountability Act of 1996; therefore, no review by an institutional review board was required.

IED case identification and subtype
IED encounters were classified as either Group 1 IED, corresponding to IED with a positive E. coli culture in blood or other normally sterile body sites and ≥ 1 sign of systemic inflammatory response syndrome (SIRS) or signs of sepsis (as per the Centers for Disease Control [CDC] clinical surveillance definition [16]) without positive culture for other bacterial or fungal pathogens, or Group 2 IED, corresponding to IED with microbiological confirmation from urine in the presence of signs of sepsis (as per the CDC clinical surveillance definition [16]) and a diagnosis code for UTI without a positive culture for other bacterial or fungal pathogens (Fig. 1).IED encounters that met the definition for both Group 1 and Group 2 IED were classified in Group 1.In addition, among patients classified in Group 1, the subgroup of patients that had signs of sepsis was identified (i.e., Group 1 IED with sepsis).

Study design and sample selection
A retrospective study design was used (Supplementary Figure S1) whereby the index date for a given patient was the date of the first positive E. coli culture during the first documented IED encounter (i.e., index encounter), and the observation period was defined as the 12-month period following the index date.Patients were included in the study if they had ≥ 1 IED encounter and were ≥ 60 years of age as of the index date.To increase the likelihood of capturing the first IED encounter as of the index date and to ensure an adequate observation period, the IED encounter was required to occur in a hospital that contributed microbiology data to the database continuously for ≥ 6 months before and ≥ 12 months after the index date.

Measures, outcomes, and statistical analyses
Patient and hospital characteristics were descriptively reported, as well as the characteristics and course of the index encounter which included the point of origin (e.g., clinic, transfer from another hospital), the IED onset (hospital or community, defined respectively based on the date of the positive E. coli culture ≥ 3 days vs. ≤2 days after hospital admission, and whether communityonset IED was healthcare-associated [17,18]), the type of encounter (inpatient stay, emergency room visit, or outpatient hospital visit), the type of IED (i.e., Group 1, Group 1 with sepsis, or Group 2), infection type (e.g., urosepsis with/without bacteremia, meningitis; Supplementary Table S1), IED-related treatments, and discharge status.Patterns of antibiotic resistance, including multi-drug resistance (MDR), were explored among IED encounters for which antibiotic susceptibility tests were available.MDR was defined as isolates resistant to ≥ 1 agent in ≥ 3 relevant antibiotic categories (Supplementary Table S2), based on a joint initiative by the European and U.S. CDC [19].Trends in antibiotic resistance over time between 2015 and 2019 were also assessed.IED recurrences, defined as an encounter for IED with a gap of ≥ 14 days from the last positive E. coli culture from a prior IED, were assessed during the 12month observation period.Analyses were conducted overall and stratified by type of IED (i.e., Group 1, Group 1 with sepsis, Group 2).Stratified analyses were also conducted by patient age (i.e., 60-75 or ≥ 75 years old), onset of IED (i.e., hospitalonset, community-onset), and MDR status.Statistical comparisons for these variables were conducted using Wilcoxon rank-sum and Chi-square tests.All analyses were performed using SAS Enterprise software programs (version 7.1).

Study sample and characteristics
A total of 19,773 patients with ≥ 1 IED encounter in a U.S. hospital were included in the study Supplementary Figure S2).The characteristics of patients with IED are reported in Table 1.In the overall sample, mean age was 76.8 years, 67.4% were female, and 82.1% were White.

Characteristics of index encounters
Most index encounters were related to communityacquired IED (94.3%), and among those, 25.7% were healthcare-associated.The most frequent infection types were urosepsis without bacteremia (48.2%) and with bacteremia (29.3%;Table 2).
Most patients required an inpatient stay at their index encounter (96.5%) with a mean duration of 6.9 days.A total of 8.6% required mechanical ventilation and 32.4% received medical services in an intensive care unit (ICU), of whom 74.5% were transferred to ICU on the day of admission.Among index encounters with an inpatient hospitalization, patients had a mean length of stay of 6.4 days in Group 1 IED, 7.2 days in Group 1 IED with sepsis, and 7.4 days in Group 2 IED, with 29.6%, 35.4%, and 43.2% of patients, respectively, transferred to ICU during their index encounter (Table 2).

Treatments patterns and antibiotic resistance during index encounter
Nearly all patients (99.3%) received antibiotic treatment and were typically treated with several antibiotic courses, with a mean of 2.9 different antibiotics.Notably, 30.1% of patients received ≥ 4 antibiotics.The most frequently observed antibiotics were ceftriaxone (66.2%), vancomycin (36.3%), and piperacillin (35.0%;Fig. 2).Of note, 87.9% of patients received ≥ 1 antibiotic prior to the confirmation of E.coli as the source of infection, with a mean of 1.57 different antibiotics per patient, which may  2017) and details and diagnosis codes were updated using the CDC's Hospital Toolkit for Adult Sepsis Surveillance (March 2018).The algorithm was validated using medical records from 510 randomly selected hospitalizations, stratified into those that did and did not meet sepsis surveillance criteria  During the index encounter, most patients had ≥ 1 antibiotic susceptibility test performed (98.0%).From nearly two-thirds of patients (61.7%),E. coli cultures displayed resistance to ≥ 1 antibiotic category, and 34.4% were resistant to ≥ 3 categories (i.e., MDR).Notably, rates for resistance of E. coli isolates to selected antibiotics were as follows: 51.7% to penicillins, 34.5% to fluoroquinolones, 20.5% to first and second generation non-extended spectrum cephalosporins, and 16.1% to third and fourth generation extended spectrum cephalosporins.Based on microbiology data, 13.3% of IED encounters were recorded as extended spectrum beta-lactamase (ESBL) positive.The proportion of E. coli isolates resistant to most of the antibiotic categories remained stable between 2015 and 2019, though a decreasing trend in the proportion of E. coli isolates resistant to fluoroquinolones (37.8-32.0%,p < 0.001) and aminoglycosides (15.6-11.9%,p = 0.002) was observed over time (Fig. 3).

Point of origin, discharge status, and in-hospital death
The most common point of origin was a non-healthcare facility (85.1%).In contrast, only 44% of patients were discharged home, while 34.8% were discharged to a skilled nursing facility (SNF) or an intermediate care facility (ICF).During the index encounter, 6.8% of patients died (Fig. 4), and the in-hospital fatality rate increased to 10.9% during the 12-month observation period; specifically, 3.6% of patients died within 2 days of the index date and 8.0% died within 1 month.
The in-hospital fatality rate during the index encounter was 6.6% in Group 1 IED, 9.6% in Group 1 IED with sepsis, and 7.0% in Group 2 IED.At 12 months postindex, 9.7% of patients in Group 1 IED died in the hospital relative to 13.1% in Group 1 IED with sepsis and 12.2% in Group 2 IED.

Clinical outcomes post-IED
A total of 7,275 patients (36.8%) had ≥ 1 all-cause hospitalization during the 12-month observation period, of which 38.5% had a hospitalization related to invasive infectious disease based on primary diagnosis, and 21.9% and 34.4% of patients had an all-cause emergency room or outpatient hospital visit, respectively, during the same period.Of these, 477 patients (2.4%) had ≥ 1 IED recurrence, with a mean of 4.6 months between the index date and the first recurrence.During the observation period, 34.0%, 34.9%, 39.8% of patients in Group 1 IED, Group 1 IED with sepsis, and Group 2 IED, respectively, had ≥ 1 all-cause hospitalization (Table 3).

Further stratified analyses
Patient characteristics varied by age; compared to patients 60-75 years old, those in the ≥ 75 years old subgroup had a more severe comorbidity profile based on a Charlson Comorbidity Index (CCI) score ≥ 3 (45.3% vs. 38.4%,p < 0.001), and were less likely to be discharged to their home (35.2% vs. 56.7%,p < 0.001) and more likely to be discharged to a SNF or ICF (42.0% vs. 24.2%,p < 0.001).Further, a higher proportion of patients ≥ 75 years old died during the index encounter (7.3% vs. 6.1%, p < 0.001) and at 12 months post-index (11.8% vs. 9.6%; p < 0.001).
Patients with hospital-onset IED tended to have a more severe comorbidity profile compared to those with Encounters with MDR isolates were more likely to be associated with hospital-onset IED (6.5% vs. 5.3%, p < 0.001), occur in hospitals of ≥ 500 beds (33.2% vs. 29.1%,p < 0.001), and originate from a SNF/ICF (5.2% vs. 3.6%, p < 0.001) compared to non-MDR isolates.For their index encounter, a higher proportion of patients with MDR than non-MDR isolates received ≥ 4 agents (33.9% vs. 28.1%,p < 0.001).During the 12-month observation period, the proportion of patients who had ≥ 1 IED recurrence was higher among those with MDR isolates (4.1% vs. 1.5%, p < 0.001).The proportion of patients who had ≥ 1 hospitalization during this period was also higher among those with MDR isolates (40.8% vs. 34.8%,p < 0.001).The rate of inhospital death was not

Discussion
E. coli is the most commonly reported pathogen leading to hospitalizations for sepsis in older adults in the U.S. [5,7].Considering the epidemiological data showing an increased incidence of E. coli infection worldwide [5,20,21], it is important to characterize the course of IED in U.S. hospitals.The results of the current study highlight the substantial burden associated with IED in the U.S. in terms of hospitalizations, ICU admissions, and inhospital fatality rates.Almost all index encounters led to hospitalization and nearly 1 in 3 patients were admitted to ICU.In addition to the acute burden observed at the index encounter, patients continued to experience poor outcomes up to one year post-encounter.More than 1 in 10 patients died in a hospital within a year of their first IED encounter, with the majority of deaths occurring within the first month post-IED.Further, while most IED originated in a non-healthcare facility-and only 4.2% through SNF/ICF-approximately one-third of patients were discharged to an SNF/ICF after their index encounter, underscoring the long-term consequences among those who survive IED.Moreover, older patients, who had a more severe comorbidity profile, experienced a higher burden of IED and were less likely to be discharged to their home and more likely to be discharged to a SNF/ICF.Together, these results highlight the importance of maintaining continuity of care after the index encounter.
While published data on the clinical burden of IED is limited, our findings are consistent with a recent publication using similar administrative data from the PHD database by Begier et al. [14].However, Begier et al. described a more limited range of clinical outcomes and focused on an IED subtype with microbiological confirmation from blood or other normally sterile body sites.In many instances, clinical sepsis cases lack confirmation from a positive blood culture.Sensitivity and specificity of blood culture depends on blood volume drawn, timing, prior treatment with antibiotics, and the presence of viable organisms [22].Fay et al. 2020 reported that a specific pathogen was identified in only 56.9% of sepsis cases, leaving almost half of sepsis cases with an unidentified infection source [6].A recent publication (Rhee et al., 2020) reporting on community-onset sepsis found that urine was the most common source of positive culture, allowing for pathogen identification in 52% of patients [5].Therefore, microbiological confirmation from sources other than blood culture (i.e., urine culture) are deemed important to appropriately capture the full burden of IED, especially for community-onset sepsis.As such, the present study incorporated a two-part definition of IED, whereby encounters were considered as an IED event if they included a positive E. coli culture in urine with UTI and signs of sepsis (i.e., Group 2 IED) [16], in addition to IED identified from a positive E. coli culture in blood or other normally sterile body sites (i.e., Group 1 IED).Findings from this study suggest that patients who presented with sepsis of likely urinary tract origin (Group 2; i.e., non-bacteremic urosepsis), though lacking microbiological confirmation from normally sterile body sites, can incur a substantial clinical burden comparable to those who present with bacteremic disease and microbiological confirmation from normally sterile body sites.
This study also provides a comparison of the burden of IED between those with community-vs.hospitalonset.Consistent with previous literature, most patients acquired IED in a community setting [11,14].Though this resulted in a substantial burden, patients with hospital-onset IED incurred a significant burden, including a higher rate of ICU admissions and in-hospital fatality compared to community-onset IED, which confirms prior research [23].
Antibiotic treatment patterns also suggest that IED can be complex to manage and involve a broad range of antibiotics being received within a short timeframe.For example, more than 1 in 4 patients were treated with ≥ 4 agents during their index encounter.A high rate of antibiotic resistance was observed in our study sample, with MDR isolates being observed in more than 1 in 3 index encounters.Though the exact patterns of antibiotic   [23][24][25].In the current study, more than half of the patient population had ExPEC that was resistant to penicillins consistently over time.A high level of resistance was also observed for fluoroquinolones, though this appears to be trending downwards over time (38% in 2015 to 32% in 2019).Furthermore, MDR isolates were associated with an increased number of antibiotic agents received and higher incidence of IED recurrence, which supports prior evidence of the association between inadequate treatment and resistant pathogens [6,26,27].Antibiotic resistance may lead to treatment failure, increased rates of hospitalization, morbidity, mortality, and associated costs [2,[28][29][30][31][32], and can drive the evolution of novel pathogenic clones, such as ST131 [33].The use of the PHD database, which encompasses detailed admission-level data of inpatient services for patients admitted to over 1,000 U.S. hospitals, is an important strength of this study as it provides a large representative sample from all U.S. regions.Importantly, the database includes microbiology laboratory data, which is not available in most other administrative claims databases, with information on specimen source, tests performed, and results for these tests that allow for the identification of IED encounters.The study relied on the CDC's clinical surveillance definition for sepsis, which has been previously validated, and demonstrates its value for research purposes.
This retrospective study is subject to inherent limitations.IED encounters were identified based on microbiological data from laboratory records and diagnosis and procedure codes in claims data; therefore, some patients may have been misidentified as having IED due to any limitations in the various data sources (e.g., coding errors, etc.).Furthermore, the definition of IED used in this study included sepsis, for which a range of definitions exist in the literature; these may affect epidemiological estimates of sepsis by as much as three-fold [34,35].Comparisons with other studies that use different definitions of IED and sepsis are therefore inherently limited.Further, no information on prescription fills was available in the database, thus antibiotic use was identified based on the medications received in the hospital setting only.It should also be noted that, specimens are not systematically tested for resistance to all possible antibiotics in real-world clinical practice; therefore, MDR incidence may have been underestimated.Additionally, information in the PHD database is limited to IED encounters occurring in a hospital setting such that medical resource utilization for a given patient is only captured for encounters at a given hospital.Similarly, since death was identified based on discharge status, deaths occurring outside of the hospital also were not captured.Finally, this study is descriptive in nature, such that no causal inference can be made.

Conclusions
This study described the course of IED in U.S. hospitals among a large representative sample of older adults.The findings suggest that IED is associated with an acute burden during the initial hospital encounter and may lead to poor outcomes even after the encounter is resolved.This burden is particularly high in the presence of antibiotic resistance, which is an important consideration for an increasing aging population.

Fig. 3 Fig. 2
Fig. 3 Patterns of antibiotic resistance during the index encounter and by agent over time Abbreviations: ICF: intermediate care facility; SNF: skilled nursing facility

Fig. 4
Fig. 4 Point of origin and discharge status of the index encounter Abbreviations: ICF: intermediate care facility; SNF: skilled nursing facility

Table 1
Patient and hospital characteristics on the index date explain why some patients received antibiotics not commonly used to treat E. coli infections (data not shown).

Table 2
Characteristics of the index encounter Escherichia coli disease; SD: standard deviation resistance in E. coli isolates reported in recent literature vary depending on the study population (i.e., target age, country), disease definition, or study design, resistance to penicillins and fluoroquinolones has been consistently high Abbreviations: IED: invasive