Abstract
Objective:
Although infections caused by Acinetobacter baumannii (AB) are often healthcare-acquired, difficult to treat, and associated with high mortality, epidemiologic data for this organism are limited. This study’s aim was to describe epidemiology, clinical characteristics, and outcomes for patients with XDRAB.
Design:
Retrospective cohort study
Setting:
Department of Veterans Affairs Medical Centers (VAMCs)
Participants:
Patients with XDRAB cultures (defined as non-susceptible to at least 1 agent in all but 2 or fewer classes) at VAMCs between 2012–2018.
Methods:
Microbiology and clinical data was extracted from national VA datasets. Descriptive statistics summarized patient characteristics and outcomes, and bivariate analyses compared outcomes by culture source.
Results:
Among 11,546 patients with 15,364 A. baumannii cultures, 408 (3.5%) patients had 667 (4.3%) XDRAB cultures. Patients with XDRAB were older [mean age (SD)=68 (12.2) years] with median (IQR) Charlson index 3 (1–5). Respiratory (n=244, 36.6%) and urine (n=187, 28%) were the most frequent sources; the greatest proportion of patients were from the South (n=162, 39.7%). Most patients had antibiotic exposures (n=362, 88.7%) and hospital or long-term care admissions (n=331, 81%) in the prior 90 days. Polymyxins, tigecycline, and minocycline demonstrated the highest susceptibility. 30-day (n=96, 23.5%) and one-year (n=199, 48.8%) mortality were high, with significantly higher mortality in patients with blood cultures.
Conclusions:
The proportion of AB in the VA that was XDR was low, but treatment options were extremely limited and clinical outcomes were poor. Prevention of healthcare associated XDRAB infection should remain a priority, and novel antibiotics for XDRAB treatment are urgently needed.
Introduction:
Members of the Acinetobacter baumannii complex (subsequently referred to as A. baumannii) can cause severe healthcare-associated infections such as hospital-acquired bacterial pneumonia/ventilator-associated pneumonia (HABP/VAP) and bloodstream infections (BSIs). In 2017, carbapenem-resistant A. baumannii caused an estimated 8,500 infections in hospitalized patients and 700 deaths in the United States.1 Although incidence is lower than for other healthcare-associated pathogens, A. baumannii infections are frequently multidrug resistant (MDR), making them difficult to treat and associated with high mortality.2,3 Increased mortality from MDR A. baumannii (MDRAB) infections has been associated with inappropriate antibiotic treatment due to multi-drug resistance.4,5
Extensively-drug resistant (XDR) A. baumannii (XDRAB) are a subset of MDRAB that have been categorized as non-susceptible to at least one agent in all but two or fewer antimicrobial classes.6 From 2015–2017, the Centers for Disease Control and Prevention’s (CDC) National Healthcare Safety Network (NHSN) reported that 46% of Acinetobacter spp. causing central line-associated BSI in hospital intensive care units (ICUs) and 76% in long-term acute care hospitals (LTACHs) were MDR.7 Prior large, multicenter epidemiologic studies of A. baumannii have focused on carbapenem-resistant A. baumannii without specifically characterizing XDRAB.2,7,13 Although carbapenem-resistance in Acinetobacter is often observed in association with resistance to multiple antibiotic classes, not all carbapenem-resistant A. baummanii are XDR; therefore, important epidemiologic and clinical differences may exist for the subgroup of patients with XDRAB. Existing data on XDRAB comes largely from smaller, single center studies conducted outside the U.S.8–10 In this national cohort study, we used data from U.S. Department of Veterans Affairs (VA) hospitals to describe the epidemiology, clinical characteristics, and outcomes for patients with XDRAB in the VA.
Methods:
This was a retrospective cohort study including microbiology and clinical data from adult patients with utilization at any VA medical center (VAMC) between January 1, 2012 and December 31, 2018. Microbiology, clinical, and facility data were obtained from the VA Corporate Data Warehouse (CDW), which is a national repository including clinical and administrative data from Veterans Health Administration (VHA). Data are stored in a relational database and are updated on a continual basis. CDW datasets were used to collect data on patient demographics, Charlson comorbidity index11, healthcare utilization, microbiologic data, and medication exposures. VA uses the Rural-Urban Commuting Areas system to classify VAMCs into urban vs. rural.12 Urban VAMCs are in census tracts with at least 30% of the population residing in an urbanized area as defined by the U.S. Census Bureau. Rural VAMCs are in areas not defined as urban. The institutional review board at the Edward Hines, Jr. VA Hospital approved this study.
All bacterial cultures collected from patients during the study period that grew XDRAB were included. Performance and reporting of bacterial speciation and antibiotic susceptibility testing was performed by each VA laboratory according to their own protocol. Isolates were classified as XDR if they were non-susceptible to at least one agent in all but two or fewer antimicrobial classes active against Acinetobacter.6 To validate the XDR classification from the CDW data, medical records were reviewed for a stratified sample of 63 inpatient cultures (17 blood, 21 urine, and 25 respiratory) that had an associated ICD10 code for sepsis, urinary tract infection, or pneumonia during the admission. Agreement between XDRAB categorization for these cultures using CDW data and medical record review was 95%. Discrepancies were due to antibiotic susceptibilities that had been manually entered as text into Microbiology culture reports. Multiple cultures from the same patient within 30 days were removed. Descriptive statistics were used to summarize patient demographics, clinical characteristics, and prior healthcare and antibiotic exposures as well as hospital characteristics. For the analysis of clinical outcomes, we analyzed data for all patients together as well as patients grouped by culture source. If one patient had XDRAB cultures > 30 days apart from multiple sources over the course of the study, a hierarchical approach was taken. For any patient with XDRAB isolated from blood, outcomes were analyzed with the source as blood. For patients without blood isolates but positive respiratory isolates, outcomes were analyzed with the source as respiratory. For patients without blood or respiratory isolates but positive urine isolates, outcomes were analyzed with the source as urine. Finally, for patients without blood, respiratory, or urine isolates, outcomes were analyzed with the source as other. Fisher’s Exact test and Wilcoxon rank-sum test were used to assess differences in clinical outcomes by culture source. Bonferroni correction for multiple comparisons was used, with p<0.008 considered significant. Statistical analyses were carried out using SAS, version 9.4 (SAS Institute) and Stata, version 12.1 (Stata Corp LP).
Results:
Out of 11,546 unique patients with 15,364 cultures that grew A. baumannii during the study period, 408 (3.5%) patients had 667 (4.3%) cultures that grew XDRAB. Patient demographics, clinical characteristics, and culture characteristics are in Table 1. Most patients were older men, and many had comorbidities such as diabetes (n=165, 40.4%) and chronic kidney disease (n=162, 37.9%). Most cultures were obtained from inpatients (n=468, 70.2%), with the greatest proportion of isolates coming from the respiratory tract (n=244, 36.6%) followed by urine (n=187, 28%). The proportion of all XDRAB isolated during the study period that occurred each study year declined from 33.7% in 2012 to 7.5% in 2018.
Table 1.
Patient demographics, clinical and culture characteristics, and exposures.
| Patient characteristics (n=408) | Number (%)a |
|---|---|
| Demographics | |
| Age, years, mean (SD) | 68.1 (12.2) |
| Sex, female | 6 (1.5) |
| Comorbidities | |
| Charlson comorbidity index, median (IQR) | 3 (1–5) |
| Chronic kidney disease | 162 (39.7) |
| Chronic liver disease | 36 (8.8) |
| HIV/AIDS | 5 (1.2) |
| Malignancy or tumor | 49 (12.0) |
| CHF | 90 (22.1) |
| Diabetes | 165 (40.4) |
| Cerebrovascular disease | 60 (14.7) |
| Peripheral vascular disease | 84 (20.6) |
| Healthcare exposures in past 90 days | |
| Hospital admission | 331 (81.1) |
| LTCF or rehabilitation stay | 32 (7.8) |
| Surgery | 57 (14.0) |
| ICU admission | 184 (45.1) |
| Mechanical ventilation | 118 (28.9) |
| Antibiotic exposures in past 90 days | |
| Any antibiotic | 362 (88.7) |
| Penicillins | 97 (23.8) |
| Extended spectrum penicillins | 228 (55.9) |
| 1st/2nd gen cephalosporins | 70 (17.1) |
| 3rd/4th gen cephalosporins | 171 (41.9) |
| Carbapenems | 78 (19.1) |
| Tetracyclines | 74 (18.1) |
| Aminoglycosides | 79 (19.3) |
| Fluoroquinolones | 216 (52.9) |
| Vancomycin | 289 (70.8) |
| Culture characteristics (n=667) | Number (%)a |
| Care setting where culture was obtained | |
| Inpatient | 468 (70.2) |
| Outpatient | 114 (17.1) |
| Long-term care | 85 (12.7) |
| Culture source | |
| Blood | 49 (7.4) |
| Urine | 187 (28.0) |
| Respiratory | 244 (36.6) |
| Other | 187 (28.0) |
| Culture year | |
| 2012 | 225 (33.7) |
| 2013 | 126 (18.9) |
| 2014 | 81 (12.1) |
| 2015 | 79 (11.8) |
| 2016 | 48 (7.2) |
| 2017 | 58 (8.7) |
| 2018 | 50 (7.5) |
Data reported are number (%) unless otherwise indicated
SD, standard deviation; IQR, interquartile range; HIV/AIDS, human immunodeficiency virus/acquired immune deficiency syndrome; CHF, congestive heart failure; LTCF, long-term care facility; ICU, intensive care unit
Most patients (n=362, 88.7%) had antibiotic exposures in the 90 days prior to their XDRAB culture, with vancomycin (n=289, 70.8%) and extended spectrum penicillins (n=128, 55.9%) being the most common. Most patients (n=331, 81.1%) also had a hospital or long-term care admission in the prior 90 days, with nearly half (45.1%) having an ICU admission and nearly a third (28.3%) having had mechanical ventilation in the prior 90 days. Antibiotic susceptibilities of the XDRAB isolates were variable (Figure 1). Polymyxins (n=128/133, 96.2%), tigecycline (n=72/106, 67.9%), and minocycline (n=52/121, 43.0%) demonstrated the highest susceptibility. By contrast, susceptibilities to anti-Pseudomonal fluoroquinolones and extended spectrum penicillins were quite low at 0.2% and 0.3%, respectively. The geographic distribution of VAMCs with patients with XDRAB is shown in Figure 2. Overall, XDRAB cultures were identified from patients at 41 VAMCs in 23 states and Puerto Rico. The Southern region (which included Puerto Rico) had the largest proportion of patients with XDRAB (n=162, 39.7%), while the Midwest had the smallest (n=55, 13.5%). Almost all patients were cared for at urban VAMCs (n=404, 99%).
Figure 1. Antibiotic susceptibility of XDR Acinetobacter isolates.
Percent of XDRAB isolates testing susceptible to key antibiotics. Individual antibiotics are grouped into relevant classes by color.
Figure 2. Geographic distribution of XDR Acinetobacter.
Geographic distribution of patients with XDRAB cultures in VAMCs. Circle size corresponds to the number of patients with XDRAB cultures at VAMCs in that state or territory (Puerto Rico). Varying color shades indicate U.S. Census Bureau regions.
Clinical outcomes for patients with XDRAB are shown in Table 2. Almost a quarter of patients died within 30 days following their XDRAB culture. When analyzed by culture source, all mortality outcomes were significantly more frequent in patients with XDRAB from blood cultures compared to respiratory, urine, and other culture sources. Hospital readmission within 90 days and length of stay (LOS) were calculated for the subset of patients whose cultures were obtained from inpatient or long-term care facility (LTCF) settings. Median post-culture LOS was high at 31 days. Neither outcome differed significantly by culture source. When patients with cultures obtained from LTCF settings were excluded, post-culture LOS decreased for urine [median (IQR) of 22 (8–49) days vs 32 (9–77) days] and other [12 (6–55) days vs. 19 (17–110) days] culture sources but remained relatively unchanged for blood [16 (9–32) days vs. 18 (11–38) days] and respiratory [20 (8–42) days vs. 21 (8–52) days] culture sources.
Table 2.
Clinical outcomes in patients with XDRAB.
| Number (%) | ||||||
|---|---|---|---|---|---|---|
| Outcomea | Total | Blood (n=34) | Respiratory (n=140) | Urine (n=116) | Other (n=118) | p-value |
| In-hospital mortality (n=335) | 92 (24.5) | 15 (44.1) | 51 (36.4) | 11 (9.5) | 15 (12.7) | <0.01 |
| 30-day mortality (n=408) | 96 (23.5) | 20 (58.9) | 54 (38.6) | 7 (6.0) | 15 (12.7) | <0.01 |
| 1-year mortality (n=408) | 199 (48.8) | 25 (73.5) | 98 (70.0) | 39 (33.6) | 37 (31.4) | <0.01 |
| Outcomeb | Total | Blood (n=30) | Respiratory (n=133) | Urine (n=77) | Other (n=95) | p-value |
| 90-day hospital readmission (n=553) | 86 (25.7) | 5 (16.7) | 30 (22.6) | 19 (24.7) | 32 (33.7) | 0.16 |
| Post-culture LOS, days, median (IQR)b | 31 (0–128) | 18 (11–38) | 21 (8–52) | 32 (9–77) | 19 (7–110) | NSc |
LOS, length of stay; IQR, interquartile range
These outcomes are reported at the patient level. In-hospital mortality is reported for the subset of patients with unique cultures obtained from inpatient or LTCF settings.
These outcomes are reported at the unique culture level and were calculated for the subset of cultures obtained in inpatient or LTCF settings. Post-culture LOS was summed for all unique hospital and LTCF admissions.
P-values were calculated for each individual comparison and were all non-significant with p>0.008.
Discussion:
National CDC surveillance data has shown that overall incidence of MDRAB infections remains low compared to other MDROs2; however, MDRAB can cause severe, nosocomial infections with higher attributable mortality and fewer antibiotic treatment options compared to many other MDROs.4,13 Therefore, accurate and up-to-date characterization of the epidemiology and outcomes of diverse patient populations with MDRAB and XDRAB is critical to inform local and national surveillance, to guide infection prevention and antibiotic stewardship efforts, and to assist clinicians in management of these infections.
In this national cohort study of Veterans with XDRAB cared for at over 40 different geographically diverse VAMCs, we found an overall low prevalence of XDR (3.5%) among patients with A. baumannii. Furthermore, the proportion of all XDRAB cultures that were isolated each study year decreased over time, from a high of 33.7% in 2012 to 7.5% in 2018. This decline is consistent with NHSN data on healthcare-associated infections, where the percentage of A. baumannii that were carbapenem-resistant decreased from 58% in 201114 to 39% between 2015–20177, as well as data recently published from a national cohort of U.S. hospitals where the incidence of carbapenem-resistant A. baumannii declined between 2012–2017 from 3.33 to 2.47 per 10,000 hospitalizations.15 Similar to many healthcare systems, the VA implemented various infection prevention and antimicrobial stewardship interventions during our study period that likely contributed to declines in multiple MDRO types, including MDRAB.16 Declines may also be due to changes in factors specific to the virulence and spread of Acinetobacter.
Most patients in our study were older, with chronic comorbidities and recent healthcare and antibiotic exposures, and most cultures were collected from the respiratory or urinary tract. Recent prior healthcare and antibiotic exposures have been shown in multiple other studies to correlate strongly with an increased risk of MDRAB.2,3 Furthermore, almost all XDRAB cultures were collected from patients at urban VAMCs, with the South having the greatest proportion of patients. Geographic variability in the epidemiology of MDRAB and other MDROs has been described, and may stem from local spread of resistant clonal isolates, regional differences in antimicrobial stewardship, variability in infection control practices, or other factors.2,17 Taken collectively, this epidemiologic data informs clinicians and infection control practitioners to have heightened suspicion for XDRAB in patients with prior healthcare and antibiotic exposures, particularly if they have respiratory or urinary tract infections and are being cared for at urban medical centers.
Another interesting finding from our study was that two of the most common prior antibiotic exposures in patients with XDRAB were extended spectrum penicillins and anti-Pseudomonal fluoroquinolones. Although we did not report on treatments, one possibility for the high exposure to these classes is because they are common empiric antibiotics prescribed for infections frequently caused by XDRAB (e.g., sepsis, nosocomial pneumonia, complicated urinary tract infections). Unfortunately, our data showed almost negligible susceptibility of XDRAB isolates to these antibiotic classes, highlighting the low likelihood that common empiric antibiotic regimens are appropriate for patients with XDRAB infections. Multiple studies have identified associations between delays in appropriate antibiotic treatment and increased mortality in patients with MDRAB,4,5 which may partly account for the poor clinical outcomes we observed. Many new antibiotics (e.g., ceftazidime/avibactam, ceftolozane/tazobactam, meropenem/vaborbactam, imipenem/relebactam) have fewer toxicities compared to existing treatments for MDR Gram-negative bacteria but lack activity against MDRAB,18,19 often leaving polymyxins, tigecycline, and minocycline as the only treatment options. These drugs have substantial limitations, including high rates of adverse reactions and limited efficacy for certain infection sites. Thus, additional studies are needed to determine the effectiveness and outcomes of various treatment regimens for XDRAB, and drug development pipelines for novel antibiotics with activity against XDRAB should be supported.20
Finally, clinically outcomes in patients with XDRAB were generally poor. Almost a quarter of patients died within 30 days following the positive culture, and almost half of patients had died within a year after a positive culture. Among inpatients and those in LTCFs, a quarter were re-hospitalized within 90-days, and median post-culture LOS was a month. As anticipated, outcomes were worse for patients with positive blood and/or respiratory cultures compared to urine or other cultures, which may indicate a greater likelihood that XDRAB cultured from non-blood, non-respiratory sites reflects colonization rather than true infection. Isolation of XDRAB has been associated with high in-hospital and 30-day mortality in prior studies.8–10 Although some of this association is explained by the propensity of Acinetobacter to infect hospitalized, medically complex patients with high baseline risk for mortality, prior studies have shown substantial attributable mortality from MDRAB infections specifically.4,12
Our study had several important limitations. First, it was retrospective and observational, and, consistent with our aim to provide a descriptive analysis, did not include a comparator group of patients with susceptible Acinetobacter cultures. Second, our study was conducted using VA data and may not be fully representative of XDRAB epidemiology in non-VA populations. Third, although the national VA databases used in this study were necessary to amass a large and diverse cohort with a low prevalence MDRO such as XDRAB, they lacked key information regarding presence of indwelling devices and variables needed to differentiate colonized vs infected patients from those with true infection. We hypothesized that patients with XDRAB isolated in the blood or respiratory tract were may be more likely to have true infection than those with urine or other cultures, and our observation of worse outcomes for these patients supports this hypothesis. However, many of the respiratory tract cultures may also have been colonization, and patients with XDRAB blood and respiratory tract cultures could also have been more medically complex and had greater healthcare and antibiotic exposures. Finally, the identification and reporting of bacterial susceptibilities by individual VA microbiology labs is expected to follow Clinical and Laboratory Standards Institutes guidelines, but may have varied during the study period, leading to limitations in the accuracy of XDRAB identification and aggregated antibiotic susceptibilities reported.
In conclusion, the proportion of A. baumannii isolates in the VA that were XDR was overall low (3.5%), with substantial declines noted between 2012–2018. XDRAB was more common among patients with recent healthcare and antibiotic exposures who were cared for at urban VAMCs, was associated with poor clinical outcomes, and demonstrated extremely limited antibiotic susceptibilities. Therefore, providers should continue to suspect XDRAB infection in patients with these epidemiologic risks and should continue to monitor and disseminate local surveillance and antibiogram data for this pathogen.
Acknowledgments:
This work was supported by The Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development IIR 16-028 (PI: Evans, Charlesnika). The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the U.S. government. All authors report no conflicts of interest or financial disclosures relevant to this article.
Footnotes
This data was accepted as a poster presentation for the SHEA Decennial Conference 2020.
Contributor Information
Margaret A. Fitzpatrick, Department of Veterans Affairs, Center of Innovation for Complex Chronic Healthcare, Edward Hines, Jr. VA Hospital, Hines, IL, USA; Department of Medicine, Division of Infectious Diseases, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA, 5000 S. Fifth Ave., Hines, IL 60141.
Katie J. Suda, Department of Veterans Affairs, Center for Health Equity Research and Promotion, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA; Department of Medicine, Division of General Internal Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Martin Evans, VHA MRSA/MDRO Program Office, the National Infectious Diseases Service, Patient Care Services, VA Central Office and the Lexington VA Medical Center, Lexington, KY, USA; Department of Internal Medicine, University of Kentucky School of Medicine, Lexington, KY, USA.
Charlesnika T. Evans, Department of Veterans Affairs, Center of Innovation for Complex Chronic Healthcare, Edward Hines, Jr. VA Hospital, Hines, IL, USA; 5Center for Health Services and Outcomes Research, Department of Preventive Medicine Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
References:
- 1.CDC. Antibiotic Resistance Threats in the United States, 2019. Atlanta, GA: U.S. Department of Health and Human Services, CDC; 2019. https://www.cdc.gov/drugresistance/biggest-threats.html.Accessed2 June, 2020. [Google Scholar]
- 2.Bulens SN, Yi SH, Walters MS, et al. Carbapenem-nonsusceptible Acinetobacter baumannii, 8 US metropolitan areas, 2012–2015. Emerg Infect Dis. 2018;24(4):727–734. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Ramanathan S, Suda KJ, Fitzpatrick MA, et al. Multidrug-resistant Acinetobacter: Risk factors and outcomes in veterans with spinal cord injuries and disorders. Am J Infect Control. 2017;45(11):1183–1189. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Falagas ME, Rafailidis PI. Attributable mortality of Acinetobacter baumannii: no longer a controversial issue. Crit Care. 2007;11(3):134. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Fitzpatrick MA, Ozer E, Bolon MK, Hauser AR. Influence of ACB complex genospecies on clinical outcomes in a U.S. hospital with high rates of multidrug resistance. J Infect. 2015;70(2):144–152. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Magiorakos AP, Srinivasan A, Carey RB, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect. 2012;18(3):268–281. [DOI] [PubMed] [Google Scholar]
- 7.Weiner-Lastinger LM, Abner S, Edwards JR, et al. Antimicrobial-resistant pathogens associated with adult healthcare-associated infections: Summary of data reported to the National Healthcare Safety Network, 2015–2017. Infect Control Hosp Epidemiol. 2020;41(1):1–18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Hsu LY, Apisarnthanarak A, Khan E, Suwantarat N, Ghafur A, Tambyah PA. Carbapenem-resistant Acinetobacter baumannii and Enterobacteriaceae in South and Southeast Asia. Clin Microbiol Rev. 2017;30(1):1–22. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Katsiari M, Mavroidi A, Platsouka ED, Nikolaou C. Extensively drug-resistant Acinetobacter baumannii bacteraemia in a multidisciplinary intensive care unit during a 6-year period: Risk factors for fulminant sepsis. J Glob Antimicrob Resist. 2018;14:51–57. [DOI] [PubMed] [Google Scholar]
- 10.Jean SS, Hsieh TC, Lee WS, Hsueh PR, Hsu CW, Lam C. Treatment outcomes of patients with non-bacteremic pneumonia caused by extensively drug-resistant Acinetobacter calcoaceticus-Acinetobacter baumannii complex isolates: Is there any benefit of adding tigecycline to aerosolized colistimethate sodium? Medicine (Baltimore). 2018;97(39):e12278. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation, J Chronic Dis. 1987; 40 (5): 373–383. [DOI] [PubMed] [Google Scholar]
- 12.Department of Veterans Affairs. Office of Rural Health. 2018. www.ruralhealth.va.gov/aboutus/ruralvets.asp.AccessedJuly 10, 2018.
- 13.Nelson RE, Schweizer ML, Perencevich EN, et al. Costs and mortality associated With multidrug-resistant healthcare-associated Acinetobacter infections. Infect Control Hosp Epidemiol. 2016;37(10):1212–1218. [DOI] [PubMed] [Google Scholar]
- 14.Weiner LM, Webb AK, Limbago B, et al. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2011–2014. Infect Control Hosp Epidemiol. 2016;37(11):1288–1301. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Jernigan JA, Hatfield KM, Wolford H, et al. Multidrug-Resistant Bacterial Infections in U.S. Hospitalized Patients, 2012–2017. N Engl J Med. 2020;382(14):1309–1319. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Goto M, O’Shea AMJ, Livorsi DJ, et al. The effect of a nationwide infection control program expansion on hospital-onset Gram-negative rod bacteremia in 130 Veterans Health Administration Medical Centers: an interrupted time-series analysis. Clin Infect Dis. 2016;63(5):642–650. [DOI] [PubMed] [Google Scholar]
- 17.Guh AY, Bulens SN, Mu Y, et al. Epidemiology of carbapenem-resistant Enterobacteriaceae in 7 US communities, 2012–2013. JAMA. 2015;314(14):1479–1487. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Zhanel GG, Lawrence CK, Adam H, et al. Imipenem-relebactam and meropenem-vaborbactam: two novel carbapenem-β-Lactamase inhibitor combinations. Drugs. 2018;78(1):65–98. [DOI] [PubMed] [Google Scholar]
- 19.Sader HS, Castanheira M, Flamm RK. Antimicrobial activity of Ceftazidime-avibactam against Gram-negative bacteria Isolated from patients hospitalized with pneumonia in U.S. Medical Centers, 2011 to 2015. Antimicrob Agents Chemother. 2017;61(4):e02083–16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Fitzpatrick MA. Real-world antibiotic needs for resistant Gram-negative infections. The Lancet Infectious Diseases [Preprint].4June2020[cited2020 Jun 5]. Available from: 10.1016/S1473-3099(20)30178-X. [DOI] [PubMed] [Google Scholar]