Abstract
Background
We investigated hospitalized carbapenem-resistant Enterobacterales (CRE) and extended-spectrum β-lactamase–producing Enterobacterales (ESBL-E) cases with and without COVID-19, as identified through Emerging Infections Program surveillance in 10 sites from 2020 to 2022.
Methods
We defined a CRE case as the first isolation of Escherichia coli, Enterobacter cloacae complex, Klebsiella aerogenes, K oxytoca, K pneumoniae, or K variicola resistant to any carbapenem. We defined an ESBL-E case as the first isolation of E coli, K pneumoniae, or K oxytoca resistant to any third-generation cephalosporin and nonresistant to all carbapenems tested. Specimens were drawn from a normally sterile site or urine among hospitalized residents of the surveillance area in a 30-day period. We defined COVID-19 as a positive SARS-CoV-2 test result (SC2+) within 14 days before CRE or ESBL-E specimen collection and performed multivariable logistic regression analyses.
Results
Of 1595 CRE and 1866 ESBL-E hospitalized cases, 38 (2.4%) and 60 (3.2%), respectively, had a SC2+. Among these cases, a SC2+ was associated with intensive care unit admission (adjusted odds ratio [aOR], 1.69 [95% CI, 1.14–2.50]; aOR, 1.48 [95% CI, 1.03–2.12]) and 30-day mortality (aOR, 1.79 [95% CI, 1.22–2.64]; aOR, 1.94 [95% CI, 1.39–2.70]).
Conclusions
CRE and ESBL-E infections among hospitalized patients with preceding COVID-19 were uncommon but had worse outcomes when compared with cases without COVID-19. COVID-19 prevention in patients at risk of CRE and ESBL-E infections is needed, as well as continued infection control measures and antibiotic stewardship for patients with COVID-19.
Keywords: carbapenem-resistant Enterobacterales, COVID-19, extended spectrum beta-lactamase-producing Enterobacterales, SARS-CoV-2
From 2020 to 2022, hospitalized carbapenem-resistant Enterobacterales and extended-spectrum β-lactamase–producing Enterobacterales cases with preceding COVID-19 were rare but associated with worse outcomes when compared with cases without COVID-19, with significantly higher rates of intensive care unit admission and 30-day mortality, even after adjusting for potential confounders.
Multidrug-resistant Enterobacterales, including carbapenem-resistant Enterobacterales (CRE) and extended-spectrum β-lactamase–producing Enterobacterales (ESBL-E), are major concerns for patients in health care settings and the community [1]. Multidrug-resistant Enterobacterales are known to cause infections with high mortality and limited treatment options [2]. These organisms can also carry mobile genetic elements encoding carbapenemases or ESBLs, as well as other resistance determinants, that can transfer between organisms, leading to further dissemination.
Among hospitalized patients in 2017, CRE caused 13 100 cases and 1100 deaths, and ESBL-E caused 197 400 cases and 9100 deaths [2]. Prior to the COVID-19 pandemic, US hospital rates of CRE had remained largely stable between 2012 and 2017, followed by a significant decline in 2018, while rates of ESBL-E had steadily increased during this period [2, 3]. However, between 2019 and the first year of the COVID-19 pandemic in 2020, hospital-onset CRE and ESBL-E rates increased by >30% [3]. Studies of past viral pandemics have shown that bacterial coinfections or secondary infections were associated with more severe clinical outcomes [4, 5]. Yet, current literature on the clinical outcomes of patients with multidrug-resistant Enterobacterales and COVID-19 coinfection or secondary infections is limited, with most studies focusing on patients hospitalized with COVID-19 or patients who were critically ill at single institutions [6–11]. We conducted a multisite investigation comparing the clinical characteristics and outcomes of hospitalized patients with CRE and ESBL-E infections with and without COVID-19.
METHODS
Surveillance Area and Case Definitions
The Centers for Disease Control and Prevention’s (CDC's) Emerging Infections Program (EIP) Multi-site Gram-Negative Surveillance Initiative conducts laboratory and population-based surveillance for CRE in 43 metropolitan counties in 10 EIP sites (Oakland, California; Denver, Colorado; Atlanta, Georgia; Baltimore, Maryland; Minneapolis/St Paul, Minnesota; Albuquerque, New Mexico; Rochester, New York; Portland, Oregon; Nashville, Tennessee; and all of Connecticut) and ESBL-E in 10 metropolitan counties in 6 EIP sites (Boulder, Colorado; Atlanta, Georgia; Baltimore, Maryland; Albuquerque, New Mexico; Rochester, New York; Columbia, Tennessee). Hospitalized CRE cases identified in 2020 to 2022 from all 10 EIP sites were included in our analysis, whereas due to significant delays in data collection during the COVID-19 pandemic, hospitalized ESBL-E cases identified from 2020 to 2022 from 5 of the 6 EIP sites were included.
We defined an incident CRE case as the first isolation of Escherichia coli, Enterobacter cloacae complex, Klebsiella aerogenes, K oxytoca, K pneumoniae, or K variicola resistant to any carbapenem (doripenem, ertapenem, imipenem, or meropenem) from a normally sterile site (eg, blood) or urine from a resident of the EIP surveillance area in a 30-day period. An incident ESBL-E case was defined as the first isolation of E coli, K pneumoniae, or K oxytoca resistant to any third-generation cephalosporin (ceftazidime, cefotaxime, or ceftriaxone) and nonresistant to all carbapenems tested from a normally sterile site or urine from a resident of the EIP surveillance area in a 30-day period. We restricted the analysis to include only CRE and ESBL-E cases among patients hospitalized at a short-stay acute care hospital on the day of incident specimen collection.
Local clinical laboratories performed antimicrobial susceptibility testing using their primary testing method, and all isolates meeting the CRE and ESBL-E phenotypic case definitions per the most recent interpretive criteria available from the Clinical and Laboratory Standards Institute were reported to EIP site staff [12].
Data Collection
Patient charts were reviewed via a standardized case report form for all incident CRE cases. Because of the high burden of ESBL-E and some patients having multiple incident cases, a case report form was completed for all incident ESBL-E cases from normally sterile sites and for the first incident urine ESBL-E case per species per patient for each year of surveillance. Information collected from charts included patient demographics, location of incident specimen collection, health care exposures, types of associated infections, comorbidities, clinical outcomes, and isolate testing data. The Charlson Comorbidity Index was calculated per the comorbidities collected from chart reviews [13]. Based on documentation in the patient chart or the state notifiable disease system, we determined whether cases had a positive SARS-CoV-2 test result (SC2+) on or in the 14 days before the date of incident CRE or ESBL-E specimen collection. State vital records were queried by EIP site staff to determine mortality within 30 days of incident specimen collection.
Based on chart reviews, CRE and ESBL-E cases were classified as follows:
Hospital onset: if the specimen was obtained ≥3 days after hospital admission
Health care associated, community onset: if the specimen was obtained in a nonhospital setting or <3 days after hospital admission in (1) a person with a history of hospitalization, surgery, or residence in a long-term care facility or long-term acute care hospital in the prior year or (2) a patient undergoing chronic dialysis or having an indwelling device or external urinary catheter in the 2 days prior to specimen collection
Community associated: if there were no health care risk factors
Statistical Analysis
CRE and ESBL-E cases were analyzed separately. We compared cases with and without a preceding SC2+ with a χ2 test or a Fisher exact test (for cell sizes <5) for categorical variables and the Wilcoxon rank sum test for continuous variables. For cases with missing values for race or ethnicity, we performed multiple imputation using the fully conditional specification method based on age, sex, state, county, and epidemiologic class [14].
We used separate multivariable logistic regression models to determine if a SC2+ was independently associated with each outcome: intensive care unit (ICU) admission on the day of or in the 7 days after incident specimen collection and mortality within 30 days of the incident specimen collection. Each model was adjusted for age, sex, race and ethnicity, Charlson Comorbidity Index (<2 vs ≥2), epidemiologic class, invasive infection (sterile site vs urine), and prior incident case in the year before specimen collection.
We performed a sensitivity analysis for CRE, including only cases that underwent carbapenemase testing by the local clinical laboratory, public health laboratory, or CDC laboratory and adjusted for carbapenemase status in each model.
Adjusted odds ratio (aOR) and 95% CI were calculated for the variables in each model. A 2-tailed P < .05 was considered statistically significant. Data management and analyses were conducted with SAS version 9.4 (SAS Institute Inc).
Ethical Review
This activity was reviewed by the CDC, deemed not research, and was conducted consistent with applicable federal law and CDC policy (see, eg, 45 CFR part 46; 21 CFR part 56; 42 USC §241(d), 5 USC §552a, 44 USC §3501 et seq). It was also reviewed by EIP sites and either deemed nonresearch or granted institutional review board approval with a waiver of informed consent.
RESULTS
We identified 1595 CRE cases among 1475 hospitalized patients and 1866 ESBL-E cases among 1724 hospitalized patients (Table 1). Among these cases, 38 (2.4%) CRE and 60 (3.2%) ESBL-E had a SC2+. The median number of days between a SC2+ and the date of incident specimen collection was 2 (IQR, 0–10) for CRE cases and 4 (IQR, 0–10) for ESBL-E cases. Of the 38 CRE cases with a SC2+, the median age was 70 years (IQR, 61–77), and the majority were female (n = 24, 63.2%) and non-Hispanic White (n = 20, 52.6%). Similarly, among the 60 ESBL-E cases with a SC2+, the median age was 70 years (IQR, 63–79), and the majority were female (n = 42, 70.0%) and non-Hispanic White (n = 24, 40.0%). There were no significant differences in comorbidities among CRE or ESBL-E cases.
Table 1.
Patient Demographics and Clinical Characteristics of Hospitalized CRE and ESBL-E Cases With and Without a SC2+, 10 US Sites, 2020–2022
| CRE Cases, No. (%) | ESBL-E Cases, No. (%) | |||||||
|---|---|---|---|---|---|---|---|---|
| Characteristic | SC2+ (n = 38) | No SC2+ (n = 1557) | All (n = 1595) | P Value | SC2+ (n = 60) | No SC2+ (n = 1806) | All (n = 1866) | P Value |
| Sex | .14 | .21 | ||||||
| Female | 24 (63.2) | 792 (50.9) | 816 (51.2) | 42 (70.0) | 1119 (62.1) | 1161 (62.3) | ||
| Male | 14 (36.8) | 763 (49.1) | 777 (48.8) | 18 (30.0) | 684 (37.9) | 702 (37.7) | ||
| Unknown | 0 (0) | 2 (0.1) | 2 (0.1) | 0 (0) | 3 (0.1) | 3 (0.1) | ||
| Age, y, median (IQR) | 70 (61–77) | 68 (55–78) | 68 (55–78) | .41h | 70 (63–79) | 69 (55–79) | 69 (56–79) | .31h |
| Age at time of culture, y | .61 | .36 | ||||||
| 0–18 | 0 (0) | 38 (2.4) | 38 (2.4) | 0 (0) | 29 (1.6) | 29 (1.6) | ||
| 19–49 | 4 (10.5) | 229 (14.7) | 233 (14.6) | 8 (13.3) | 284 (15.7) | 292 (15.7) | ||
| 50–64 | 11 (29.0) | 366 (23.5) | 377 (23.6) | 10 (16.7) | 414 (22.9) | 424 (22.7) | ||
| ≥65 | 23 (60.5) | 924 (59.3) | 947 (59.4) | 42 (70.0) | 1079 (59.8) | 1121 (60.1) | ||
| Race and ethnicity | .98a | .13 | ||||||
| Hispanic, any race | 4 (10.5) | 155 (10.0) | 159 (10.0) | 16 (26.7) | 368 (20.4) | 384 (20.6) | ||
| Not known to be Hispanic—White | 20 (52.6) | 798 (51.3) | 818 (51.3) | 24 (40.0) | 968 (53.6) | 992 (53.2) | ||
| Not known to be Hispanic—other or multiple racesb | 14 (36.8) | 586 (37.6) | 600 (37.6) | 20 (33.3) | 447 (24.8) | 467 (25.0) | ||
| Unknown race and ethnicity | 0 (0) | 18 (1.2) | 18 (1.1) | 0 (0) | 23 (1.3) | 23 (1.2) | ||
| Comorbiditiesc | ||||||||
| Cardiovascular diseased | 15 (39.5) | 723 (46.4) | 738 (46.3) | .40 | 22 (36.7) | 793 (43.9) | 815 (43.7) | .26 |
| Diabetes mellitus | 20 (52.6) | 677 (43.5) | 697 (43.7) | .26 | 28 (46.7) | 736 (40.8) | 764 (41.0) | .36 |
| Neurologic condition, any | 12 (31.6) | 628 (40.3) | 640 (40.1) | .28 | 29 (48.3) | 783 (43.4) | 812 (43.5) | .45 |
| Urinary tract problems/abnormalities | 9 (23.7) | 511 (32.8) | 520 (32.6) | .24 | 11 (18.3) | 618 (34.2) | 629 (33.7) | .01 |
| Chronic renal disease | 17 (44.7) | 526 (33.8) | 543 (34.0) | .16 | 21 (35.0) | 534 (29.6) | 555 (29.8) | .37 |
| Chronic pulmonary diseasee | 12 (31.6) | 395 (25.4) | 407 (25.5) | .39 | 16 (26.7) | 441 (24.4) | 457 (24.5) | .69 |
| Malignancy (hematologic or solid organ) | 12 (31.6) | 378 (24.3) | 390 (24.5) | .30 | 7 (11.7) | 307 (17.0) | 314 (16.8) | .28 |
| Skin conditionf | 13 (34.2) | 512 (32.9) | 525 (32.9) | .86 | 10 (16.7) | 420 (23.3) | 430 (23.1) | .23 |
| Gastrointestinal diseaseg | 7 (18.4) | 262 (16.8) | 269 (16.9) | .80 | 6 (10.0) | 353 (19.6) | 359 (19.3) | .06 |
| Transplant (hematopoietic stem cell or solid organ) | 4 (10.5) | 79 (5.1) | 83 (5.2) | .13 | 2 (3.3) | 38 (2.1) | 40 (2.1) | .37 |
| Any documented comorbidity | 37 (97.4) | 1510 (97.0) | 1547 (97.0) | >.99a | 56 (93.3) | 1700 (94.2) | 1756 (94.2) | .78 |
| None | 1 (2.6) | 47 (3.0) | 48 (3.0) | >.99a | 4 (6.7) | 105 (5.8) | 109 (5.8) | .78a |
| Unknown | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (0.1) | 1 (0.1) | >.99a | |
| Charlson Comorbidity Index score, median (IQR) | 3 (1–4) | 3 (1–4) | 3 (1–4) | .84h | 2 (1–4) | 2 (1–4) | 2 (1–4) | .35h |
Abbreviations: CRE, carbapenem-resistant Enterobacterales; ESBL-E, extended-spectrum ß-lactamase-producing Enterobacterales; SC2+, positive SARS-CoV-2 test result.
aFisher exact test.
bAll non-Hispanic, non-White patients were grouped into a single category due to small numbers. These included patients of Black, Asian, American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, or ≥2 races.
cPatients could have >1 underlying condition reported.
dDefined as myocardial infarction, congestive heart failure, congenital heart disease, stroke, transient ischemic attack, or peripheral vascular disease.
eDefined as cystic fibrosis or any chronic respiratory condition resulting in symptomatic dyspnea.
fDefined as burn, decubitus/pressure ulcer, surgical wound, or other chronic ulcer or chronic wound.
gDefined as diverticular disease, inflammatory bowel disease, peptic ulcer disease, short gut syndrome, or liver disease.
hWilcoxon rank sum test.
ESBL-E cases with a SC2+ were more likely to have pneumonia (n = 4 [6.7%] vs 33 [1.8%], P = .03) than those without a SC2+, whereas there were no significant differences in types of infection for CRE cases (Table 2). CRE cases with a SC2+ were more likely than those without a SC2+ to be classified epidemiologically as community associated (n = 7 [18.4%] vs 111 [7.1%], P = .02), whereas there were no significant differences in epidemiologic classification for ESBL-E cases. A higher proportion of ESBL-E cases with a SC2+ than those without a SC2+ were from a urine specimen (n = 55 [91.7%] vs 1394 [77.2%], P = .03), whereas there were no significant differences in culture sources for CRE cases.
Table 2.
Culture Source, Epidemiologic Classification, Infection Syndromes, and Prior Health Care Risk Factors Among Hospitalized CRE and ESBL-E Cases With and Without a SC2+, 10 US Sites, 2020–2022
| CRE Cases, No. (%) | ESBL-E Cases, No. (%) | |||||||
|---|---|---|---|---|---|---|---|---|
| Characteristic | SC2+ (n = 38) | No SC2+ (n = 1557) | All (n = 1595) | P Value | SC2+ (n = 60) | No SC2+ (n = 1806) | All (n = 1866) | P Value |
| Culture source | .09 | .03 | ||||||
| Blood | 5 (13.2) | 314 (20.2) | 319 (20.0) | 5 (8.3) | 347 (19.2) | 352 (18.9) | ||
| Other sterile site | 0 (0) | 119 (7.6) | 119 (7.5) | 0 (0) | 65 (3.6) | 65 (3.5) | ||
| Urine | 33 (86.8) | 1124 (72.2) | 1157 (72.5) | 55 (91.7) | 1394 (77.2) | 1449 (77.7) | ||
| Epidemiologic classification | .02a | .13a | ||||||
| Community associated | 7 (18.4) | 111 (7.1) | 118 (7.4) | 12 (20.0) | 375 (20.8) | 387 (20.7) | ||
| Health care associated, community onset | 20 (52.6) | 877 (56.3) | 897 (56.2) | 30 (50.0) | 1073 (59.4) | 1103 (59.1) | ||
| Hospital onset | 10 (26.3) | 564 (36.2) | 574 (36.0) | 18 (30.0) | 353 (19.6) | 371 (19.9) | ||
| Unknown | 1 (2.6) | 5 (0.3) | 6 (0.4) | 0 (0) | 5 (0.3) | 5 (0.3) | ||
| Selected types of infection | ||||||||
| Lower urinary tract infection | 27 (71.1) | 914 (59.0) | 941 (59.3) | .14 | 42 (70.0) | 1119 (62.1) | 1161 (62.4) | .22 |
| Bacteremia | 5 (13.2) | 325 (21.0) | 330 (20.8) | .24 | 5 (8.3) | 388 (21.5) | 393 (21.1) | .01 |
| Pyelonephritis | 0 (0) | 64 (4.1) | 64 (4.0) | .40a | 2 (3.3) | 143 (7.9) | 145 (7.8) | .32a |
| Septic shock | 2 (5.3) | 150 (9.7) | 152 (9.6) | .57a | 3 (5.0) | 142 (7.9) | 145 (7.8) | .62a |
| Pneumonia | 3 (7.9) | 39 (2.5) | 42 (2.7) | .08a | 4 (6.7) | 33 (1.8) | 37 (2.0) | .03a |
| Otherb | 0 (0) | 163 (10.5) | 163 (10.3) | .03a | 1 (1.7) | 120 (6.7) | 121 (6.5) | .18a |
| None or colonized | 6 (15.8) | 194 (12.5) | 200 (12.6) | .47a | 11 (18.3) | 247 (13.7) | 258 (13.9) | .31 |
| Unknown | 0 (0) | 9 (0.6) | 9 (0.6) | >.99a | 0 (0) | 5 (0.3) | 5 (0.3) | >.99a |
| Health care exposures in the prior year | ||||||||
| Hospitalization | 26 (68.4) | 1124 (72.2) | 1150 (72.1) | .61 | 32 (53.3) | 1060 (58.7) | 1092 (58.5) | .41 |
| Surgery (outpatient or inpatient) | 9 (23.7) | 624 (40.1) | 633 (39.7) | .04 | 10 (16.7) | 435 (24.1) | 445 (23.9) | .18 |
| Long-term care facility stay | 15 (39.5) | 432 (27.8) | 447 (28.0) | .11 | 12 (20.0) | 478 (26.5) | 490 (26.3) | .26 |
| Long-term acute care hospitalization | 2 (5.3) | 56 (3.6) | 58 (3.6) | .64a | 0 (0) | 18 (1.0) | 18 (1.0) | >.99a |
| Current chronic dialysis | 2 (5.3) | 121 (7.8) | 123 (7.7) | .76a | 7 (11.7) | 102 (5.7) | 109 (5.8) | .08a |
| Any indwelling device in the 2 d prior | 16 (42.1) | 1016 (65.3) | 1032 (64.7) | <.01 | 28 (46.7) | 817 (45.2) | 845 (45.3) | .83 |
| Central venous catheter | 5 (13.2) | 437 (28.1) | 442 (27.7) | .04 | 10 (16.7) | 261 (14.5) | 271 (14.5) | .63 |
| Urinary catheter | 15 (39.5) | 696 (44.7) | 711 (44.6) | .52 | 22 (36.7) | 602 (33.3) | 624 (33.4) | .59 |
| Other indwelling devices | 7 (18.4) | 541 (34.8) | 548 (34.4) | .04 | 11 (18.3) | 316 (17.5) | 327 (17.5) | .87 |
| Any documented health care exposure | 30 (79.0) | 1441 (92.6) | 1471 (92.2) | <.01 | 48 (80.0) | 1426 (79.0) | 1474 (79.0) | .85 |
| Clinical outcomes | ||||||||
| Admission to the ICU on the date of or in the 7 d after culture collectionc | 11/31 (35.5) | 234/1288 (18.2) | 245/1319 (18.6) | .01 | 10/53 (18.9) | 238/1689 (14.1) | 248/1742 (14.2) | .33 |
| Length of hospital stay, d, median (IQR) | 10 (4,19) | 10 (5,28) | 10 (5,27) | .28 | 13 (7,19) | 7 (4,14) | 7 (4,14) | <.01 |
| 30-d mortalityd | 10 (26.3) | 201 (12.9) | 211 (13.2) | .02 | 14 (23.3) | 157 (8.7) | 171 (9.2) | <.01 |
Abbreviations: CRE, carbapenem-resistant Enterobacterales; ESBL-E, extended-spectrum ß-lactamase-producing Enterobacterales; ICU, intensive care unit; SC2+, positive SARS-CoV-2 test result.
aFisher exact test.
bOther infection syndromes include septic shock, peritonitis, abscess (not skin), arteriovenous fistula/graft infection, bursitis, catheter site infection, cellulitis, chronic ulcer/wound (not decubitus), decubitus/pressure ulcer, empyema, endocarditis, epidural abscess, meningitis, osteomyelitis, septic arthritis, septic emboli, skin abscess, surgical incision infection, surgical site infection, traumatic wound, or other infection.
cRestricted to patients who were not in an ICU prior to CRE or ESBL culture collection.
dMortality data reported in the medical record or state vital statistics registry.
Among CRE cases, a higher proportion of those with a SC2+ than those without a SC2+ required admission to the ICU on the date of incident specimen collection or in the following 7 days (35.5% vs 18.2%, P = .01) and died within 30 days of incident specimen collection (26.3% vs 12.9%, P = .02; Table 2). Among ESBL-E cases, a higher proportion of those with a SC2+ than those without a SC2+ also died within 30 days (23.3% vs 8.7%, P < .01), but there was no difference in the proportion admitted to the ICU. There was a significant difference in length of hospitalization between those with and without a SC2+ among ESBL-E cases (P = .0001) but no significant difference among CRE cases (P = .28).
In multivariable analyses, among CRE cases, a SC2+ was significantly associated with ICU admission (aOR, 1.69; 95% CI, 1.14–2.50) and 30-day mortality (aOR, 1.79; 95% CI, 1.22–2.64; Table 3, Supplementary Table 1). In multivariable analyses, among ESBL-E cases, a SC2+ was also significantly associated with ICU admission (aOR, 1.48; 95% CI, 1.03–2.12) and 30-day mortality (aOR, 1.94; 95% CI, 1.39–2.70; Supplementary Table 2).
Table 3.
Adjusted Odds of ICU Admission and 30-Day Mortality Among Hospitalized CRE and ESBL-E Cases With a SC2+, 10 US Sites, 2020–2022
| CRE Cases | ESBL-E Cases | |||||
|---|---|---|---|---|---|---|
| Clinical Outcome | Odds Ratioa | 95% CI | P Value | Odds Ratioa | 95% CI | P Value |
| Admission to the ICU on the date of or in the 7 d after culture collectionb | 1.69 | 1.14–2.50 | <.01 | 1.48 | 1.03–2.12 | .03 |
| 30-d mortalityc | 1.79 | 1.22–2.64 | <.01 | 1.94 | 1.39–2.70 | <.01 |
Abbreviations: CRE, carbapenem-resistant Enterobacterales; ESBL-E, extended-spectrum ß-lactamase-producing Enterobacterales; ICU, intensive care unit; SC2+, positive SARS-CoV-2 test result.
aAdjusted for age, sex, race and ethnicity, Charlson Comorbidity Index, epidemiologic class, invasive infection (sterile vs urine), and prior incident case in the year before culture collection.
bRestricted to patients who were not in an ICU prior to the date of incident specimen collection.
cMortality data reported in the medical record.
In the sensitivity analysis including only CRE cases that underwent carbapenemase testing (n = 1411), similar results were seen after adjusting for carbapenemase status for 30-day mortality, but there was no significant association for ICU admission (Table 4, Supplementary Table 3).
Table 4.
Adjusted Odds of ICU Admission and 30-Day Mortality Among Hospitalized CRE and ESBL-E Cases With a SC2+ When Adjusting for Carbapenemase Testing Status From Any Laboratory, 10 US Sites, 2020–2022
| CRE Cases | |||
|---|---|---|---|
| Clinical Outcome | Odds Ratioa | 95% CI | P Value |
| Admission to the ICU on the date of or in the 7 d after culture collectionb | 1.53 | .94–2.49 | .09 |
| 30-d mortalityc | 1.74 | 1.13–2.69 | .01 |
Abbreviations: CRE, carbapenem-resistant Enterobacterales; ESBL-E, extended-spectrum ß-lactamase-producing Enterobacterales; ICU, intensive care unit; SC2+, positive SARS-CoV-2 test result.
aAdjusted for age, sex, race and ethnicity, Charlson Comorbidity Index, epidemiologic class, invasive infection (sterile vs urine), and prior incident case in the year before culture collection.
bRestricted to patients who were not in an ICU prior to the date of incident specimen collection.
cMortality data reported in the medical record.
DISCUSSION
We utilized data from active laboratory- and population-based surveillance to describe the epidemiology of hospitalized patients with multidrug-resistant Enterobacterales and COVID-19 coinfection or secondary infections across diverse geographic locations. We found that among hospitalized patients, CRE (2.4%) and ESBL-E (3.2%) cases with preceding COVID-19 were uncommon but had worse outcomes when compared with cases without COVID-19, with significantly higher rates of ICU admission and 30-day mortality, even after adjusting for potential confounders.
Among our hospitalized CRE and ESBL-E cases, we found a low prevalence of COVID-19 coinfections or secondary infections. Conversely, among patients with COVID-19, a higher prevalence of coinfections or secondary infections with other pathogens has been reported, ranging from 6.9% to 8.2% among all hospitalized patients to 40.7% to 76.4% among ICU patients [8, 9, 15–17]. In a study of patients with COVID-19, 20% had a bloodstream infection and/or pneumonia caused by carbapenemase-producing Enterobacterales and carbapenem-resistant Acinetobacter baumannii [18]. Notably, we found that pneumonia was significantly more common among ESBL-E cases with a SC2+ than those without a SC2+. While Enterobacterales can cause lower respiratory tract infections and is commonly linked to ventilator-associated pneumonia [19], likely damage of the airway epithelium and mucosal barrier function by SARS-CoV-2 could have predisposed some patients to secondary ESBL-E pneumonia.
In general, there were no major differences in clinical characteristics and epidemiologic classification between ESBL cases with and without a SC2+. This may result from our analysis including only hospitalized ESBL-E cases, which were more likely to have underlying comorbidities and prior health care exposures irrespective of the presence of a SC2+. Interestingly, a higher proportion of CRE cases with a SC2+ were community associated than those without a SC2+, but this finding could have been influenced by the low number of CRE cases with a SC2+.
Our findings from multivariable analyses are consistent with previous studies finding that patients with bacterial and COVID-19 coinfections or secondary infections were at an increased odds of ICU admission and mortality [20]. Furthermore, bacterial coinfection or secondary infections with a multidrug-resistant strain have been shown to be an independent risk factor for in-hospital mortality [16]. Among studies describing COVID-19 and CRE, 30-day mortality rates of 28.6% to 33.3% have been reported [21, 22], similar to what we observed among CRE cases (26.3%). Surprisingly, we found that ESBL-E cases with a SC2+ had a similarly high mortality rate (23.3%); however, this could be due to the analysis being limited to hospitalized patients, who are likely to be sicker. When adjusting for carbapenemase status, we also found a higher 30-day mortality among CRE cases with a SC2+ but not a higher ICU admission rate. Why there is no difference in ICU admission is unclear but could be partly explained by a general increase in carbapenemase-producing CRE among ICU patients during the COVID-19 pandemic due to challenges with infection prevention and control, as observed in some institutions [23].
Our findings have implications for the prevention and general management of COVID-19. Among patients at risk of hospitalization with a multidrug-resistant Enterobacterales infection, efforts should be made to prevent COVID-19 through increasing the uptake of vaccination and promoting the use of personal protective measures. Among patients with COVID-19, effective interventions to prevent secondary multidrug-resistant Enterobacterales infections should be implemented. This consists of strict adherence to recommended infection prevention and control practices and ensuring appropriate use of antibiotics to reduce the selective pressure for multidrug-resistant Enterobacterales [24]. Additional strategies may include investigating innovative approaches to reduce the burden of multidrug-resistant Enterobacterales in patients with COVID-19 through decolonization, given that up to 30% of patients with COVID-19 can be colonized with carbapenem-resistant organisms [18]. Although data are limited, multidrug-resistant Enterobacterales decolonization has been successfully demonstrated in certain patient populations [25–27]; however, further research is needed to evaluate the clinical impact of decolonization and to identify effective agents with minimal potential for cross-resistance.
This analysis had several limitations. First, we could have underestimated the prevalence of COVID-19 among our patients if we misclassified some cases as not having a SC2+ due to varying sensitivity of SARS-CoV-2 assays or incomplete documentation of test results. However, to limit the impact of this misclassification, we restricted our analysis to hospitalized patients, who were more likely to undergo COVID-19 testing and have test results documented. Second, we did not collect CRE and ESBL-E treatment information and thus were unable to adjust for differences in treatment in our models when assessing mortality. We also did not collect data on COVID-19 testing intensity and treatment, including use of immunomodulators, which could have affected the prevalence of COVID-19 and associated outcomes among our cases. Yet, to account for changes in treatment practices over the study period, we adjusted for year of CRE and ESBL-E diagnosis in the models and obtained similar results (data not shown). Third, we did not collect data on the signs and symptoms related to the SC2+, so it is possible that some cases tested by polymerase chain reaction were persistently positive with SARS-CoV-2 but no longer had an infection. Fourth, the percentage of ESBL-E cases with severe outcomes could have been inflated due to the overrepresentation of sterile site infections in our analysis from our sampling procedures for completing ESBL-E case report forms, although we adjusted for sterile infections in our multivariate models. Fifth, the CRE and ESBL-E case definition allowed for patients to have multiple incident cases if the cultures were collected >30 days apart. Yet, we adjusted for cases with a prior incident case in the year before culture collection in the multivariate models. Sixth, data were retrospectively abstracted from patient medical records, and the quality and completeness may have varied among health care systems and inpatient vs outpatient records, which may have resulted in incomplete data for some variables. Furthermore, we assigned infection types according to what the clinicians indicated in the medical records; we did not attempt to capture all associated symptoms to confirm the presence of an infection, and it is possible that some cases were only colonized (eg, asymptomatic bacteriuria instead of actual urinary tract infection). Last, although we included cases from geographically diverse areas, our results might not be representative of the entire country.
In conclusion, we found that CRE and ESBL-E infections among hospitalized patients with preceding COVID-19 were uncommon but associated with significantly worse outcomes than CRE and ESBL-E infections in persons without evidence of COVID-19. Prevention of these infections may require (1) a multidirectional approach consisting of efforts to prevent COVID-19 in patients at risk of CRE and ESBL-E infections and (2) continued emphasis on infection prevention and control measures and antibiotic stewardship to prevent secondary multidrug-resistant Enterobacterales infections in patients with COVID-19.
Supplementary Material
Contributor Information
Julian E Grass, Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
Sandra N Bulens, Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
Uzma A Ansari, Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
Nadezhda Duffy, Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
Jesse T Jacob, Emory University School of Medicine, Atlanta, Georgia, USA; Georgia Emerging Infections Program, Atlanta, Georgia, USA.
Gillian Smith, Emory University School of Medicine, Atlanta, Georgia, USA; Georgia Emerging Infections Program, Atlanta, Georgia, USA; Atlanta Veterans Affairs Medical Center, Decatur, Georgia, USA.
Paulina A Rebolledo, Emory University School of Medicine, Atlanta, Georgia, USA; Georgia Emerging Infections Program, Atlanta, Georgia, USA.
Ana Mesa Restrepo, Emory University School of Medicine, Atlanta, Georgia, USA; Georgia Emerging Infections Program, Atlanta, Georgia, USA; Atlanta Veterans Affairs Medical Center, Decatur, Georgia, USA.
Elisabeth Vaeth, Maryland Department of Health, Baltimore, Maryland, USA.
Ghinwa Dumyati, New York Rochester Emerging Infections Program at the University of Rochester Medical Center, Rochester, New York, USA.
Rebecca Tsay, New York Rochester Emerging Infections Program at the University of Rochester Medical Center, Rochester, New York, USA.
Hsioa Che Looi, New York Rochester Emerging Infections Program at the University of Rochester Medical Center, Rochester, New York, USA.
Erin Phipps, University of New Mexico, Albuquerque, New Mexico, USA; New Mexico Emerging Infections Program, Santa Fe, New Mexico, USA.
Kristina G Flores, University of New Mexico, Albuquerque, New Mexico, USA; New Mexico Emerging Infections Program, Santa Fe, New Mexico, USA.
Christopher Wilson, Tennessee Department of Health, Nashville Tennessee, USA.
Daniel Muleta, Tennessee Department of Health, Nashville Tennessee, USA.
Christopher A Czaja, Colorado Department of Public Health and Environment, Denver, Colorado, USA.
Jennifer Driscoll, Colorado Department of Public Health and Environment, Denver, Colorado, USA.
Helen Johnston, Colorado Department of Public Health and Environment, Denver, Colorado, USA.
Ruth Lynfield, Minnesota Department of Health, St Paul, Minnesota, USA.
Sean O’Malley, Minnesota Department of Health, St Paul, Minnesota, USA.
Meghan Maloney, Connecticut Department of Public Health, Hartford, Connecticut, USA.
Nicole Stabach, Connecticut Department of Public Health, Hartford, Connecticut, USA.
Joelle Nadle, California Emerging Infections Program, Oakland, California, USA.
Rebecca Pierce, Oregon Public Health Division, Oregon Health Authority, Portland, Oregon, USA.
Heather Hertzel, Oregon Public Health Division, Oregon Health Authority, Portland, Oregon, USA.
Alice Y Guh, Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
Supplementary Data
Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
Notes
Acknowledgments . We thank the staff at the clinical and public health laboratories and EIP sites that contributed to this surveillance.
Data availability . The data are not publicly available.
Disclaimer . The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC.
Financial support. This work was supported by the CDC through the Emerging Infections Program (cooperative agreement CDC-RFA-CK17-1701).
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