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Clinical characteristics, risk factors, and outcomes of patients hospitalized in the US military health system with carbapenem-resistant Enterobacteriaceae infection
ARTICLE IN PRESS American Journal of Infection Control 000 (2019) 1−6
Contents lists available at ScienceDirect
American Journal of Infection Control journal homepage: www.ajicjournal.org
Major Article
Clinical characteristics, risk factors, and outcomes of patients hospitalized in the US military health system with carbapenem-resistant Enterobacteriaceae infection Daniel J. Adams MD a,b,*, Apryl Susi MS b, Cade M. Nylund MD b a b
Department of Pediatrics, Naval Medical Center Portsmouth, Portsmouth, VA Department of Pediatrics, Uniformed Services University, Bethesda, MD
Key Words: Hospital mortality Hospital costs Drug resistance
Background: We aimed to characterize the epidemiology, identify risk factors, and measure outcomes of carbapenem-resistant Enterobacteriaceae (CRE) infections among hospitalized patients. Methods: We performed a retrospective study of hospitalized patients with CRE infection using records from the US military health system database. Cases included patients admitted for ≥2 days from 2008-2015, with a clinical culture growing any Enterobacteriaceae reported as resistant to a carbapenem. Multivariable logistic regression was used to identify comorbid conditions and procedures associated with CRE infection, and a high-dimensional propensity score was used for a case-mix adjusted evaluation of CRE-associated in-hospital mortality, length of stay, and hospitalization costs. Results: From 1,162,686 hospitalized patients, we identified 143 with CRE infection over the 7-year study period. Conditions associated with CRE infection included manipulation of the gastrointestinal tract, musculoskeletal trauma, orthopedic procedures, septicemia, and both recent and remote exposure to broad-spectrum b-lactam antibiotics. Patients hospitalized with CRE infection had significantly higher hospitalization costs (attributable difference, $206,664; P < .001), longer hospital stays (attributable difference, 28.8 days; P < .001), and increased odds of in-hospital mortality (adjusted odds ratio, 3.34; 95% confidence interval, 1.82-6.12). Conclusions: CRE are a significant threat to hospitalized patients. Our study quantifies the health care burden associated with CRE infection in the inpatient setting and highlights the importance of initiatives aimed at curbing the spread of these costly infections. Published by Elsevier Inc. on behalf of Association for Professionals in Infection Control and Epidemiology, Inc.
Amid the growing public health crisis of antimicrobial resistant pathogens, carbapenem-resistant Enterobacteriaceae (CRE) are among the most dreaded, given the few available antimicrobial treatment options that exist to combat them and their high associated mortality.1-3 The rise of CRE has been driven in large part by increases in carbapenemase-producing Enterobacteriaceae, such as Klebsiella pneumoniae carbapenemase (KPC), which readily share the carbapenemase enzymes with other Enterobacteriaceae through mobile genetic
*Address correspondence to Daniel J. Adams, MD, Department of Pediatrics, Naval Medical Center Portsmouth, 620 John Paul Jones Circle, Portsmouth, VA 23708. E-mail address: [email protected] (D.J. Adams). Funding/support: This work was supported by funding from the Armed Forces Health Surveillance Center-Global Emerging Infections Surveillance (AFHSC-GEIS) Partners under award number 20160590205. The views expressed in this manuscript are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, US Air Force, Department of Defense, or the United States Government. Conflicts of interest: None to report.
elements, leading to rapid spread.4 Because of the relative infrequency of these infections, sufficiently powered studies of the epidemiology and outcomes of CRE infection are limited. The US military health system (MHS) database, containing comprehensive microbiologic and clinical data on a very large, demographically and geographically diverse population of patients with universal access to care, serves as a valuable tool for studying these rare and serious pathogens. Several groups have identified previous exposure to broad-spectrum antibiotics, indwelling devices, immunosuppression, and longterm health care facility exposure as independent risk factors for CRE colonization or infection.3,5,6 Three previous studies of US military service members and Department of Defense beneficiaries examined the CRE burden, trend, and association with antibiotic exposure in this population.7-9 They found that CRE infections occur rarely in the US MHS compared with the rest of the US population, but their prevalence is rising.9 Additionally, CRE were associated with inpatient exposure to fluoroquinolones.8 Our study aims to more broadly characterize the demographic, diagnostic, procedural, and pharmacologic
https://doi.org/10.1016/j.ajic.2019.10.006 0196-6553/Published by Elsevier Inc. on behalf of Association for Professionals in Infection Control and Epidemiology, Inc.
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D.J. Adams et al. / American Journal of Infection Control 00 (2019) 1−6
risk factors for CRE infection among patients hospitalized in the US MHS, and to evaluate important CRE health care outcomes in this patient population, including length of hospital stay, hospitalization costs, and attributable mortality. METHODS We performed a retrospective study of hospitalized patients with CRE using the TRICARE Management Activity MHS database. This database includes inpatient and outpatient demographic, billing, and clinical data from the electronic medical records of all Department of Defense beneficiaries cared for in all US military treatment facilities (MTF) worldwide, including 60 acute care hospitals and 385 standalone medical clinics. Cases were selected from all patients admitted to an MTF for at least 2 days with a CRE infection from October 2008 to September 2015. CRE infections were defined using the January 2015 Centers for Disease Control and Prevention surveillance definition of growth of any Enterobacteriaceae spp (Enterobacter spp, Escherichia coli, Klebsiella spp, Citrobacter spp, Morganella spp, Proteus spp, Providencia spp, and Serratia spp) reported as resistant to meropenem, ertapenem, imipenem, and/or doripenem.10 For determining carbapenem resistance, we used the existing Clinical Laboratory Standards Institute (CLSI) breakpoints at the time the organism was isolated. In 2010 and 2013, the CLSI breakpoints for defining carbapenem resistance changed, lowering the threshold for defining carbapenem resistance.11 The new breakpoints, however, were adopted variably by different MTF.7 We therefore chose to adopt the definition of CRE used by each individual laboratory at the time of its isolation. Morganella spp, Proteus spp, and Providencia spp, are intrinsically resistant to ertapenem and were therefore included only if found to have resistance to one or more of the other carbapenems. Samples from urine cultures, blood cultures, cerebrospinal fluid cultures, respiratory cultures, wound cultures, and cultures from other sites were included. Isolates from rectal, perianal, and groin swab cultures were excluded to limit our evaluation to CRE infections rather than CRE colonization. Once a patient was selected as a case, he or she was no longer eligible to have future hospitalizations included in the study. Controls for inclusion in the model to generate the highdimensional propensity score were selected from all other hospitalized patients in MTF who were admitted for at least 2 days. For all studied subjects, demographic, clinical, and outpatient prescription data were obtained, including age, sex, Department of Defense beneficiary status (active duty, retired, dependent, or ‘other’ [which includes dependents of retirees, dependent survivors, and NATO or foreign military service members and their families]), hospital region (North, South, West, and Overseas) and hospital size (large, medium, or small). To evaluate associated conditions, we collected diagnosis and procedure codes from outpatient and inpatient encounters at both civilian and military facilities in the 52 weeks preceding hospital admission for all subjects. The diagnosis codes were then grouped into clinically relevant categories using the Clinical Classification Software 3-level system from the Agency of Healthcare Quality and Research’s Healthcare Cost and Utilization Project.12 Inpatient and outpatient diagnosis codes were evaluated separately. Current Procedural Terminology codes, procedure codes, and American Hospital Formulary Service medication class codes (including antibiotic class codes) were included in the analysis. A 2-step approach was used to determine the association between these comorbid conditions and CRE infection. Independent variables with the strongest classification were identified by fitting a lasso-regularized generalized logistic model via penalized maximum likelihood with the dependent variable being CRE infection. After narrowing of predictors using lasso, a multivariable logistic regression was performed to calculate unadjusted and adjusted odds ratios and 95% confidence intervals. The independent variables included
demographic factors and significant prior year predictors (those with a lambda minimum greater than 0). The outcomes used to evaluate the impact of CRE infection included in-hospital death, hospital length of stay (LOS), and hospitalization costs. The outcome of death was defined as a subject death during the recorded hospitalization. LOS was evaluated as the number of days hospitalized. Costs were adjusted to 2018 dollars using the US consumer price index for inpatient hospital services. A highdimensional propensity score was calculated to account for important known and unknown confounders. This allowed comparisons under nonrandomized groups. Counts of the diagnostic and procedure codes from outpatient and inpatient encounters, day supply of medication classes of outpatient prescriptions, and day supply by preceding quarter of antibiotics in the 52 weeks preceding hospital admission were used in conjunction with demographics to obtain a propensity score. The propensity score was then ranked and converted into deciles and included as independent variables in each of the models with the outcomes as dependent variables. All analyses were performed using SAS 9.4 (SAS Institute, Cary, NC). This study was approved by the Uniformed Services University institutional review board. RESULTS Our analysis identified 1,162,686 hospitalizations to MTF during the 7-year study period. Of these, 143 patients were found to have CRE infection (3.1 CRE cases per 100,000 hospital days). Characteristics of these patients are summarized in Table 1. Compared with those patients hospitalized without CRE infection, those with CRE infection were significantly older, mostly men, active duty, retired, or “other” service members, and admitted to large MTF in the TRICARE North region of the United States (Northeast, MidAtlantic, and Midwest states east of the Mississippi River) (Table 1). From these 143 patients, 173 bacterial cultures resulted in growth of 180 CRE pathogens, which were mostly Enterobacter spp, Klebsiella spp, Escherichia coli, and Serratia spp (Table 2). The antimicrobial susceptibilities of these isolates are summarized in Table 2, and of note, most CRE isolates had high levels of resistance to most other classes of antimicrobials commonly used to treat Enterobacteriaceae, such as fluoroquinolones, trimethoprim/sulfamethoxazole, and piperacillin/ tazobactam. Most CRE isolates were from urine cultures (55, 31.8%), followed by respiratory cultures (38, 22.0%), wound cultures/abscesses (24, 13.9%), and blood cultures (12, 6.9%). The remaining 44 (25.4%) CRE isolates were grown from a variety of other sources including catheter tips, peritoneal or pleural fluid, and tissue cultures. CRE infections remained relatively stable over the 7-year study period without a significant trend identified (Table 1). The diagnosis and procedure codes most strongly associated with CRE infection included International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 52.22, representing other excision or destruction of lesion or tissue of pancreas or pancreatic duct, followed by enterostomy, orthopedic procedures, and diagnoses relating to trauma, including internal fixation without fracture reduction of carpals and metacarpals, disarticulation of the hip, amputation above the knee, and skin grafting (Table 3). CRE infection also was associated with temporary placement of a tracheostomy, septicemia, and both recent and remote outpatient parenteral antibiotic treatment (OPAT) with broad-spectrum b-lactam antibiotics, such as fourth and fifth generation cephalosporins, piperacillin/tazobactam, and carbapenems (Table 3). The in-hospital mortality rate for patients with CRE infection was 9.1% (13 of 143 patients), compared with 0.46% (5,317 of 1,162,543 patients) in those without CRE infection. In-hospital mortality was highest in patients with CRE isolated from respiratory and blood
ARTICLE IN PRESS D.J. Adams et al. / American Journal of Infection Control 00 (2019) 1−6 Table 1 Characteristics of patients hospitalized with CRE infection compared with patients hospitalized without CRE infection Indication of CRE on hospital discharge file Characteristic Discharges, total number (percent) Age in years, median (IQR)* Age group, years (percent)* 0-5 5-18 18-65 >65 Male* Geographic region* North South West Overseas Hospital size* Large Medium Small Beneficiary status* Dependents Retired Active duty Other Health care exposure Hospitalizations in preceding 12 months, median (IQR) Outpatients visits in preceding 12 months, median (IQR) Yeary 2009 (percent) 2010 (percent) 2011 (percent) 2012 (percent) 2013 (percent) 2014 (percent) 2015 (percent)
CRE
Table 3 Comorbid clinical diagnoses and procedure classifications (Clinical Classification Software codes) most strongly associated with carbapenem-resistant Enterobacteriaceae infection
No CRE
143 (0.012) 56 (30-74)
1,162,543 (99.987) 26 (7-46)
5 (3.5) 1 (0.7) 82 (57.34) 55 (38.46) 95 (66.4)
286,735 (24.66) 19,827 (1.71) 697,855 (60.03) 158,126 (13.61) 472,493 (40.64)
59 (41.26) 52 (36.36) 22 (15.38) 10 (6.99)
313,010 (26.92) 363,257 (31.25) 389,823 (33.53) 96,453 (8.30)
116 (81.12) 24 (16.78) 2 (1.40)
746,712 (64.23) 336,080 (28.91) 71,897 (6.18)
20 (13.99) 50 (34.97) 32 (22.38) 41 (28.67)
577,863 (49.71) 147,935 (12.73) 246,380 (21.19) 190,365 (16.37)
2 (0-4)
0 (0-1)
28 (12-62)
17 (2-31)
17 (11.89) 23 (16.08) 29 (20.28) 20 (13.99) 19 (13.29) 18 (12.59) 17 (11.89)
169,627 (14.59) 170,442 (14.66) 169,130 (14.55) 165,700 (14.25) 164,316 (14.13) 165,080 (14.20) 158,248 (13.61)
Data are reported as number (%) unless otherwise indicated. Missing values are the reason some numbers or percentages do not sum to total discharges. Percentages reported for each year are the proportion of the total number of ‘CRE’ or ‘No CRE’ hospitalizations that occurred in that year of the study. CRE, carbapenem-resistant Enterobacteriaceae; IQR, interquartile range. *Across all variable categories, there is a significant difference between patients with CRE compared with those without CRE (P < .001). y P = .57.
specimens. Those with a respiratory culture growing CRE had a 21.4% mortality rate (6 of 28 patients), and in those with CRE bloodstream infection the mortality rate was 16.7% (2 of 12 patients). After propensity score adjustment, CRE infection was associated with a more than 3-times increased odds of in-hospital mortality (adjusted odds ratio, 3.34; 95% confidence interval, 1.82-6.12).
3
Condition or procedure
Adjusted OR (95% CI)
Other excision or destruction of lesion or tissue of pancreas or pancreatic duct Internal fixation of bone without fracture reduction, carpals and metacarpals Other enterostomy Temporary tracheostomy Amputation above knee Disarticulation of hip Dermal regenerative graft Heel loop/holder, any type, with or without ankle strap, each (wheelchair) Injection, certolizumab pegol, 1 mg Other mycoses (inpatient) Powered pressure-reducing air mattress Septicemia (except in labor) Piperacillin/tazobactam prescribed in last 6-9 months* Carbapenem prescribed in the last 3-6 months* Carbapenem prescribed in the last 9-12 months* Fifth generation cephalosporin prescribed in the last 0-3 months* Fourth generation cephalosporin prescribed in the last 9-12 months* Metronidazole prescribed in the last 9-12 months*
52.16 (11.82-230.13) 10.09 (2.65-38.46) 8.86 (3.82-20.56) 7.01 (4.12-11.93) 6.14 (2.99-12.61) 5.98 (1.66-21.52) 5.29 (2.81-9.93) 3.30 (2.25-4.84) 1.93 (1.56-2.38) 1.74 (1.32-2.30) 1.67 (1.32-2.11) 1.65 (1.40-1.93) 1.15 (1.06-1.25) 1.08 (1.002-1.16) 1.08 (1.03-1.13) 1.24 (1.11-1.39) 1.22 (1.11-1.34) 1.02 (1.01-1.04)
The International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9CM) codes for diagnoses and procedures were grouped into clinically relevant categories using the Healthcare Cost and Utilization Project’s Clinical Classification Software. CI, confidence interval; OR, odds ratio. *For antibiotic prescriptions, the adjusted OR represents the odds of carbapenem-resistant Enterobacteriaceae infection with each additional day the antibiotic was prescribed during that time period.
Additionally, after propensity score adjustment, CRE infection was shown to have a significant impact on hospitalization LOS and costs. Patients hospitalized with CRE infection had an attributable difference of a 28.8 day longer hospital stay (P < .001) and $206,664 (P < .001) greater hospitalization costs than those without CRE infection (Table 4).
DISCUSSION Our study identified that CRE infections among patients hospitalized in the US MHS are relatively stable in recent years, have significant cross-resistance to most other classes of antibiotics, are clustered among older men in large MTF, and occur mostly in the TRICARE North region of the United States. CRE infection in these patients was associated with gastrointestinal tract surgery,
Table 2 Antimicrobial susceptibility of carbapenem-resistant Enterobacteriaceae isolates reported as percent susceptible
Antimicrobial Cefotaxime/ Ceftriaxone Ceftazidime Cefepime Aztreonam Amikacin Trimethoprim/ sulfamethoxazole Ciprofloxacin Piperacillin/ tazobactam Tigecycline Colistin
Enterobacter spp N = 57 n (%S)
Klebsiella spp N = 53 n (%S)
Escherichia coli N = 37 n (%S)
Serratia spp N = 27 n (%S)
Proteus spp N = 2 n (%S)
Citrobacter spp N = 2 n (%S)
Providencia spp N = 1 n (%S)
Morganella spp N = 1 n (%S)
42 (11.9) 25 (20) 50 (42) 26 (7.7) 43 (88.4) 57 (61.4) 54 (55.6) 39 (12.8) 9 (77.8) NT
45 (8.9) 32 (9.4) 41 (14.6) 31 (3.2) 31 (64.5) 47 (17.0) 44 (15.9) 37 (8.1) 12 (83.3) 1 (100)
30 (33.3) 12 (25) 26 (38.5) 15 (33.3) 19 (89.5) 37 (45.9) 37 (40.5) 18 (33.3) 9 (100) NT
15 (46.7) 10 (80) 17 (76.5) 4 (75) 12 (75) 23 (87.0) 27 (66.7) 10 (70) 1 (0) NT
2 (0) 1 (100) 2 (50) 1 (100) 2 (100) 2 (50) 2 (50) 2 (50) 1 (0) NT
1 (100) 0 (0) 2 (50) 1 (100) 1 (100) 2 (100) 2 (100) 2 (50) NT NT
1 (100) 1 (100) 1 (100) 1 (100) 1 (100) 1 (0) 1 (0) 1 (100) NT NT
1 (100) NT 1 (100) 1 (100) NT 1 (0) 1 (0) 1 (100) NT NT
N, number of total isolates; n, number of isolates tested; %S, percent susceptible; NT, not tested.
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Table 4 Hospitalization costs and length of stay attributable to CRE infection Outcome
CRE
No CRE
Attributable difference
P value
Hospitalization costs, mean full direct costs in dollars Length of stay in days
$231,413 33.77
$24,749 5.01
$206,664 28.76
<.0001 <.0001
Length of stay and costs values represent propensity score adjusted least-squared estimate means. Costs were adjusted to 2018 dollars using the US Consumer Price Index for inpatient hospital services. CRE, carbapenem-resistant Enterobacteriaceae.
orthopedic procedures, septicemia, and previous receipt of OPAT with certain broad-spectrum antibiotics. Consistent with other studies of CRE outcomes, CRE infection was associated with longer and more costly hospitalizations and a significant increase in the odds of in-hospital death. In 1996, the first KPC pathogen was isolated from a patient hospitalized in North Carolina.13 Over the last 20 years, KPC-producing bacteria, which constitute approximately half of all CRE isolates, have spread to 48 states, but remain concentrated in the Mid-Atlantic and Northeast United States, which corresponds to our findings of the TRICARE North region having the highest burden of inpatient CRE infection.14,15 Consistent with our cohort, other groups have found CRE infections to occur predominantly in older men.16,17 Health care exposure may be the best established risk factor for CRE acquisition and infection; however, when evaluating health care exposure based on the frequency of hospitalizations and outpatient visits in the preceding year, we found no significant differences between those with and without CRE infection.2,4,18 The prevailing sources of CRE isolates included urine, respiratory, and wound cultures. This is consistent with the known clinical manifestations of Enterobacteriaceae infections, which most commonly present as urinary tract infections, pneumonia, and skin and soft-tissue infections.18 We observed that CRE isolates from our patients, especially Klebsiella spp, exhibited significant cross-resistance with alternate antibiotic agents commonly used to treat infections caused by gram-negative pathogens. This is expected, as many CRE carry additional antibiotic resistance genes on plasmids, leading to multidrug resistance.15,19,20 Tigecycline and amikacin were the only antibiotics in our study to demonstrate consistent in vitro activity against CRE isolates, and only one CRE isolate was tested for colistin resistance. All 3 of these agents have significant shortcomings in the treatment of CRE infections, including high rates of nephrotoxicity for colistin and aminoglycosides, and poor penetration of several anatomic spaces in the case of tigecycline.18,21 Resistance to multiple antibiotic classes, and poor efficacy of remaining active antibiotic agents, are thought to be the major contributors to the increased mortality seen with CRE infections, and could have played a role in the high mortality seen in our patient population.18 We were unable, however, to identify which antimicrobials were used in the treatment of CRE in patients in this study. An especially sobering reminder of the public health crisis of antibiotic-resistant pathogens, such as CRE, are new reports of colistin-resistant Enterobacteriaceae from food sources in China, and from long-term acute care hospitals in the United States, known for high rates and spread of CRE.22,23 These reports, along with our findings of CRE infections with significant in vitro cross-resistance to other antimicrobial classes, underscore the importance of developing novel antimicrobial treatments for combating CRE infections. Since the completion of our study, newer antimicrobial agents such as ceftazidime-avibactam, meropenem-vaborbactam, and other combination b-lactam plus b-lactamase inhibitors have been US Food and Drug Administration −approved for the treatment of complicated Enterobacteriaceae infections harboring extended spectrum b-lactamase, AmpC, and certain classes of carbapenemases.24,25 These agents have certain limitations and are costly, but hold significant promise for the treatment of these challenging infections.
Conditions and procedures associated with CRE infection in our study include invasive procedures, especially those involving the gastrointestinal tract, and temporary tracheostomy placement, along with critical illnesses such as septicemia. These conditions are known to be associated with prolonged hospitalization and broad-spectrum antibiotic exposure, which are both well-established risk factors for CRE colonization and infection.2,26 These identified conditions are consistent with the natural history of CRE infection, in which CRE first colonizes ill patients with prolonged hospitalization in critical care environments, and then invades multiple anatomic sites from the digestive tract or respiratory tract in patients made vulnerable through invasive procedures and placement of indwelling devices.18 Our analysis of conditions and procedures associated with CRE infection, specifically amputation, skin grafting, and other orthopedic procedures, also highlights an at-risk population unique to the MHS, namely individuals wounded in combat. Multidrug-resistant wound infections have previously been reported in this group.9,27-29 Based on our findings, active CRE surveillance of this patient population should be considered owing to their increased CRE infection risk. In a multivariate analysis of outpatient antibiotic class exposure in the preceding year as a predictor for CRE infection, there was a slight increase in the odds of CRE infection for each day of carbapenem exposure in the 3-6 months and 9-12 months before hospitalization (Table 3). This association of CRE infection with preceding carbapenem exposure is consistent with the hypothesis that these broadspectrum antibiotic agents provide the necessary antimicrobial pressure to select out CRE pathogens. Data showing a reduction in CRE infections with decreased use of carbapenem agents, however, are lacking. Efforts to reduce carbapenem use by 60% in one group were not associated with any change in carbapenem resistance in Klebsiella spp.30 In addition to carbapenem exposure, CRE infection was associated with both recent and remote outpatient exposure to other broad-spectrum b-lactam and glycopeptide agents, in accordance with the findings of similar studies of antibiotic exposure in cases of CRE colonization and infection.2,8,26 These results highlight the importance of antimicrobial stewardship initiatives, especially aimed at curbing carbapenem and other broad-spectrum antimicrobial use in the OPAT setting, to help prevent CRE infection and associated adverse outcomes. After adjusting for the severity of illness and other confounders, patients hospitalized with CRE infection carried more than 3-times increased odds of in-hospital mortality, which is comparable to that reported elsewhere, and confirms CRE as a deadly group of pathogens in this population.2,26,31 The reason(s) for this increased attributable mortality are unclear and require further study. Future studies of CRE infection in the US MHS could evaluate which antimicrobial treatment regimens are most successful. In addition to increased mortality, those with CRE infection had significantly longer and more costly hospitalizations, which provides a significant financial incentive for infection control and antimicrobial stewardship initiatives aimed at preventing CRE transmission, CRE infection, and treatment with costly antimicrobials. Our study examines culture-confirmed CRE infections among hospitalized patients in the US MHS. Use of the large MHS database, which includes a geographically and demographically diverse
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population with universal access to care, allowed for broad characterization of the epidemiology of these relatively rare infections, which should be generalizable to patients in other US health care networks. Through use of the Healthcare Cost and Utilization Project’s Clinical Classification Software, we were able to identify specific, yet clinically relevant, CRE-associated conditions and procedures, which can help providers identify the patient populations at highest risk for CRE infection. Additionally, through the use of high-dimensional propensity score ranking, we adjusted for patient severity, comorbid conditions, and other potential known and unknown confounders to provide the most accurate measurement of health care outcomes attributable to CRE infection. Our study does have significant limitations. Although we removed CRE isolates from cultures of skin and rectal swabs, those included from urine and respiratory cultures certainly could have identified some patients with CRE colonization, instead of true infection. Because of limitations in the MHS database we were unable to further refine the definition of CRE urinary tract infection and CRE pneumonia through in-depth chart review. However, the high mortality rate among patients with CRE respiratory cultures implies infection over colonization. Additionally, because of variability in the adoption of updated CLSI breakpoints for carbapenem resistance among different institutions, the microbiologic definition of CRE over the course of our study certainly changed. However, our definition of CRE infection was the same as that used by the clinician interpreting the laboratory report at the time the culture was reported, which closer approximates “real-world” clinical practice. Although we report in vitro antimicrobial susceptibility among CRE isolates, we were unable to report the actual antimicrobials used to treat CRE infections, and therefore cannot comment on the efficacy of any CRE treatment regimen. Our study was limited by the inability to differentiate between carbapenemase-producing CRE and noncarbapenemase CRE, which can have different epidemiology and clinical outcomes.15 We did measure recent outpatient exposure to antimicrobials as a CRE infection risk factor; however, because of limitations in our electronic medical record, we were unable to evaluate antibiotic exposure in the inpatient setting, or recent exposure to skilled nursing or inpatient rehabilitation facilities for their contribution to CRE infection. Finally, given inherent limitations of retrospective studies, we cannot definitively conclude that CRE infection caused the hospitalization outcomes measured. CONCLUSIONS Our findings serve as a valuable tool for providers caring for hospitalized patients, identifying the at-risk population for inpatient CRE infections, which can inform targeted active surveillance programs. Of all available antimicrobials, aminoglycosides and tigecycline had the best in vitro activity against our CRE isolates, which can help to inform empiric CRE infection treatment strategies for certain types of CRE infection. Additionally, we demonstrated that inpatient CRE infections are just as costly and deadly among patients cared for in US MTF as they are in other US and worldwide populations. This underscores the importance of continued development and ongoing evaluation of novel therapeutic agents, adherence to infection control guidance, and of the growing antimicrobial stewardship movement, which aims both to prevent the rise of CRE pathogens and preserve the efficacy of the few existing antimicrobial treatment options. Acknowledgments The authors would like to thank Dr. Matthew D. Eberly for his assistance in proofreading the article.
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Centers for Disease Control and Prevention. FAQs about choosing and implementing a CRE definition. Available from: https://www.cdc.gov/hai/organisms/cre/definition.html. Accessed September 1, 2019. 11. Rennie RP, Jones RN. Effects of breakpoint changes on carbapenem susceptibility rates of Enterobacteriaceae: results from the SENTRY antimicrobial surveillance program, United States, 2008 to 2012. Can J Infect Dis Med Microbiol 2014;25:285-7. 12. Healthcare Cost and Utilization Project. Clinical classifications software (CCS) for ICD9-CM. Available from: www.hcup-us.ahrq.gov/toolssoftware/ccs/ccs.jsp. Accessed October 4, 2018. 13. Yigit H, Queenan AM, Anderson GJ, Domenech-Sanchez A, Biddle JW, Steward CD, et al. Novel carbapenem-hydrolyzing beta-lactamase, KPC-1, from a carbapenemresistant strain of Klebsiella pneumoniae. Antimicrob Agents Chemother 2001;45: 1151-61. 14. Guh AY, Bulens SN, Mu Y, Jacob JT, Reno J, Scott J, et al. Epidemiology of carbapenem-resistant Enterobacteriaceae in 7 US communities, 2012-2013. JAMA 2015; 314:1479-87. 15. Logan LK, Weinstein RA. The epidemiology of carbapenem-resistant Enterobacteriaceae: the impact and evolution of a global menace. J Infect Dis 2017;215:28-36. 16. Falagas ME, Rafailidis PI, Kofteridis D, Virtzili S, Chelvatzoglou FC, Papaioannou V, et al. Risk factors of carbapenem-resistant Klebsiella pneumoniae infections: a matched case control study. J Antimicrob Chemother 2007;60:1124-30. 17. Jeong SH, Kim HS, Kim JS, Shin DH, Kim HS, Park MJ, et al. Prevalence and molecular characteristics of carbapenemase-producing Enterobacteriaceae from five hospitals in Korea. Ann Lab Med 2016;36:529-35. 18. Temkin E, Adler A, Lerner A, Carmeli Y. Carbapenem-resistant Enterobacteriaceae: biology, epidemiology, and management. Ann N Y Acad Sci 2014;1323:22-42. 19. Bush K, Fisher JF. Epidemiological expansion, structural studies, and clinical challenges of new beta-lactamases from gram-negative bacteria. Annu Rev Microbiol 2011;65:455-78. 20. Jacoby GA, Munoz-Price LS. The new beta-lactamases. N Engl J Med 2005;352:38091. 21. Munoz-Price LS, Poirel L, Bonomo RA, Schwaber MJ, Daikos GL, Cormican M, et al. Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases. Lancet Infect Dis 2013;13:785-96. 22. Han JH, Goldstein EJ, Wise J, Bilker WB, Tolomeo P, Lautenbach E. Epidemiology of carbapenem-resistant Klebsiella pneumoniae in a network of long-term acute care hospitals. Clin Infect Dis 2017;64:839-44. 23. Liu YY, Wang Y, Walsh TR, Yi LX, Zhang R, Spencer J, et al. Emergence of plasmidmediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis 2016;16: 161-8. 24. Dhillon S. Meropenem/vaborbactam: a review in complicated urinary tract infections. Drugs 2018;78:1259-70. 25. Zasowski EJ, Rybak JM, Rybak MJ. The beta-lactams strike back: ceftazidime-avibactam. Pharmacotherapy 2015;35:755-70. 26. Schwaber MJ, Klarfeld-Lidji S, Navon-Venezia S, Schwartz D, Leavitt A, Carmeli Y. Predictors of carbapenem-resistant Klebsiella pneumoniae acquisition among hospitalized adults and effect of acquisition on mortality. Antimicrob Agents Chemother 2008;52:1028-33. 27. Lesho E, Yoon EJ, McGann P, Snesrud E, Kwak Y, Milillo M, et al. Emergence of colistin-resistance in extremely drug-resistant Acinetobacter baumannii containing a novel pmrCAB operon during colistin therapy of wound infections. J Infect Dis 2013;208:1142-51.
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28. Lohr B, Pfeifer Y, Heudorf U, Rangger C, Norris DE, Hunfeld KP. High prevalence of multidrug-resistant bacteria in Libyan war casualties admitted to a tertiary care hospital, Germany. Microb Drug Resist 2018;24:578-84. 29. McGann P, Snesrud E, Ong AC, Appalla L, Koren M, Kwak YI, et al. War wound treatment complications due to transfer of an IncN plasmid harboring bla(OXA181) from Morganella morganii to CTX-M-27-producing sequence type 131 Escherichia coli. Antimicrob Agents Chemother 2015;59:3556-62.
30. Sistanizad M, Kouchek M, Miri M, Goharani R, Solouki M, Ayazkhoo L, et al. Carbapenem restriction and its effect on bacterial resistance in an intensive care unit of a teaching hospital. Iran J Pharm Res 2013;12:503-9. 31. Tumbarello M, Viale P, Viscoli C, Trecarichi EM, Tumietto F, Marchese A, et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin Infect Dis 2012;55:943-50.
Contents lists available at ScienceDirect
American Journal of Infection Control journal homepage: www.ajicjournal.org
Major Article
Clinical characteristics, risk factors, and outcomes of patients hospitalized in the US military health system with carbapenem-resistant Enterobacteriaceae infection Daniel J. Adams MD a,b,*, Apryl Susi MS b, Cade M. Nylund MD b a b
Department of Pediatrics, Naval Medical Center Portsmouth, Portsmouth, VA Department of Pediatrics, Uniformed Services University, Bethesda, MD
Key Words: Hospital mortality Hospital costs Drug resistance
Background: We aimed to characterize the epidemiology, identify risk factors, and measure outcomes of carbapenem-resistant Enterobacteriaceae (CRE) infections among hospitalized patients. Methods: We performed a retrospective study of hospitalized patients with CRE infection using records from the US military health system database. Cases included patients admitted for ≥2 days from 2008-2015, with a clinical culture growing any Enterobacteriaceae reported as resistant to a carbapenem. Multivariable logistic regression was used to identify comorbid conditions and procedures associated with CRE infection, and a high-dimensional propensity score was used for a case-mix adjusted evaluation of CRE-associated in-hospital mortality, length of stay, and hospitalization costs. Results: From 1,162,686 hospitalized patients, we identified 143 with CRE infection over the 7-year study period. Conditions associated with CRE infection included manipulation of the gastrointestinal tract, musculoskeletal trauma, orthopedic procedures, septicemia, and both recent and remote exposure to broad-spectrum b-lactam antibiotics. Patients hospitalized with CRE infection had significantly higher hospitalization costs (attributable difference, $206,664; P < .001), longer hospital stays (attributable difference, 28.8 days; P < .001), and increased odds of in-hospital mortality (adjusted odds ratio, 3.34; 95% confidence interval, 1.82-6.12). Conclusions: CRE are a significant threat to hospitalized patients. Our study quantifies the health care burden associated with CRE infection in the inpatient setting and highlights the importance of initiatives aimed at curbing the spread of these costly infections. Published by Elsevier Inc. on behalf of Association for Professionals in Infection Control and Epidemiology, Inc.
Amid the growing public health crisis of antimicrobial resistant pathogens, carbapenem-resistant Enterobacteriaceae (CRE) are among the most dreaded, given the few available antimicrobial treatment options that exist to combat them and their high associated mortality.1-3 The rise of CRE has been driven in large part by increases in carbapenemase-producing Enterobacteriaceae, such as Klebsiella pneumoniae carbapenemase (KPC), which readily share the carbapenemase enzymes with other Enterobacteriaceae through mobile genetic
*Address correspondence to Daniel J. Adams, MD, Department of Pediatrics, Naval Medical Center Portsmouth, 620 John Paul Jones Circle, Portsmouth, VA 23708. E-mail address: [email protected] (D.J. Adams). Funding/support: This work was supported by funding from the Armed Forces Health Surveillance Center-Global Emerging Infections Surveillance (AFHSC-GEIS) Partners under award number 20160590205. The views expressed in this manuscript are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, US Air Force, Department of Defense, or the United States Government. Conflicts of interest: None to report.
elements, leading to rapid spread.4 Because of the relative infrequency of these infections, sufficiently powered studies of the epidemiology and outcomes of CRE infection are limited. The US military health system (MHS) database, containing comprehensive microbiologic and clinical data on a very large, demographically and geographically diverse population of patients with universal access to care, serves as a valuable tool for studying these rare and serious pathogens. Several groups have identified previous exposure to broad-spectrum antibiotics, indwelling devices, immunosuppression, and longterm health care facility exposure as independent risk factors for CRE colonization or infection.3,5,6 Three previous studies of US military service members and Department of Defense beneficiaries examined the CRE burden, trend, and association with antibiotic exposure in this population.7-9 They found that CRE infections occur rarely in the US MHS compared with the rest of the US population, but their prevalence is rising.9 Additionally, CRE were associated with inpatient exposure to fluoroquinolones.8 Our study aims to more broadly characterize the demographic, diagnostic, procedural, and pharmacologic
https://doi.org/10.1016/j.ajic.2019.10.006 0196-6553/Published by Elsevier Inc. on behalf of Association for Professionals in Infection Control and Epidemiology, Inc.
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risk factors for CRE infection among patients hospitalized in the US MHS, and to evaluate important CRE health care outcomes in this patient population, including length of hospital stay, hospitalization costs, and attributable mortality. METHODS We performed a retrospective study of hospitalized patients with CRE using the TRICARE Management Activity MHS database. This database includes inpatient and outpatient demographic, billing, and clinical data from the electronic medical records of all Department of Defense beneficiaries cared for in all US military treatment facilities (MTF) worldwide, including 60 acute care hospitals and 385 standalone medical clinics. Cases were selected from all patients admitted to an MTF for at least 2 days with a CRE infection from October 2008 to September 2015. CRE infections were defined using the January 2015 Centers for Disease Control and Prevention surveillance definition of growth of any Enterobacteriaceae spp (Enterobacter spp, Escherichia coli, Klebsiella spp, Citrobacter spp, Morganella spp, Proteus spp, Providencia spp, and Serratia spp) reported as resistant to meropenem, ertapenem, imipenem, and/or doripenem.10 For determining carbapenem resistance, we used the existing Clinical Laboratory Standards Institute (CLSI) breakpoints at the time the organism was isolated. In 2010 and 2013, the CLSI breakpoints for defining carbapenem resistance changed, lowering the threshold for defining carbapenem resistance.11 The new breakpoints, however, were adopted variably by different MTF.7 We therefore chose to adopt the definition of CRE used by each individual laboratory at the time of its isolation. Morganella spp, Proteus spp, and Providencia spp, are intrinsically resistant to ertapenem and were therefore included only if found to have resistance to one or more of the other carbapenems. Samples from urine cultures, blood cultures, cerebrospinal fluid cultures, respiratory cultures, wound cultures, and cultures from other sites were included. Isolates from rectal, perianal, and groin swab cultures were excluded to limit our evaluation to CRE infections rather than CRE colonization. Once a patient was selected as a case, he or she was no longer eligible to have future hospitalizations included in the study. Controls for inclusion in the model to generate the highdimensional propensity score were selected from all other hospitalized patients in MTF who were admitted for at least 2 days. For all studied subjects, demographic, clinical, and outpatient prescription data were obtained, including age, sex, Department of Defense beneficiary status (active duty, retired, dependent, or ‘other’ [which includes dependents of retirees, dependent survivors, and NATO or foreign military service members and their families]), hospital region (North, South, West, and Overseas) and hospital size (large, medium, or small). To evaluate associated conditions, we collected diagnosis and procedure codes from outpatient and inpatient encounters at both civilian and military facilities in the 52 weeks preceding hospital admission for all subjects. The diagnosis codes were then grouped into clinically relevant categories using the Clinical Classification Software 3-level system from the Agency of Healthcare Quality and Research’s Healthcare Cost and Utilization Project.12 Inpatient and outpatient diagnosis codes were evaluated separately. Current Procedural Terminology codes, procedure codes, and American Hospital Formulary Service medication class codes (including antibiotic class codes) were included in the analysis. A 2-step approach was used to determine the association between these comorbid conditions and CRE infection. Independent variables with the strongest classification were identified by fitting a lasso-regularized generalized logistic model via penalized maximum likelihood with the dependent variable being CRE infection. After narrowing of predictors using lasso, a multivariable logistic regression was performed to calculate unadjusted and adjusted odds ratios and 95% confidence intervals. The independent variables included
demographic factors and significant prior year predictors (those with a lambda minimum greater than 0). The outcomes used to evaluate the impact of CRE infection included in-hospital death, hospital length of stay (LOS), and hospitalization costs. The outcome of death was defined as a subject death during the recorded hospitalization. LOS was evaluated as the number of days hospitalized. Costs were adjusted to 2018 dollars using the US consumer price index for inpatient hospital services. A highdimensional propensity score was calculated to account for important known and unknown confounders. This allowed comparisons under nonrandomized groups. Counts of the diagnostic and procedure codes from outpatient and inpatient encounters, day supply of medication classes of outpatient prescriptions, and day supply by preceding quarter of antibiotics in the 52 weeks preceding hospital admission were used in conjunction with demographics to obtain a propensity score. The propensity score was then ranked and converted into deciles and included as independent variables in each of the models with the outcomes as dependent variables. All analyses were performed using SAS 9.4 (SAS Institute, Cary, NC). This study was approved by the Uniformed Services University institutional review board. RESULTS Our analysis identified 1,162,686 hospitalizations to MTF during the 7-year study period. Of these, 143 patients were found to have CRE infection (3.1 CRE cases per 100,000 hospital days). Characteristics of these patients are summarized in Table 1. Compared with those patients hospitalized without CRE infection, those with CRE infection were significantly older, mostly men, active duty, retired, or “other” service members, and admitted to large MTF in the TRICARE North region of the United States (Northeast, MidAtlantic, and Midwest states east of the Mississippi River) (Table 1). From these 143 patients, 173 bacterial cultures resulted in growth of 180 CRE pathogens, which were mostly Enterobacter spp, Klebsiella spp, Escherichia coli, and Serratia spp (Table 2). The antimicrobial susceptibilities of these isolates are summarized in Table 2, and of note, most CRE isolates had high levels of resistance to most other classes of antimicrobials commonly used to treat Enterobacteriaceae, such as fluoroquinolones, trimethoprim/sulfamethoxazole, and piperacillin/ tazobactam. Most CRE isolates were from urine cultures (55, 31.8%), followed by respiratory cultures (38, 22.0%), wound cultures/abscesses (24, 13.9%), and blood cultures (12, 6.9%). The remaining 44 (25.4%) CRE isolates were grown from a variety of other sources including catheter tips, peritoneal or pleural fluid, and tissue cultures. CRE infections remained relatively stable over the 7-year study period without a significant trend identified (Table 1). The diagnosis and procedure codes most strongly associated with CRE infection included International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 52.22, representing other excision or destruction of lesion or tissue of pancreas or pancreatic duct, followed by enterostomy, orthopedic procedures, and diagnoses relating to trauma, including internal fixation without fracture reduction of carpals and metacarpals, disarticulation of the hip, amputation above the knee, and skin grafting (Table 3). CRE infection also was associated with temporary placement of a tracheostomy, septicemia, and both recent and remote outpatient parenteral antibiotic treatment (OPAT) with broad-spectrum b-lactam antibiotics, such as fourth and fifth generation cephalosporins, piperacillin/tazobactam, and carbapenems (Table 3). The in-hospital mortality rate for patients with CRE infection was 9.1% (13 of 143 patients), compared with 0.46% (5,317 of 1,162,543 patients) in those without CRE infection. In-hospital mortality was highest in patients with CRE isolated from respiratory and blood
ARTICLE IN PRESS D.J. Adams et al. / American Journal of Infection Control 00 (2019) 1−6 Table 1 Characteristics of patients hospitalized with CRE infection compared with patients hospitalized without CRE infection Indication of CRE on hospital discharge file Characteristic Discharges, total number (percent) Age in years, median (IQR)* Age group, years (percent)* 0-5 5-18 18-65 >65 Male* Geographic region* North South West Overseas Hospital size* Large Medium Small Beneficiary status* Dependents Retired Active duty Other Health care exposure Hospitalizations in preceding 12 months, median (IQR) Outpatients visits in preceding 12 months, median (IQR) Yeary 2009 (percent) 2010 (percent) 2011 (percent) 2012 (percent) 2013 (percent) 2014 (percent) 2015 (percent)
CRE
Table 3 Comorbid clinical diagnoses and procedure classifications (Clinical Classification Software codes) most strongly associated with carbapenem-resistant Enterobacteriaceae infection
No CRE
143 (0.012) 56 (30-74)
1,162,543 (99.987) 26 (7-46)
5 (3.5) 1 (0.7) 82 (57.34) 55 (38.46) 95 (66.4)
286,735 (24.66) 19,827 (1.71) 697,855 (60.03) 158,126 (13.61) 472,493 (40.64)
59 (41.26) 52 (36.36) 22 (15.38) 10 (6.99)
313,010 (26.92) 363,257 (31.25) 389,823 (33.53) 96,453 (8.30)
116 (81.12) 24 (16.78) 2 (1.40)
746,712 (64.23) 336,080 (28.91) 71,897 (6.18)
20 (13.99) 50 (34.97) 32 (22.38) 41 (28.67)
577,863 (49.71) 147,935 (12.73) 246,380 (21.19) 190,365 (16.37)
2 (0-4)
0 (0-1)
28 (12-62)
17 (2-31)
17 (11.89) 23 (16.08) 29 (20.28) 20 (13.99) 19 (13.29) 18 (12.59) 17 (11.89)
169,627 (14.59) 170,442 (14.66) 169,130 (14.55) 165,700 (14.25) 164,316 (14.13) 165,080 (14.20) 158,248 (13.61)
Data are reported as number (%) unless otherwise indicated. Missing values are the reason some numbers or percentages do not sum to total discharges. Percentages reported for each year are the proportion of the total number of ‘CRE’ or ‘No CRE’ hospitalizations that occurred in that year of the study. CRE, carbapenem-resistant Enterobacteriaceae; IQR, interquartile range. *Across all variable categories, there is a significant difference between patients with CRE compared with those without CRE (P < .001). y P = .57.
specimens. Those with a respiratory culture growing CRE had a 21.4% mortality rate (6 of 28 patients), and in those with CRE bloodstream infection the mortality rate was 16.7% (2 of 12 patients). After propensity score adjustment, CRE infection was associated with a more than 3-times increased odds of in-hospital mortality (adjusted odds ratio, 3.34; 95% confidence interval, 1.82-6.12).
3
Condition or procedure
Adjusted OR (95% CI)
Other excision or destruction of lesion or tissue of pancreas or pancreatic duct Internal fixation of bone without fracture reduction, carpals and metacarpals Other enterostomy Temporary tracheostomy Amputation above knee Disarticulation of hip Dermal regenerative graft Heel loop/holder, any type, with or without ankle strap, each (wheelchair) Injection, certolizumab pegol, 1 mg Other mycoses (inpatient) Powered pressure-reducing air mattress Septicemia (except in labor) Piperacillin/tazobactam prescribed in last 6-9 months* Carbapenem prescribed in the last 3-6 months* Carbapenem prescribed in the last 9-12 months* Fifth generation cephalosporin prescribed in the last 0-3 months* Fourth generation cephalosporin prescribed in the last 9-12 months* Metronidazole prescribed in the last 9-12 months*
52.16 (11.82-230.13) 10.09 (2.65-38.46) 8.86 (3.82-20.56) 7.01 (4.12-11.93) 6.14 (2.99-12.61) 5.98 (1.66-21.52) 5.29 (2.81-9.93) 3.30 (2.25-4.84) 1.93 (1.56-2.38) 1.74 (1.32-2.30) 1.67 (1.32-2.11) 1.65 (1.40-1.93) 1.15 (1.06-1.25) 1.08 (1.002-1.16) 1.08 (1.03-1.13) 1.24 (1.11-1.39) 1.22 (1.11-1.34) 1.02 (1.01-1.04)
The International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9CM) codes for diagnoses and procedures were grouped into clinically relevant categories using the Healthcare Cost and Utilization Project’s Clinical Classification Software. CI, confidence interval; OR, odds ratio. *For antibiotic prescriptions, the adjusted OR represents the odds of carbapenem-resistant Enterobacteriaceae infection with each additional day the antibiotic was prescribed during that time period.
Additionally, after propensity score adjustment, CRE infection was shown to have a significant impact on hospitalization LOS and costs. Patients hospitalized with CRE infection had an attributable difference of a 28.8 day longer hospital stay (P < .001) and $206,664 (P < .001) greater hospitalization costs than those without CRE infection (Table 4).
DISCUSSION Our study identified that CRE infections among patients hospitalized in the US MHS are relatively stable in recent years, have significant cross-resistance to most other classes of antibiotics, are clustered among older men in large MTF, and occur mostly in the TRICARE North region of the United States. CRE infection in these patients was associated with gastrointestinal tract surgery,
Table 2 Antimicrobial susceptibility of carbapenem-resistant Enterobacteriaceae isolates reported as percent susceptible
Antimicrobial Cefotaxime/ Ceftriaxone Ceftazidime Cefepime Aztreonam Amikacin Trimethoprim/ sulfamethoxazole Ciprofloxacin Piperacillin/ tazobactam Tigecycline Colistin
Enterobacter spp N = 57 n (%S)
Klebsiella spp N = 53 n (%S)
Escherichia coli N = 37 n (%S)
Serratia spp N = 27 n (%S)
Proteus spp N = 2 n (%S)
Citrobacter spp N = 2 n (%S)
Providencia spp N = 1 n (%S)
Morganella spp N = 1 n (%S)
42 (11.9) 25 (20) 50 (42) 26 (7.7) 43 (88.4) 57 (61.4) 54 (55.6) 39 (12.8) 9 (77.8) NT
45 (8.9) 32 (9.4) 41 (14.6) 31 (3.2) 31 (64.5) 47 (17.0) 44 (15.9) 37 (8.1) 12 (83.3) 1 (100)
30 (33.3) 12 (25) 26 (38.5) 15 (33.3) 19 (89.5) 37 (45.9) 37 (40.5) 18 (33.3) 9 (100) NT
15 (46.7) 10 (80) 17 (76.5) 4 (75) 12 (75) 23 (87.0) 27 (66.7) 10 (70) 1 (0) NT
2 (0) 1 (100) 2 (50) 1 (100) 2 (100) 2 (50) 2 (50) 2 (50) 1 (0) NT
1 (100) 0 (0) 2 (50) 1 (100) 1 (100) 2 (100) 2 (100) 2 (50) NT NT
1 (100) 1 (100) 1 (100) 1 (100) 1 (100) 1 (0) 1 (0) 1 (100) NT NT
1 (100) NT 1 (100) 1 (100) NT 1 (0) 1 (0) 1 (100) NT NT
N, number of total isolates; n, number of isolates tested; %S, percent susceptible; NT, not tested.
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4
Table 4 Hospitalization costs and length of stay attributable to CRE infection Outcome
CRE
No CRE
Attributable difference
P value
Hospitalization costs, mean full direct costs in dollars Length of stay in days
$231,413 33.77
$24,749 5.01
$206,664 28.76
<.0001 <.0001
Length of stay and costs values represent propensity score adjusted least-squared estimate means. Costs were adjusted to 2018 dollars using the US Consumer Price Index for inpatient hospital services. CRE, carbapenem-resistant Enterobacteriaceae.
orthopedic procedures, septicemia, and previous receipt of OPAT with certain broad-spectrum antibiotics. Consistent with other studies of CRE outcomes, CRE infection was associated with longer and more costly hospitalizations and a significant increase in the odds of in-hospital death. In 1996, the first KPC pathogen was isolated from a patient hospitalized in North Carolina.13 Over the last 20 years, KPC-producing bacteria, which constitute approximately half of all CRE isolates, have spread to 48 states, but remain concentrated in the Mid-Atlantic and Northeast United States, which corresponds to our findings of the TRICARE North region having the highest burden of inpatient CRE infection.14,15 Consistent with our cohort, other groups have found CRE infections to occur predominantly in older men.16,17 Health care exposure may be the best established risk factor for CRE acquisition and infection; however, when evaluating health care exposure based on the frequency of hospitalizations and outpatient visits in the preceding year, we found no significant differences between those with and without CRE infection.2,4,18 The prevailing sources of CRE isolates included urine, respiratory, and wound cultures. This is consistent with the known clinical manifestations of Enterobacteriaceae infections, which most commonly present as urinary tract infections, pneumonia, and skin and soft-tissue infections.18 We observed that CRE isolates from our patients, especially Klebsiella spp, exhibited significant cross-resistance with alternate antibiotic agents commonly used to treat infections caused by gram-negative pathogens. This is expected, as many CRE carry additional antibiotic resistance genes on plasmids, leading to multidrug resistance.15,19,20 Tigecycline and amikacin were the only antibiotics in our study to demonstrate consistent in vitro activity against CRE isolates, and only one CRE isolate was tested for colistin resistance. All 3 of these agents have significant shortcomings in the treatment of CRE infections, including high rates of nephrotoxicity for colistin and aminoglycosides, and poor penetration of several anatomic spaces in the case of tigecycline.18,21 Resistance to multiple antibiotic classes, and poor efficacy of remaining active antibiotic agents, are thought to be the major contributors to the increased mortality seen with CRE infections, and could have played a role in the high mortality seen in our patient population.18 We were unable, however, to identify which antimicrobials were used in the treatment of CRE in patients in this study. An especially sobering reminder of the public health crisis of antibiotic-resistant pathogens, such as CRE, are new reports of colistin-resistant Enterobacteriaceae from food sources in China, and from long-term acute care hospitals in the United States, known for high rates and spread of CRE.22,23 These reports, along with our findings of CRE infections with significant in vitro cross-resistance to other antimicrobial classes, underscore the importance of developing novel antimicrobial treatments for combating CRE infections. Since the completion of our study, newer antimicrobial agents such as ceftazidime-avibactam, meropenem-vaborbactam, and other combination b-lactam plus b-lactamase inhibitors have been US Food and Drug Administration −approved for the treatment of complicated Enterobacteriaceae infections harboring extended spectrum b-lactamase, AmpC, and certain classes of carbapenemases.24,25 These agents have certain limitations and are costly, but hold significant promise for the treatment of these challenging infections.
Conditions and procedures associated with CRE infection in our study include invasive procedures, especially those involving the gastrointestinal tract, and temporary tracheostomy placement, along with critical illnesses such as septicemia. These conditions are known to be associated with prolonged hospitalization and broad-spectrum antibiotic exposure, which are both well-established risk factors for CRE colonization and infection.2,26 These identified conditions are consistent with the natural history of CRE infection, in which CRE first colonizes ill patients with prolonged hospitalization in critical care environments, and then invades multiple anatomic sites from the digestive tract or respiratory tract in patients made vulnerable through invasive procedures and placement of indwelling devices.18 Our analysis of conditions and procedures associated with CRE infection, specifically amputation, skin grafting, and other orthopedic procedures, also highlights an at-risk population unique to the MHS, namely individuals wounded in combat. Multidrug-resistant wound infections have previously been reported in this group.9,27-29 Based on our findings, active CRE surveillance of this patient population should be considered owing to their increased CRE infection risk. In a multivariate analysis of outpatient antibiotic class exposure in the preceding year as a predictor for CRE infection, there was a slight increase in the odds of CRE infection for each day of carbapenem exposure in the 3-6 months and 9-12 months before hospitalization (Table 3). This association of CRE infection with preceding carbapenem exposure is consistent with the hypothesis that these broadspectrum antibiotic agents provide the necessary antimicrobial pressure to select out CRE pathogens. Data showing a reduction in CRE infections with decreased use of carbapenem agents, however, are lacking. Efforts to reduce carbapenem use by 60% in one group were not associated with any change in carbapenem resistance in Klebsiella spp.30 In addition to carbapenem exposure, CRE infection was associated with both recent and remote outpatient exposure to other broad-spectrum b-lactam and glycopeptide agents, in accordance with the findings of similar studies of antibiotic exposure in cases of CRE colonization and infection.2,8,26 These results highlight the importance of antimicrobial stewardship initiatives, especially aimed at curbing carbapenem and other broad-spectrum antimicrobial use in the OPAT setting, to help prevent CRE infection and associated adverse outcomes. After adjusting for the severity of illness and other confounders, patients hospitalized with CRE infection carried more than 3-times increased odds of in-hospital mortality, which is comparable to that reported elsewhere, and confirms CRE as a deadly group of pathogens in this population.2,26,31 The reason(s) for this increased attributable mortality are unclear and require further study. Future studies of CRE infection in the US MHS could evaluate which antimicrobial treatment regimens are most successful. In addition to increased mortality, those with CRE infection had significantly longer and more costly hospitalizations, which provides a significant financial incentive for infection control and antimicrobial stewardship initiatives aimed at preventing CRE transmission, CRE infection, and treatment with costly antimicrobials. Our study examines culture-confirmed CRE infections among hospitalized patients in the US MHS. Use of the large MHS database, which includes a geographically and demographically diverse
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population with universal access to care, allowed for broad characterization of the epidemiology of these relatively rare infections, which should be generalizable to patients in other US health care networks. Through use of the Healthcare Cost and Utilization Project’s Clinical Classification Software, we were able to identify specific, yet clinically relevant, CRE-associated conditions and procedures, which can help providers identify the patient populations at highest risk for CRE infection. Additionally, through the use of high-dimensional propensity score ranking, we adjusted for patient severity, comorbid conditions, and other potential known and unknown confounders to provide the most accurate measurement of health care outcomes attributable to CRE infection. Our study does have significant limitations. Although we removed CRE isolates from cultures of skin and rectal swabs, those included from urine and respiratory cultures certainly could have identified some patients with CRE colonization, instead of true infection. Because of limitations in the MHS database we were unable to further refine the definition of CRE urinary tract infection and CRE pneumonia through in-depth chart review. However, the high mortality rate among patients with CRE respiratory cultures implies infection over colonization. Additionally, because of variability in the adoption of updated CLSI breakpoints for carbapenem resistance among different institutions, the microbiologic definition of CRE over the course of our study certainly changed. However, our definition of CRE infection was the same as that used by the clinician interpreting the laboratory report at the time the culture was reported, which closer approximates “real-world” clinical practice. Although we report in vitro antimicrobial susceptibility among CRE isolates, we were unable to report the actual antimicrobials used to treat CRE infections, and therefore cannot comment on the efficacy of any CRE treatment regimen. Our study was limited by the inability to differentiate between carbapenemase-producing CRE and noncarbapenemase CRE, which can have different epidemiology and clinical outcomes.15 We did measure recent outpatient exposure to antimicrobials as a CRE infection risk factor; however, because of limitations in our electronic medical record, we were unable to evaluate antibiotic exposure in the inpatient setting, or recent exposure to skilled nursing or inpatient rehabilitation facilities for their contribution to CRE infection. Finally, given inherent limitations of retrospective studies, we cannot definitively conclude that CRE infection caused the hospitalization outcomes measured. CONCLUSIONS Our findings serve as a valuable tool for providers caring for hospitalized patients, identifying the at-risk population for inpatient CRE infections, which can inform targeted active surveillance programs. Of all available antimicrobials, aminoglycosides and tigecycline had the best in vitro activity against our CRE isolates, which can help to inform empiric CRE infection treatment strategies for certain types of CRE infection. Additionally, we demonstrated that inpatient CRE infections are just as costly and deadly among patients cared for in US MTF as they are in other US and worldwide populations. This underscores the importance of continued development and ongoing evaluation of novel therapeutic agents, adherence to infection control guidance, and of the growing antimicrobial stewardship movement, which aims both to prevent the rise of CRE pathogens and preserve the efficacy of the few existing antimicrobial treatment options. Acknowledgments The authors would like to thank Dr. Matthew D. Eberly for his assistance in proofreading the article.
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