Research
Original Investigation
Infection Management and Multidrug-Resistant Organisms in Nursing Home Residents With Advanced Dementia Susan L. Mitchell, MD, MPH; Michele L. Shaffer, PhD; Mark B. Loeb, MD, MSc; Jane L. Givens, MD, MSCE; Daniel Habtemariam, BA; Dan K. Kiely, MPH, MA; Erika D’Agata, MD, MPH
IMPORTANCE Infection management in advanced dementia has important implications for
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(1) providing high-quality care to patients near the end of life and (2) minimizing the public health threat posed by the emergence of multidrug-resistant organisms (MDROs). DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study of 362 residents with advanced dementia and their health care proxies in 35 Boston area nursing homes for up to 12 months. MAIN OUTCOMES AND MEASURES Data were collected to characterize suspected infections, use of antimicrobial agents (antimicrobials), clinician counseling of proxies about antimicrobials, proxy preference for the goals of care, and colonization with MDROs (methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and multidrug-resistant gram-negative bacteria). Main outcomes were (1) proportion of suspected infections treated with antimicrobials that met minimum clinical criteria to initiate antimicrobial treatment based on consensus guidelines and (2) cumulative incidence of MDRO acquisition among noncolonized residents at baseline. RESULTS The cohort experienced 496 suspected infections; 72.4% were treated with antimicrobials, most commonly quinolones (39.8%) and third- or fourth-generation cephalosporins (20.6%). At baseline, 94.8% of proxies stated that comfort was the primary goal of care, and 37.8% received counseling from clinicians about antimicrobial use. Minimum clinical criteria supporting antimicrobial treatment initiation were present for 44.0% of treated episodes and were more likely when proxies were counseled about antimicrobial use (adjusted odds ratio, 1.42; 95% CI, 1.08-1.86) and when the infection source was not the urinary tract (referent). Among noncolonized residents at baseline, the cumulative incidence of MDRO acquisition at 1 year was 48%. Acquisition was associated with exposure (>1 day) to quinolones (adjusted hazard ratio [AHR], 1.89; 95% CI, 1.28-2.81) and third- or fourth-generation cephalosporins (AHR, 1.57; 95% CI, 1.04-2.40). CONCLUSIONS AND RELEVANCE Antimicrobials are prescribed for most suspected infections in advanced dementia but often in the absence of minimum clinical criteria to support their use. Colonization with MDROs is extensive in nursing homes and is associated with exposure to quinolones and third- and fourth-generation cephalosporins. A more judicious approach to infection management may reduce unnecessary treatment in these frail patients, who most often have comfort as their primary goal of care, and the public health threat of MDRO emergence.
JAMA Intern Med. 2014;174(10):1660-1667. doi:10.1001/jamainternmed.2014.3918 Published online August 18, 2014. 1660
Author Affiliations: Hebrew SeniorLife Institute for Aging Research, Boston, Massachusetts (Mitchell, Givens, Habtemariam, Kiely); Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (Mitchell, Givens, D’Agata); Department of Pediatrics, University of Washington and Children’s Core for Biomedical Statistics, Seattle Children’s Research Institute, Seattle (Shaffer); Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada (Loeb). Corresponding Author: Susan L. Mitchell MD, MPH, Hebrew SeniorLife Institute for Aging Research, 1200 Centre St, Boston, MA 02131 ([email protected]). jamainternalmedicine.com
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Infection Management in Advanced Dementia
A
lzheimer disease affects over 5 million Americans, is the sixth leading cause of death in the United States,1 and is increasingly recognized as a terminal illness.2 Identifying opportunities to improve the quality of the care for patients with advanced dementia is a clinical and research priority.2-4 In advanced dementia, patients typically have profound cognitive deficits (no longer recognize family), limited verbal abilities (0).
Twelve-month cumulative incidence rates of MDRO acquisition were calculated only among residents who met both of the following conditions: (1) no MDRO at baseline and (2) at least 1 follow-up swab. These stipulations resulted in the following numbers of residents available for the acquisition analyses: any MDRO, n = 176; MDRGNB, n = 200; and MRSA, n = 278. Among these residents, the cumulative incidence rates were any MDRO, 47.9%; MDRGNB, 35.8%; and MRSA, 21.3% (Figure). Only 2 residents acquired VRE. In unadjusted analyses, greater quinolone and third- and fourth-generation cephalosporin use, measured both as greater than 1 day of treatment and higher log DOT/1000-residents days, were significantly associated with MRDO acquisition (Table 3). All antimicrobials considered together, first-generation cephalosporins, and penicillins were not significantly associated with acquisition. Among the covariates, only Foley catheters (HR, 2.20; 95% CI, 0.96-5.05) and hospitalization in the prior 90 days JAMA Internal Medicine October 2014 Volume 174, Number 10
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Table 2. Suspected Infectious Episodes Treated With Antimicrobial Agents and Association With Presence of Minimum Clinical Criteria for Such Treatment34 Infectious Episodesa Minimum Criteria Total (n = 359)
Characteristic
Present (n = 158)
Absent (n = 201)
Association of Treatment With Presence of Minimum Criteria OR (95% CI) Unadjusted
Adjusted
Resident Age, mean (SD)
86.7 (7.0)
86.4 (7.3)
87.0 (6.7)
0.98 (0.95-1.02)
NA
Female
296 (82.5)
123 (77.9)
173 (86.1)
0.58 (0.28-1.18)
NA
White
330 (91.9)
147 (93.0)
183 (91.0)
1.39 (0.55-3.52)
NA
Congestive heart failure
69 (19.2)
27 (17.1)
42 (20.9)
0.73 (0.46-1.18)
NA
Diabetes mellitus
94 (26.2)
35 (22.2)
59 (29.4)
0.72 (0.39-1.35)
NA
Chronic obstructive lung disease
58 (16.2)
24 (15.2)
34 (16.9)
0.84 (0.48-1.45)
NA
BANS-S score, mean (SD)b d
21.9 (2.9)
22.4 (2.8)
21.6 (2.9)
1.11 (1.04-1.18)c
NA
TSI = 0
216 (60.2)
91 (57.6)
125 (62.2)
0.87 (0.49-1.54)
NA
Do-not-hospitalize order
NA
109 (30.4)
50 (31.7)
59 (29.4)
1.20 (0.65-2.22)
Hospice
25 (7.0)
17 (10.8)
8 (4.0)
2.13 (1.00-4.50)c
NA
Feeding tube
22 (6.1)
8 (5.1)
14 (7.0)
0.80 (0.30-2.12)
NA
Foley catheter
39 (10.9)
22 (13.9)
17 (8.5)
1.58 (0.73-3.41)
NA
149 (41.5)
67 (42.4)
82 (40.8)
1.10 (0.74-1.64)
NA
Clinician-proxy communication Counseled to expect infections
c
Counseled about antimicrobials
164 (45.7)
82 (51.9)
82 (40.8)
1.62 (1.08-2.43)
1.42 (1.08-1.86)
Asked about preferences for antimicrobial usee
224 (62.9)
100 (63.3)
124 (61.7)
1.12 (0.76-1.65)
NA
Urinary
148 (41.2)
28 (17.7)
120 (59.7)
1 [Referent]
1 [Referent]
Respiratory
104 (29.0)
35 (22.2)
69 (34.3)
2.24 (1.04-4.85)c
2.33 (1.12-4.84)
Febrile
41 (11.4)
32 (20.3)
9 (4.5)
14.79 (4.75-46.08)c
14.92 (5.16-43.14)
Skin
66 (18.4)
63 (39.9)
3 (1.5)
95.35 (23.44-387.90)c
102.92 (28.49-371.85)
166 (46.2)
69 (43.7)
97 (48.3)
0.83 (0.54-1.26)
NA
54 (15.0)
28 (17.7)
26 (12.9)
1.66 (0.93-2.96)c
NA
42 (11.8)
23 (14.6)
19 (9.5)
1.60 (0.86-2.97)
NA
Clinical examination within 72 hours
215 (59.9)
108 (68.4)
107 (53.2)
2.20 (1.22-3.97)c
NA
Documented proxy discussione
203 (56.7)
96 (60.8)
107 (53.2)
1.34 (0.86-2.11)
NA
71 (19.8)
27 (17.1)
44 (21.9)
0.71 (0.48-1.04)c
NA
Abbreviations: BANS-S, Bedford Alzheimer Nursing Severity–Subscale; NA, not applicable; OR, odd ratio; TSI, Test for Severe Impairment. a
Unless otherwise indicated, data are reported as number (percentage) of infectious episodes.
b
Possible BANS-S score range, 7 to 28, higher scores indicating more functional disability.
c
These variables were significant at P < .10 in bivariable analyses and entered into multivariable model.
d
Possible TSI score range, 0 to 24, lower scores indicating greater cognitive impairment (dichotomized to 0 vs >0).
e
These variables had a small amount of missing data. The totals for each were as follows: asked about preferences for antimicrobials use, n = 356; hospitalized, n = 357; documented proxy discussion, n = 358.
Infectious episode Type
Physician prescriber (vs nurse practitioner) Within 30 days of death e
Hospitalized
Weekend episode
(HR, 1.70; 95% CI, 0.90-3.18) were associated with MDRO acquisition at P < .10 in the bivariable analyses. After adjusting for these covariates, we found that greater exposure to quinolones (any use adjusted HR [AHR], 1.89; 95% CI, 1.28 -2.81; higher log DOT/1000 resident-days AHR, 1.18; 95% CI, 1.061.32) and third- and fourth-generation cephalosporins (any use AHR, 1.57; 95% CI, 1.03-2.40; higher log DOT/1000 residentdays AHR,1.16; 95% CI, 1.00-1.35) remained significantly associated with MDRO acquisition.
Discussion In this prospective study of NH residents with advanced dementia, suspected infections were common; antimicrobials were prescribed for the majority of episodes; but only 44% of 1664
treated episodes met minimum clinical criteria for antimicrobial treatment initiation. These criteria were more likely to be met if the suspected source was not the urinary tract and proxies were counseled about antimicrobials. Colonization by MDROs was extensive. Over 12 months, 67% of residents were colonized, and the cumulative incidence rate of MDRO acquisition among residents not colonized at baseline was 48%. Quinolones and third- and fourth-generation cephalosporins were the most commonly used antimicrobial classes, and greater exposure to these agents was significantly associated with MDRO acquisition. This study confirms that antimicrobials are extensively prescribed in advanced dementia5,36 but further demonstrates that much of this use may be unwarranted. The proportion of treated infections meeting minimum clinical criteria for antimicrobial treatment initiation was lower in our cohort than in
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Original Investigation Research
the general NH population, particularly for respiratory and urinary tract infections.14,15 Inadequate documentation or assessment by clinicians, as well as their unfamiliarity with the criteria, may have contributed to our findings. However, the challenges associated with decisions to initiate antimicrobial therapy in the NH setting are compounded in advanced dementia. Confirmatory laboratory and radiographic investigations are often not readily available. Clinicians may be particularly reluctant to order uncomfortable or inconvenient tests in NH residents with advanced dementia. Thus, treatment decisions are often made empirically based on clinical presen-
Figure. Cumulative Incidence Rates of Resident Acquisition of Drug-Resistant Organisms During the Study Period 50
Cumulative Incidence, %
Any MDRO 40
30
MDRGNB
20 MRSA 10
0 0
3
6
9
12
71 93 160
61 85 151
Months From Baseline Participants at risk, No. Any MDRO 175 MDRGNB 200 MRSA 278
116 145 218
93 124 184
MDRGNB indicates multidrug-resistant gram-negative bacteria; MDRO indicates multidrug-resistant organism; MRSA, methicillin-resistant Staphylococcus aureus; VRE, vancomycin-resistant enterococci. “Any MDRO” includes MDGRN, MRSA, or VRE. All residents were free of all 3 types of MDROs at baseline. Only 2 residents acquired VRE over the 12 months of the study.
tation. However, patients with severe dementia are severely cognitively impaired, effectively mute, and cannot reliably express symptoms. Not surprisingly, treatment criteria were met for 95% of skin infections, which can be assessed primarily by observable signs, compared with 19% of urinary tract infections, assessment of which is more reliant on subjective complaints. While asymptomatic bacteruria is the most common reason for potentially inappropriate antimicrobial use in NHs,14,15,17,34,37,38 exactly what constitutes “symptomatic” in advanced dementia, and hence the application of the minimum criteria for treatment of urinary tract infections in these patients, is not straightforward. Diagnosing urinary tract infections in advanced dementia is further confounded by the fact that urinalyses and urine cultures are frequently positive, regardless of whether clinical criteria for antimicrobial initiation are present.34 Patients with advanced dementia are usually nearing the end of life, and infections characterize the final stage of their disease.2,39 Clinicians making care decisions must consider not only clinical criteria for starting treatment with antimicrobials but also whether such treatment aligns with the goals of care. Over 50% of our study residents received antimicrobials, yet comfort was the stated primary goal of care for 95% of them.2 For these residents, the burdens associated with assessing and treating infections may outweigh the benefits, particularly when the likelihood of a bacterial infection is low. While the extent to which NH residents with advanced dementia suffer from infections is difficult to assess, antimicrobials may not provide greater symptomatic relief than highquality palliative care. The workup and treatment of infections can be uncomfortable, particularly when parenteral therapy or hospitalization is involved.40 Even oral antimicrobials may contribute to distress, as these patients commonly have swallowing problems.2 Older persons are also particularly susceptible to adverse effects of antimicrobials,41 including Clos-
Table 3. Association Between Characteristics of Residents and Time to First Acquisition of Any MDROa Residents (n = 176)
Characteristic
HR (95% CI) Adjustedb
Unadjusted
All antimicrobial agents Any use, No. (%)c
65 (36.9)
1.20 (0.80-1.80)
NA
Days of therapy/1000 resident-days, mean (SD), log
1.4 (1.9)
1.06 (0.95-1.18)
NA
Abbreviations: HR, hazard ratio; MDRO, multidrug-resistant organism. a
Including methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and multidrug-resistant gram-negative bacteria.
b
Both the unadjusted and adjusted HRs account for clustering at the facility level in the generalized estimating equations. The adjusted HRs are also adjusted for whether the resident had a Foley catheter (n = 8 of 176 [4.6%]) and a hospitalization in the prior 90 days (n = 10 of 176 [5.7%]).
c
Any use indicates at least 1 day of antimicrobial agent use prior to the quarterly nasal and rectal swabs to determine MDRO status.
d
These exposure variables were significant at P < .05 in unadjusted analyses and entered into a multivariable model.
Quinolones Any use, No. (%)c
32 (18.2)
2.00 (1.40-2.86)d
1.89 (1.28-2.81)
Days of therapy/1000 resident-days, mean (SD), log
0.6 (1.3)
1.20 (1.08-1.33)d
1.18 (1.06-1.32)
Any use
12 (6.8)
1.73 (1.10-2.70)d
1.57 (1.03-2.40)
Days of therapy/1000 resident-days, mean (SD), log
0.2 (0.8)
1.18 (1.01-1.38)d
1.16 (1.00-1.35)
Any use, No. (%)c
14 (8.0)
2.05 (0.67-6.33)
NA
Days of therapy/1000 resident-days, mean (SD), log
0.3 (1.0)
1.21 (0.90-1.61)
NA
Any use, No. (%)c
13 (7.4)
1.83 (0.68-4.93)
NA
Days of therapy/1000 resident-days, mean (SD), log
0.3 (0.9)
1.20 (0.91-1.56)
NA
Third- or fourth-generation cephalosporins
Penicillins
First-generation cephalosporins
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tridium difficile infections.42 For the minority of NH residents for whom life prolongation remains a goal, it is unclear if antimicrobial treatment prolongs survival.5,36,43,44 Treatment of asymptomatic bacteruria does not extend life.15,17,45 In an observational study, NH residents with advanced dementia who received antimicrobials for pneumonia lived longer, but also had more discomfort, than those untreated.36 While only 38% of proxies were counseled about antimicrobial use, when they were, the minimum criteria for use were more likely to be met, suggesting that clinicians who deliberate these risks and benefits with proxies also may be more judicious in prescribing antimicrobials. Qualitative studies, involving both proxies and clinicians, may be a useful next step to further our understanding about how goals of care are integrated into these decisions. Our results support the findings of others18-23 that MDRO colonization in this setting is extensive, particularly for MDRGNB.13 Colonization by MDROs is a major public health threat, which unless curtailed will limit therapeutic options to treat infections. Nursing home residents, including those with advanced dementia, are frequently hospitalized and contribute to the spread of MDROs into the hospital setting.8-10 Infections with MDROs are associated with higher mortality rates,46-48 prolonged hospital length of stays,46-48 increased need for intensive care,47 and higher care costs.46-48 Unmeasured consequences of MDROs in NHs include the effect of isolation practices on the residents’ quality of life49 and the organizational impact of infection control policies on the facility. Our analyses highlight potentially inappropriate antimicrobial use in advanced dementia, particularly of quinolones and third- and fourth-generation cephalosporins, as an opportunity to reduce MDRO colonization in this setting. This study has limitations that warrant comment. Its generalizability is uncertain; however, facility and resident char-
Conclusions While treatment decisions regarding infections in advanced dementia are challenging, our study suggests an approach that may improve the quality of these decisions. First, as part of advance care planning, families of patients with dementia should be counseled to expect infections in the end stage of the disease.2 The risks and benefits involved in assessing and treating infections should be reviewed and aligned with the goals of care. If the decision is to forego antimicrobials, suspected infections should not be worked up, and symptoms should be treated solely with palliative measures. If the use of antimicrobials remains consistent with preferences, treatment initiation should be guided by consensus criteria. A more judicious approach to infection management in advanced dementia may avoid unnecessary treatment burden in these terminally ill patients and reduce the of rapidly growing public health threat of MDRO emergence.
Role of the Sponsor: The funding sources for this study played no role in the design or conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
ARTICLE INFORMATION Accepted for Publication: June 25, 2014. Published Online: August 18, 2014. doi:10.1001/jamainternmed.2014.3918. Author Contributions: Dr Mitchell had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analyses. Study concept and design: Mitchell, Shaffer, D’Agata. Acquisition, analysis, or interpretation of data: Mitchell, Shaffer, Loeb, Givens, Habtemariam, Kiely. Drafting of the manuscript: Mitchell, Shaffer, D’Agata. Critical revision of the manuscript for important intellectual content: Mitchell, Shaffer, Loeb, Givens, Habtemariam, Kiely, D’Agata. Statistical analysis: Mitchell, Shaffer, Givens, Habtemariam, Kiely, D’Agata. Obtained funding: Mitchell, D’Agata. Administrative, technical, or material support: Mitchell, Loeb, Habtemariam, D’Agata. Study supervision: Mitchell, Habtemariam, D’Agata.
Additional Contributions: The investigators wish to thank the SPREAD data collection and management team (Ruth Carroll, RN, Sara Hooley, BSc, Mailika Lindsay, LPN, Holly Giampetro, LPN, Laurie Terp, RN, Lata Venkataraman, MSc, Ellen Gornstein, Shirley Morris, Diane Enghorn, Margaret Bryan, and Christopher Rockett, PhD), all the staff members at the participant nursing homes, and the residents and their families who have generously given their time to this study.
Conflict of Interest Disclosures: None reported. Funding/Support: This research was supported by National Institutes of Health National Institutes on Aging (NIH-NIA) grant R01 AG032982. Dr Mitchell is supported by NIH-NIA grant K24AG033640. Dr Givens is supported by NIH-NIA K23 AG034967.
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acteristics were similar to those nationwide.24 The SPREAD study was not designed to examine facility effects on outcomes, although our analyses accounted for clustering at the facility level. As in other studies involving swabs from NH residents,22 our recruitment rate was 38%. Demographic characteristics of nonparticipants were similar to those of participants, and their exclusion is unlikely to have significantly biased our main findings. Minimum criteria for antimicrobial treatment initiation are based on consensus guidelines25 and do not reflect the nuances of individual treatment decisions. Finally, inadequate power may account for the lack of significant associations between other individual antimicrobial classes with MDRO acquisition.
4. Mitchell SL, Black BS, Ersek M, et al. Advanced dementia: state of the art and priorities for the next decade. Ann Intern Med. 2012;156(1 Pt 1):45-51. 5. D’Agata E, Mitchell SL. Patterns of antimicrobial use among nursing home residents with advanced dementia. Arch Intern Med. 2008;168(4):357-362. 6. Luchins DJ, Hanrahan P. What is appropriate health care for end-stage dementia? J Am Geriatr Soc. 1993;41(1):25-30. 7. Yoshikawa TT. Antimicrobial resistance and aging: beginning of the end of the antibiotic era? J Am Geriatr Soc. 2002;50(7)(suppl):S226-S229.
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32. Cohen AL, Calfee D, Fridkin SK, et al; Society for Healthcare Epidemiology of America and the Healthcare Infection Control Practices Advisory Committee. Recommendations for metrics for multidrug-resistant organisms in healthcare settings: SHEA/HICPAC Position paper. Infect Control Hosp Epidemiol. 2008;29(10):901-913.
37. Nicolle LE. Resistant pathogens in urinary tract infections. J Am Geriatr Soc. 2002;50(7)(suppl): S230-S235. 38. Black BS, Finucane T, Baker A, et al. Health problems and correlates of pain in nursing home residents with advanced dementia. Alzheimer Dis Assoc Disord. 2006;20(4):283-290. 39. Chen JH, Lamberg JL, Chen YC, et al. Occurrence and treatment of suspected pneumonia in long-term care residents dying with advanced dementia. J Am Geriatr Soc. 2006;54(2):290-295. 40. Morrison RS, Ahronheim JC, Morrison GR, et al. Pain and discomfort associated with common hospital procedures and experiences. J Pain Symptom Manage. 1998;15(2):91-101. 41. Faulkner CM, Cox HL, Williamson JC. Unique aspects of antimicrobial use in older adults. Clin Infect Dis. 2005;40(7):997-1004. 42. Kyne L, Merry C, O’Connell B, Kelly A, Keane C, O’Neill D. Factors associated with prolonged symptoms and severe disease due to Clostridium difficile. Age Ageing. 1999;28(2):107-113. 43. Fabiszewski KJ, Volicer B, Volicer L. Effect of antibiotic treatment on outcome of fevers in institutionalized Alzheimer patients. JAMA. 1990; 263(23):3168-3172. 44. van der Steen JT, Mehr DR, Kruse RL, et al. Predictors of mortality for lower respiratory infections in nursing home residents with dementia were validated transnationally. J Clin Epidemiol. 2006;59(9):970-979. 45. Nicolle LE. Asymptomatic bacteriuria in the elderly. Infect Dis Clin North Am. 1997;11(3):647-662. 46. Cosgrove SE, Qi Y, Kaye KS, Harbarth S, Karchmer AW, Carmeli Y. The impact of methicillin resistance in Staphylococcus aureus bacteremia on patient outcomes: mortality, length of stay, and hospital charges. Infect Control Hosp Epidemiol. 2005;26(2):166-174.
33. Olsho LE, Bertrand RM, Edwards AS, et al. Does adherence to the Loeb minimum criteria reduce antibiotic prescribing rates in nursing homes? J Am Med Dir Assoc. 2013;14(4):e1-e7.
47. Carmeli Y, Eliopoulos G, Mozaffari E, Samore M. Health and economic outcomes of vancomycin-resistant enterococci. Arch Intern Med. 2002;162(19):2223-2228.
34. D’Agata E, Loeb MB, Mitchell SL. Challenges in assessing nursing home residents with advanced dementia for suspected urinary tract infections. J Am Geriatr Soc. 2013;61(1):62-66.
48. Schwaber MJ, Navon-Venezia S, Kaye KS, Ben-Ami R, Schwartz D, Carmeli Y. Clinical and economic impact of bacteremia with extendedspectrum-beta-lactamase-producing Enterobacteriaceae. Antimicrob Agents Chemother. 2006;50(4):1257-1262.
35. Sanger JD, Willett JB, eds. Applied Longitudinal Data Analysis: Modeling Change and Event Occurrence. New York: Oxford University Press; 2003:420-422. 36. Givens JL, Jones RN, Shaffer ML, Kiely DK, Mitchell SL. Survival and comfort after treatment of pneumonia in advanced dementia. Arch Intern Med. 2010;170(13):1102-1107.
49. Loeb M, Moss L, Stiller A, et al. Colonization with multiresistant bacteria and quality of life in residents of long-term-care facilities. Infect Control Hosp Epidemiol. 2001;22(2):67-68.
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Original Investigation
Infection Management and Multidrug-Resistant Organisms in Nursing Home Residents With Advanced Dementia Susan L. Mitchell, MD, MPH; Michele L. Shaffer, PhD; Mark B. Loeb, MD, MSc; Jane L. Givens, MD, MSCE; Daniel Habtemariam, BA; Dan K. Kiely, MPH, MA; Erika D’Agata, MD, MPH
IMPORTANCE Infection management in advanced dementia has important implications for
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(1) providing high-quality care to patients near the end of life and (2) minimizing the public health threat posed by the emergence of multidrug-resistant organisms (MDROs). DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study of 362 residents with advanced dementia and their health care proxies in 35 Boston area nursing homes for up to 12 months. MAIN OUTCOMES AND MEASURES Data were collected to characterize suspected infections, use of antimicrobial agents (antimicrobials), clinician counseling of proxies about antimicrobials, proxy preference for the goals of care, and colonization with MDROs (methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and multidrug-resistant gram-negative bacteria). Main outcomes were (1) proportion of suspected infections treated with antimicrobials that met minimum clinical criteria to initiate antimicrobial treatment based on consensus guidelines and (2) cumulative incidence of MDRO acquisition among noncolonized residents at baseline. RESULTS The cohort experienced 496 suspected infections; 72.4% were treated with antimicrobials, most commonly quinolones (39.8%) and third- or fourth-generation cephalosporins (20.6%). At baseline, 94.8% of proxies stated that comfort was the primary goal of care, and 37.8% received counseling from clinicians about antimicrobial use. Minimum clinical criteria supporting antimicrobial treatment initiation were present for 44.0% of treated episodes and were more likely when proxies were counseled about antimicrobial use (adjusted odds ratio, 1.42; 95% CI, 1.08-1.86) and when the infection source was not the urinary tract (referent). Among noncolonized residents at baseline, the cumulative incidence of MDRO acquisition at 1 year was 48%. Acquisition was associated with exposure (>1 day) to quinolones (adjusted hazard ratio [AHR], 1.89; 95% CI, 1.28-2.81) and third- or fourth-generation cephalosporins (AHR, 1.57; 95% CI, 1.04-2.40). CONCLUSIONS AND RELEVANCE Antimicrobials are prescribed for most suspected infections in advanced dementia but often in the absence of minimum clinical criteria to support their use. Colonization with MDROs is extensive in nursing homes and is associated with exposure to quinolones and third- and fourth-generation cephalosporins. A more judicious approach to infection management may reduce unnecessary treatment in these frail patients, who most often have comfort as their primary goal of care, and the public health threat of MDRO emergence.
JAMA Intern Med. 2014;174(10):1660-1667. doi:10.1001/jamainternmed.2014.3918 Published online August 18, 2014. 1660
Author Affiliations: Hebrew SeniorLife Institute for Aging Research, Boston, Massachusetts (Mitchell, Givens, Habtemariam, Kiely); Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (Mitchell, Givens, D’Agata); Department of Pediatrics, University of Washington and Children’s Core for Biomedical Statistics, Seattle Children’s Research Institute, Seattle (Shaffer); Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada (Loeb). Corresponding Author: Susan L. Mitchell MD, MPH, Hebrew SeniorLife Institute for Aging Research, 1200 Centre St, Boston, MA 02131 ([email protected]). jamainternalmedicine.com
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Infection Management in Advanced Dementia
A
lzheimer disease affects over 5 million Americans, is the sixth leading cause of death in the United States,1 and is increasingly recognized as a terminal illness.2 Identifying opportunities to improve the quality of the care for patients with advanced dementia is a clinical and research priority.2-4 In advanced dementia, patients typically have profound cognitive deficits (no longer recognize family), limited verbal abilities (0).
Twelve-month cumulative incidence rates of MDRO acquisition were calculated only among residents who met both of the following conditions: (1) no MDRO at baseline and (2) at least 1 follow-up swab. These stipulations resulted in the following numbers of residents available for the acquisition analyses: any MDRO, n = 176; MDRGNB, n = 200; and MRSA, n = 278. Among these residents, the cumulative incidence rates were any MDRO, 47.9%; MDRGNB, 35.8%; and MRSA, 21.3% (Figure). Only 2 residents acquired VRE. In unadjusted analyses, greater quinolone and third- and fourth-generation cephalosporin use, measured both as greater than 1 day of treatment and higher log DOT/1000-residents days, were significantly associated with MRDO acquisition (Table 3). All antimicrobials considered together, first-generation cephalosporins, and penicillins were not significantly associated with acquisition. Among the covariates, only Foley catheters (HR, 2.20; 95% CI, 0.96-5.05) and hospitalization in the prior 90 days JAMA Internal Medicine October 2014 Volume 174, Number 10
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Table 2. Suspected Infectious Episodes Treated With Antimicrobial Agents and Association With Presence of Minimum Clinical Criteria for Such Treatment34 Infectious Episodesa Minimum Criteria Total (n = 359)
Characteristic
Present (n = 158)
Absent (n = 201)
Association of Treatment With Presence of Minimum Criteria OR (95% CI) Unadjusted
Adjusted
Resident Age, mean (SD)
86.7 (7.0)
86.4 (7.3)
87.0 (6.7)
0.98 (0.95-1.02)
NA
Female
296 (82.5)
123 (77.9)
173 (86.1)
0.58 (0.28-1.18)
NA
White
330 (91.9)
147 (93.0)
183 (91.0)
1.39 (0.55-3.52)
NA
Congestive heart failure
69 (19.2)
27 (17.1)
42 (20.9)
0.73 (0.46-1.18)
NA
Diabetes mellitus
94 (26.2)
35 (22.2)
59 (29.4)
0.72 (0.39-1.35)
NA
Chronic obstructive lung disease
58 (16.2)
24 (15.2)
34 (16.9)
0.84 (0.48-1.45)
NA
BANS-S score, mean (SD)b d
21.9 (2.9)
22.4 (2.8)
21.6 (2.9)
1.11 (1.04-1.18)c
NA
TSI = 0
216 (60.2)
91 (57.6)
125 (62.2)
0.87 (0.49-1.54)
NA
Do-not-hospitalize order
NA
109 (30.4)
50 (31.7)
59 (29.4)
1.20 (0.65-2.22)
Hospice
25 (7.0)
17 (10.8)
8 (4.0)
2.13 (1.00-4.50)c
NA
Feeding tube
22 (6.1)
8 (5.1)
14 (7.0)
0.80 (0.30-2.12)
NA
Foley catheter
39 (10.9)
22 (13.9)
17 (8.5)
1.58 (0.73-3.41)
NA
149 (41.5)
67 (42.4)
82 (40.8)
1.10 (0.74-1.64)
NA
Clinician-proxy communication Counseled to expect infections
c
Counseled about antimicrobials
164 (45.7)
82 (51.9)
82 (40.8)
1.62 (1.08-2.43)
1.42 (1.08-1.86)
Asked about preferences for antimicrobial usee
224 (62.9)
100 (63.3)
124 (61.7)
1.12 (0.76-1.65)
NA
Urinary
148 (41.2)
28 (17.7)
120 (59.7)
1 [Referent]
1 [Referent]
Respiratory
104 (29.0)
35 (22.2)
69 (34.3)
2.24 (1.04-4.85)c
2.33 (1.12-4.84)
Febrile
41 (11.4)
32 (20.3)
9 (4.5)
14.79 (4.75-46.08)c
14.92 (5.16-43.14)
Skin
66 (18.4)
63 (39.9)
3 (1.5)
95.35 (23.44-387.90)c
102.92 (28.49-371.85)
166 (46.2)
69 (43.7)
97 (48.3)
0.83 (0.54-1.26)
NA
54 (15.0)
28 (17.7)
26 (12.9)
1.66 (0.93-2.96)c
NA
42 (11.8)
23 (14.6)
19 (9.5)
1.60 (0.86-2.97)
NA
Clinical examination within 72 hours
215 (59.9)
108 (68.4)
107 (53.2)
2.20 (1.22-3.97)c
NA
Documented proxy discussione
203 (56.7)
96 (60.8)
107 (53.2)
1.34 (0.86-2.11)
NA
71 (19.8)
27 (17.1)
44 (21.9)
0.71 (0.48-1.04)c
NA
Abbreviations: BANS-S, Bedford Alzheimer Nursing Severity–Subscale; NA, not applicable; OR, odd ratio; TSI, Test for Severe Impairment. a
Unless otherwise indicated, data are reported as number (percentage) of infectious episodes.
b
Possible BANS-S score range, 7 to 28, higher scores indicating more functional disability.
c
These variables were significant at P < .10 in bivariable analyses and entered into multivariable model.
d
Possible TSI score range, 0 to 24, lower scores indicating greater cognitive impairment (dichotomized to 0 vs >0).
e
These variables had a small amount of missing data. The totals for each were as follows: asked about preferences for antimicrobials use, n = 356; hospitalized, n = 357; documented proxy discussion, n = 358.
Infectious episode Type
Physician prescriber (vs nurse practitioner) Within 30 days of death e
Hospitalized
Weekend episode
(HR, 1.70; 95% CI, 0.90-3.18) were associated with MDRO acquisition at P < .10 in the bivariable analyses. After adjusting for these covariates, we found that greater exposure to quinolones (any use adjusted HR [AHR], 1.89; 95% CI, 1.28 -2.81; higher log DOT/1000 resident-days AHR, 1.18; 95% CI, 1.061.32) and third- and fourth-generation cephalosporins (any use AHR, 1.57; 95% CI, 1.03-2.40; higher log DOT/1000 residentdays AHR,1.16; 95% CI, 1.00-1.35) remained significantly associated with MDRO acquisition.
Discussion In this prospective study of NH residents with advanced dementia, suspected infections were common; antimicrobials were prescribed for the majority of episodes; but only 44% of 1664
treated episodes met minimum clinical criteria for antimicrobial treatment initiation. These criteria were more likely to be met if the suspected source was not the urinary tract and proxies were counseled about antimicrobials. Colonization by MDROs was extensive. Over 12 months, 67% of residents were colonized, and the cumulative incidence rate of MDRO acquisition among residents not colonized at baseline was 48%. Quinolones and third- and fourth-generation cephalosporins were the most commonly used antimicrobial classes, and greater exposure to these agents was significantly associated with MDRO acquisition. This study confirms that antimicrobials are extensively prescribed in advanced dementia5,36 but further demonstrates that much of this use may be unwarranted. The proportion of treated infections meeting minimum clinical criteria for antimicrobial treatment initiation was lower in our cohort than in
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Original Investigation Research
the general NH population, particularly for respiratory and urinary tract infections.14,15 Inadequate documentation or assessment by clinicians, as well as their unfamiliarity with the criteria, may have contributed to our findings. However, the challenges associated with decisions to initiate antimicrobial therapy in the NH setting are compounded in advanced dementia. Confirmatory laboratory and radiographic investigations are often not readily available. Clinicians may be particularly reluctant to order uncomfortable or inconvenient tests in NH residents with advanced dementia. Thus, treatment decisions are often made empirically based on clinical presen-
Figure. Cumulative Incidence Rates of Resident Acquisition of Drug-Resistant Organisms During the Study Period 50
Cumulative Incidence, %
Any MDRO 40
30
MDRGNB
20 MRSA 10
0 0
3
6
9
12
71 93 160
61 85 151
Months From Baseline Participants at risk, No. Any MDRO 175 MDRGNB 200 MRSA 278
116 145 218
93 124 184
MDRGNB indicates multidrug-resistant gram-negative bacteria; MDRO indicates multidrug-resistant organism; MRSA, methicillin-resistant Staphylococcus aureus; VRE, vancomycin-resistant enterococci. “Any MDRO” includes MDGRN, MRSA, or VRE. All residents were free of all 3 types of MDROs at baseline. Only 2 residents acquired VRE over the 12 months of the study.
tation. However, patients with severe dementia are severely cognitively impaired, effectively mute, and cannot reliably express symptoms. Not surprisingly, treatment criteria were met for 95% of skin infections, which can be assessed primarily by observable signs, compared with 19% of urinary tract infections, assessment of which is more reliant on subjective complaints. While asymptomatic bacteruria is the most common reason for potentially inappropriate antimicrobial use in NHs,14,15,17,34,37,38 exactly what constitutes “symptomatic” in advanced dementia, and hence the application of the minimum criteria for treatment of urinary tract infections in these patients, is not straightforward. Diagnosing urinary tract infections in advanced dementia is further confounded by the fact that urinalyses and urine cultures are frequently positive, regardless of whether clinical criteria for antimicrobial initiation are present.34 Patients with advanced dementia are usually nearing the end of life, and infections characterize the final stage of their disease.2,39 Clinicians making care decisions must consider not only clinical criteria for starting treatment with antimicrobials but also whether such treatment aligns with the goals of care. Over 50% of our study residents received antimicrobials, yet comfort was the stated primary goal of care for 95% of them.2 For these residents, the burdens associated with assessing and treating infections may outweigh the benefits, particularly when the likelihood of a bacterial infection is low. While the extent to which NH residents with advanced dementia suffer from infections is difficult to assess, antimicrobials may not provide greater symptomatic relief than highquality palliative care. The workup and treatment of infections can be uncomfortable, particularly when parenteral therapy or hospitalization is involved.40 Even oral antimicrobials may contribute to distress, as these patients commonly have swallowing problems.2 Older persons are also particularly susceptible to adverse effects of antimicrobials,41 including Clos-
Table 3. Association Between Characteristics of Residents and Time to First Acquisition of Any MDROa Residents (n = 176)
Characteristic
HR (95% CI) Adjustedb
Unadjusted
All antimicrobial agents Any use, No. (%)c
65 (36.9)
1.20 (0.80-1.80)
NA
Days of therapy/1000 resident-days, mean (SD), log
1.4 (1.9)
1.06 (0.95-1.18)
NA
Abbreviations: HR, hazard ratio; MDRO, multidrug-resistant organism. a
Including methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and multidrug-resistant gram-negative bacteria.
b
Both the unadjusted and adjusted HRs account for clustering at the facility level in the generalized estimating equations. The adjusted HRs are also adjusted for whether the resident had a Foley catheter (n = 8 of 176 [4.6%]) and a hospitalization in the prior 90 days (n = 10 of 176 [5.7%]).
c
Any use indicates at least 1 day of antimicrobial agent use prior to the quarterly nasal and rectal swabs to determine MDRO status.
d
These exposure variables were significant at P < .05 in unadjusted analyses and entered into a multivariable model.
Quinolones Any use, No. (%)c
32 (18.2)
2.00 (1.40-2.86)d
1.89 (1.28-2.81)
Days of therapy/1000 resident-days, mean (SD), log
0.6 (1.3)
1.20 (1.08-1.33)d
1.18 (1.06-1.32)
Any use
12 (6.8)
1.73 (1.10-2.70)d
1.57 (1.03-2.40)
Days of therapy/1000 resident-days, mean (SD), log
0.2 (0.8)
1.18 (1.01-1.38)d
1.16 (1.00-1.35)
Any use, No. (%)c
14 (8.0)
2.05 (0.67-6.33)
NA
Days of therapy/1000 resident-days, mean (SD), log
0.3 (1.0)
1.21 (0.90-1.61)
NA
Any use, No. (%)c
13 (7.4)
1.83 (0.68-4.93)
NA
Days of therapy/1000 resident-days, mean (SD), log
0.3 (0.9)
1.20 (0.91-1.56)
NA
Third- or fourth-generation cephalosporins
Penicillins
First-generation cephalosporins
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tridium difficile infections.42 For the minority of NH residents for whom life prolongation remains a goal, it is unclear if antimicrobial treatment prolongs survival.5,36,43,44 Treatment of asymptomatic bacteruria does not extend life.15,17,45 In an observational study, NH residents with advanced dementia who received antimicrobials for pneumonia lived longer, but also had more discomfort, than those untreated.36 While only 38% of proxies were counseled about antimicrobial use, when they were, the minimum criteria for use were more likely to be met, suggesting that clinicians who deliberate these risks and benefits with proxies also may be more judicious in prescribing antimicrobials. Qualitative studies, involving both proxies and clinicians, may be a useful next step to further our understanding about how goals of care are integrated into these decisions. Our results support the findings of others18-23 that MDRO colonization in this setting is extensive, particularly for MDRGNB.13 Colonization by MDROs is a major public health threat, which unless curtailed will limit therapeutic options to treat infections. Nursing home residents, including those with advanced dementia, are frequently hospitalized and contribute to the spread of MDROs into the hospital setting.8-10 Infections with MDROs are associated with higher mortality rates,46-48 prolonged hospital length of stays,46-48 increased need for intensive care,47 and higher care costs.46-48 Unmeasured consequences of MDROs in NHs include the effect of isolation practices on the residents’ quality of life49 and the organizational impact of infection control policies on the facility. Our analyses highlight potentially inappropriate antimicrobial use in advanced dementia, particularly of quinolones and third- and fourth-generation cephalosporins, as an opportunity to reduce MDRO colonization in this setting. This study has limitations that warrant comment. Its generalizability is uncertain; however, facility and resident char-
Conclusions While treatment decisions regarding infections in advanced dementia are challenging, our study suggests an approach that may improve the quality of these decisions. First, as part of advance care planning, families of patients with dementia should be counseled to expect infections in the end stage of the disease.2 The risks and benefits involved in assessing and treating infections should be reviewed and aligned with the goals of care. If the decision is to forego antimicrobials, suspected infections should not be worked up, and symptoms should be treated solely with palliative measures. If the use of antimicrobials remains consistent with preferences, treatment initiation should be guided by consensus criteria. A more judicious approach to infection management in advanced dementia may avoid unnecessary treatment burden in these terminally ill patients and reduce the of rapidly growing public health threat of MDRO emergence.
Role of the Sponsor: The funding sources for this study played no role in the design or conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
ARTICLE INFORMATION Accepted for Publication: June 25, 2014. Published Online: August 18, 2014. doi:10.1001/jamainternmed.2014.3918. Author Contributions: Dr Mitchell had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analyses. Study concept and design: Mitchell, Shaffer, D’Agata. Acquisition, analysis, or interpretation of data: Mitchell, Shaffer, Loeb, Givens, Habtemariam, Kiely. Drafting of the manuscript: Mitchell, Shaffer, D’Agata. Critical revision of the manuscript for important intellectual content: Mitchell, Shaffer, Loeb, Givens, Habtemariam, Kiely, D’Agata. Statistical analysis: Mitchell, Shaffer, Givens, Habtemariam, Kiely, D’Agata. Obtained funding: Mitchell, D’Agata. Administrative, technical, or material support: Mitchell, Loeb, Habtemariam, D’Agata. Study supervision: Mitchell, Habtemariam, D’Agata.
Additional Contributions: The investigators wish to thank the SPREAD data collection and management team (Ruth Carroll, RN, Sara Hooley, BSc, Mailika Lindsay, LPN, Holly Giampetro, LPN, Laurie Terp, RN, Lata Venkataraman, MSc, Ellen Gornstein, Shirley Morris, Diane Enghorn, Margaret Bryan, and Christopher Rockett, PhD), all the staff members at the participant nursing homes, and the residents and their families who have generously given their time to this study.
Conflict of Interest Disclosures: None reported. Funding/Support: This research was supported by National Institutes of Health National Institutes on Aging (NIH-NIA) grant R01 AG032982. Dr Mitchell is supported by NIH-NIA grant K24AG033640. Dr Givens is supported by NIH-NIA K23 AG034967.
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acteristics were similar to those nationwide.24 The SPREAD study was not designed to examine facility effects on outcomes, although our analyses accounted for clustering at the facility level. As in other studies involving swabs from NH residents,22 our recruitment rate was 38%. Demographic characteristics of nonparticipants were similar to those of participants, and their exclusion is unlikely to have significantly biased our main findings. Minimum criteria for antimicrobial treatment initiation are based on consensus guidelines25 and do not reflect the nuances of individual treatment decisions. Finally, inadequate power may account for the lack of significant associations between other individual antimicrobial classes with MDRO acquisition.
4. Mitchell SL, Black BS, Ersek M, et al. Advanced dementia: state of the art and priorities for the next decade. Ann Intern Med. 2012;156(1 Pt 1):45-51. 5. D’Agata E, Mitchell SL. Patterns of antimicrobial use among nursing home residents with advanced dementia. Arch Intern Med. 2008;168(4):357-362. 6. Luchins DJ, Hanrahan P. What is appropriate health care for end-stage dementia? J Am Geriatr Soc. 1993;41(1):25-30. 7. Yoshikawa TT. Antimicrobial resistance and aging: beginning of the end of the antibiotic era? J Am Geriatr Soc. 2002;50(7)(suppl):S226-S229.
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