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American Journal of Hospice and Palliative
http://ajh.sagepub.com/content/29/8/599
The online version of this article can be found at:

DOI: 10.1177/1049909111432625
2012 29: 599 originally published online 4 January 2012 AM J HOSP PALLIAT CARE
Andrew J. Thompson, Maria J. Silveira, Caroline A. Vitale and Preeti N. Malani
Antimicrobial Use at the End of Life Among Hospitalized Patients With Advanced Cancer

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Original Article
Antimicrobial Use at the End of Life Among
Hospitalized Patients With Advanced Cancer
Andrew J. Thompson, MD
1
, Maria J. Silveira, MD, MA, MPH
2,3
,
Caroline A. Vitale, MD
4,5
, and Preeti N. Malani, MD, MSJ
1,4,5
Abstract
Background: We sought to evaluate antimicrobial use among patients with advanced cancer. Methods: Retrospective review of
patients experiencing cancer-related death while hospitalized. Results: Among 145 patients, 126 (86.9%) received antimicrobials
for a mean of 12.5 +12.9 days. 88 (69.8%) of 126 had clinical findings suggestive of infection. Sixty-one patients (48.4%) had pos-
itive cultures, the remaining were treated empirically. Comfort care was ultimately pursued in 99 (78.5%) of 126; 35 (35.4%) of
99 continued to receive antimicrobials after a transition to comfort care for an average of 1.6 +1.1 days. On average, antimi-
crobials were discontinued <1 day prior to death. Conclusion: Antimicrobial use was common among patients with advanced
cancer. Even after transition to comfort care, more than one third of patients remained on antimicrobials. The risks and burdens
of antimicrobials should be carefully examined when comfort is the stated goal.
Keywords
antimicrobials, ethics, palliative care
Introduction
Treatment of cancer patients with antimicrobials at the end of
life is a common practice.
1-3
Previous studies note the presence
of infection at the time of death in as many as 47% to 63% of
patients,
4
and a large portion of patients (64%-84%) with
advanced cancer receive antimicrobial treatment during their
last week of life.
5-7
Patients with advanced cancer are suscep-
tible to infection both due to their underlying malignancy and
as a result of cancer therapies. Conditions such as bronchial
obstruction, poor nutritional status, frequent hospitalizations,
treatment with chemotherapy and radiation, tumor necrosis,
indwelling catheters, and compromised mucosal barriers are
among the myriad of factors that may contribute to cancer-
associated infection. The threshold to treat probable or even
possible infection is therefore low, and aggressive management
in terms of broad-spectrum antimicrobials is sometimes pur-
sued even when the overall prognosis is extremely poor.
Antimicrobial therapy prescribed during the final weeks of
life may be intended to treat a potentially reversible condition
or symptomatic infection. In such cases, antimicrobial therapy
is typically viewed as usual care, rather than an aggressive
intervention.
8
Often antimicrobials are used when other aggres-
sive treatments such as chemotherapy, mechanical ventilation,
and hemodialysis are not considered appropriate by patients
and physicians.
9
Yet antimicrobial treatment, especially par-
enteral therapy, is not without significant risks including
drug-related adverse effects, the need for indwelling lines, and
Clostridium difficile infection. In addition to these burdens, the
threat of increasing antimicrobial resistance is an important
consideration both for individual patients and society at large.
Several previous reports have examined the patterns of antimi-
crobial use among patients with advanced cancer in hospice and
palliative care settings.
1-3,7,10
We sought to better understand pat-
terns of antimicrobial use at the end of life among a cohort of
patients with advanced cancer who died while hospitalized.
Methods
Setting and Population
The University of Michigan Health System (UMHS) is an
850-bed tertiary care facility that includes the University of
1
Department of Internal Medicine Divisions of Infectious Diseases, University
of Michigan Medical School, Ann Arbor, MI, USA
2
Department of General Medicine, University of Michigan Medical School, Ann
Arbor, MI, USA
3
Veterans Affairs Ann Arbor Healthcare System, Center for Clinical Man-
agement Research, Ann Arbor, MI, USA
4
Department of Geriatric Medicine, University of Michigan Medical School,
Ann Arbor, MI, USA
5
Veterans Affairs Ann Arbor Healthcare System, Geriatric Research Education
and Clinical Center (GRECC), Ann Arbor, MI, USA
Corresponding Author:
Preeti N. Malani, MD, MSJ, VA Healthcare System, 2215 Fuller Road, Ann
Arbor, MI 48105, USA
Email: pmalani@umich.edu
American Journal of Hospice
& Palliative Medicine

29(8) 599-603
The Author(s) 2012
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Michigan Comprehensive Cancer Center (UMCCC). Our
study population includes all adult patients in the University
of Michigan Cancer Registry who were inpatients from January
1, 2004 through December 31, 2007 and met the following
inclusion criteria: (1) age 18 at the time of cancer diagnosis,
(2) estimated 5-year survival <20%as predicted by the Surveil-
lance, Epidemiology, and End Results (SEER) Cancer Statis-
tics Review,
11
and (3) died while an inpatient at UMHS.
For these patients, medical records were reviewed and
clinical information abstracted with a focus on timing of
end-of-life decision making and the use of antimicrobial
therapy. The hospital pharmacy database was queried to
obtain administration records for all parenteral and parental-
equivalent antimicrobial medications. The unit of time was
delineated in 1-day increments. Demographic data, type of
malignancy, location of death (intensive care unit [ICU] vs
general floor), and the presence of advanced care planning
were ascertained. Microbiology results and antimicrobial
use was also recorded. Clinical records were abstracted by
a physician and reviewed by an attending infectious diseases
physician (P.N.M.) in order to distinguish between culture-
based and empiric antimicrobial therapy.
Data Analysis
Continuous data were described and summarized by mean +
standard deviation or median with interquartile range (IQR).
Chi-square and Fisher exact tests were used to compare propor-
tions. Student t tests were used for comparing means of contin-
uous variables. A 2-tailed P value of .05 or less was considered
statistically significant. All statistical analysis was performed
using SAS 9.1 (SAS Institute Inc, Cary, North Carolina). This
study was approved by the University of Michigan Medical
School Institutional Review Board.
Results
We identified 145 patients who experienced cancer-related
deaths while hospitalized at UMHS from January 1, 2004
through December 31, 2007; mean age was 60.3 +11.7 years
(range 22-88) and 57.6%were male. The most common cancer
sites included lung (35.2%), liver (6.9%), esophageal (6.9%),
colorectal (5.5%), and leukemia (28.3%).
Reasons for admission varied and included progression of
known cancer (29.0%) and infectious complications (27.6%)
as the 2 most common. Twenty-five (17.2%) were admitted for
newly diagnosed cancer; the majority with leukemia, 17 (68%)
of 25. Median length of stay was 9 days (IQR 4-16). In terms
of advanced care plans, 32 (25.4%) had their preferences for-
mally documented prior to admission and another 26 (17.9%)
completed a plan within 24 hours of admission.
Among 145 patients, 126 (86.9%) received parenteral (or par-
enteral equivalent) antimicrobials at some point during hospitali-
zation for suspected or proven infections. Medical records
document clinical concern for possible infection in 88 (69.8%)
of 126; 34 (27.0%) had fever at the time of admission.
Sixty-one patients (48.4%) had positive microbiologic cultures,
while the remaining 65 (51.6%) were treated empirically.
Among patients treated with antimicrobials, the most com-
mon infectious diagnosis was pneumonia in 58 (46.0%) of
126. The presence of pneumonia was established by clinical
findings in 39 (67.2%) of 58, and by sputum or bronchoscopic
cultures in 19 (32.8%) of 58. Bloodstream infections were
present in 34 (27.0%) of 126; urinary tract infections (UTIs)
in 10 (7.9%) of 126. Intra-abdominal infections were present
in 15 (11.9%) of 126 patients; specific infections included
peritonitis (6), cholangitis (6), and spontaneous bacterial peri-
tonitis (3). Empiric antimicrobial treatment for fever of
unclear source occurred in 15 (11.9%) of 126. Among the
patients who received antimicrobials, 7 (5.6%) patients devel-
oped C difficile infection. Among the 61 patients with positive
microbiologic cultures, 19 (31.1%) demonstrated multidrug-
resistant organisms.
In terms of specific antimicrobial agents, vancomycin was
administered most frequently with use recorded in 91 (72.2%)
patients (Table 1). Among patients receiving vancomycin, 9 had
documented infection with methicillin-resistant Staphylococcus
aureus (MRSA), 3 had coagulase-negative staphylococcus, and
1 had Enterococcus faeciumresistant to ampicillin. The major-
ity of the remaining patients (85.7%) received vancomycin with-
out a clear microbiologic indication.
Eighty-nine patients (70.6%) received extended-spectrum
penicillins, mostly pipercillin/tazobactam (81 patients). Cepha-
losporins were given to 49 (38.9%) and carbapenems to 15
(11.9%). Nearly two thirds of patients treated with antimicro-
bials received a fluoroquinolone (82 of 126; 65.1%), mostly
Table 1. Use of Specific Antimicrobials Among Hospitalized Patients
With Advanced Cancer (n 126)
a
Antimicrobial Agents Number (%)*
Penicillins 89 (70.6)
Pipercillin/tazobactam 81 (64.2)
Ampicillin 20 (15.9)
Cephalosporins 49 (38.9)
Cefepime 30 (23.8)
Ceftriaxone 12 (9.5)
Cefazolin 5 (4.0)
Cefuroxime 1 (0.7)
Cefoxitin 1 (0.7)
Meropenem 15 (11.9)
Fluoroquinolones 82 (65.1)
Ciprofloxacin 15 (11.9)
Levofloxacin 75 (59.5)
Aztreonam 14 (11.1)
Vancomycin 91 (72.2)
Daptomycin 10 (7.9)
Linezolid 7 (5.5)
Metronidazole 39 (30.1)
Aminoglycosides 25 (19.8)
Amikacin 5 (4.0)
Gentamicin 10 (7.9)
Tobramycin 13 (10.3)
a
Several patients received more than 1 agent.
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levofloxacin (75 of 82 patients). Besides vancomycin, other
gram-positive agents were given including daptomycin (10
patients, 7.9%) and linezolid (7 patients, 5.6%); 3 patients
received both. Metronidazole use was also frequent with 39
(30.1%) patients receiving this agent.
Among the patients who received antimicrobial therapy, the
mean duration of treatment was 12.5 + 12.9 days (median 8,
range 1-81). Among patients with leukemia (n 37), the mean
duration of antimicrobial use was 19.2 +14.5, which was sig-
nificantly longer than use among patients with nonleukemic
malignancy (9.6 +11.1 days), P < .01. Among the 65 patients
receiving empiric treatment, the average duration was 8.0 +
6.9 days (median 6, range 1-34), while patients who received
culture-guided therapy (n 61), the duration was 17.2 +
15.8 days (median 13, range 1-81), P < .01. Among the patients
with an advanced care plan (n 75), the average duration of
antimicrobial therapy was 10.5 +10.4 days, while those with-
out a care plan (n 51) were treated longer with an average of
13.7 +14.2 days, although the difference did not achieve sta-
tistical significance (P .17).
Among the entire study population (n 145), 64 (44.1%)
patients died in the ICU and 59 (40.7%) underwent mechanical
ventilation at some point during hospitalization. As expected,
antimicrobial use among these patients was extensive. On
average, duration of antimicrobial use was longer among
patients undergoing mechanical ventilation (n 54) compared
to those who did not receive mechanical ventilation (n 72),
16.4 +15.9 days versus 9.5 +9.1 days, P < .01. Patients that
died in the ICU (n 59) were treated for an average of 14.6 +
15.3 days, while patients that died on non-ICU services (n
67) received an average of 10.6 +10 days, P .08.
Patients were identified as actively dying by the use of
terminology such as end stage, dying, terminally ill,
moribund, situation hopeless/grave, and prognosis
grim in 100 (79.4%) of 126 of cases. The first occurrence
of such documentation occurred an average of 3.3 + 4.1
(median 2) days prior to death. A comfort care goal was
ultimately pursued for 99 (78.5%) of 126, however 35
(35.4%) of 99 continued to receive antimicrobials after a
transition to comfort care for an average of 1.6 + 1.1 days
(median 1, range 1-6).
Among all patients who received antimicrobial therapy,
57 (45.2%) of 126 had therapy discontinued prior to death.
On average, the time between antimicrobial discontinuation
to death was 0.8 days +2.1 (median 0). Time from antimicro-
bial discontinuation to death did not vary based on underlying
disease, type of infection, type of treatment (empiric vs
culture-guided), comfort care status, or presence of an
advanced care plan.
Discussion
The preceding results characterize the nature of antimicrobial
use among hospitalized patients with cancer near the end of
life. These findings offer additional confirmation that antimi-
crobial treatment is common among patients with advanced
cancer. Overall, we identified antimicrobial use among 87%
of our patient population. More remarkable is that even when
overall goals of care shifted to comfort care, the use continued
in more than one third of patients. Although the issue of anti-
microbial use at the end of life has been addressed by other
investigators,
1,6,7,12-14
this study is unique in its description
of antimicrobial use among a cohort of patients with advanced
cancer in an acute care setting.
Among patients receiving antimicrobials, more than half
were treated empirically. The use of broad-spectrum agents
was frequent, especially vancomycin (72%) and pipercillin/
tazobactam (64%). Among the 91 patients who received van-
comycin, only 14% had a clear microbiologic indication for
use. Although some of the remaining patients may have had
an acceptable indication (ie, intolerance to beta-lactam
agents), the majority likely received vancomycin inappropri-
ately. This extensive use of vancomycin is particularly nota-
ble, given focused efforts to limit inappropriate use of this
agent.
15
Besides vancomycin-related toxicities (nephrotoxi-
city, ototoxicity, leukopenia, etc), excess use increases the
risk of acquiring resistant organisms such as vancomycin-
resistant Enterococcus (VRE), as well as vancomycin-
intermediate and vancomycin-resistant S aureus (VISA and
VRSA).
16
Although we did not specifically record the pres-
ence of antimicrobial related adverse effects, we did identify
7 cases of C difficile infection, a rate that is many times higher
than the general inpatient population.
The use of parenteral antimicrobials can be considered
aggressive care in that it requires intravenous access and
drug level monitoring. Besides significant drug-related toxici-
ties and health care costs, patients receiving antimicrobials are
at increased risk of acquisition of antimicrobial-resistant
organisms as well as C difficile infection. Yet, observational
studies have shown that antimicrobials are withdrawn later
than other aggressive interventions, including parenteral
nutrition, mechanical ventilation, hemodialysis, and blood
transfusions.
9
Generally speaking, in the acute medical-
surgical setting, the goals of care are usually to decrease both
morbidity and mortality. If the goals of care shift to focus
solely on quality of life and comfort as the death becomes
imminent, the treatment of empiric and even proven infection
should be carefully reevaluated.
Though a majority of patients in our study were noted to be
actively dying at some point during their hospitalization, anti-
microbials were continued until an average of 0.8 days prior
to death. Although the current study is limited both by retro-
spective design and by sample size, we were not able to iden-
tify any specific patient-related factors, such as the presence
of an advanced care plan or comfort care status, that appeared
to impact the time from discontinuation of antimicrobials
to death.
Possible reasons for the persistence of treatment include the
desire to treat all potentially reversible causes, the belief that
antimicrobials are part of usual care, and the notion that anti-
microbials provide symptomatic or even symbolic comfort to
patients, family members, and providers. Previous studies
Thompson et al 601
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have shown that terminally ill patients with cancer often
receive antimicrobials in hospice settings despite the absence
of survival benefit.
1
Numerous investigators have attempted to determine
whether antimicrobial therapy provides symptomatic relief at
the end of life. Most of the existing literature examines patients
either with cancer or advanced dementia. For patients with
malignancy, apart from specific conditions such as a sympto-
matic UTI, treatment of infections at the end of life has not
been shown to improve symptoms.
17
Although there is some
evidence to suggest that antimicrobial treatment of pneumo-
nia may provide symptomatic benefit among patients with
advanced dementia,
18
a recent prospective study of patients
with advanced dementia and pneumonia demonstrated an
association between antimicrobials and increased discom-
fort.
19
The treatment of pain, fever, and dyspnea with modal-
ities such as opioids and antipyretics remain effective means
of providing symptomatic benefit.
20,21
Additionally, prolon-
gation of the dying process may be an unintended conse-
quence of antimicrobial treatment.
19,22
In our study a substantial portion of patients remained on
antimicrobials after a decision to pursue comfort-oriented care
was made. Though the average duration of continued therapy
was brief, the continuation of antimicrobials represents a pos-
sible distraction from the focus of comfort at the end of life.
Although the reasons for continuing therapy are not clear, one
possibility is that providers may not want to pursue active dis-
cussions with patients family members or surrogates about
discontinuing antimicrobials as these medications are often
perceived by patients, family members, and even providers as
benevolent, nonburdensome, and almost basic care.
4
A discus-
sion about withdrawing antimicrobials may be perceived as
a daunting task not worth pursuing for a clinician who likely
has already discussed the pros and cons of other major life-
sustaining treatments such as cardiopulmonary resuscitation,
dialysis, or feeding tubes, for example. Rather than discussing
the particulars of treatment, a more productive approach might
be one focused around goals of care.
On the other hand, the unintended consequences of antimi-
crobial therapy not only include burdens to the individual
patient but also extend to other patients through the possible
selection of antimicrobial resistance.
8
For instance, previous
work demonstrates that futile care in the critical care setting
increases the risk of bacterial resistance
22
and as such, may
cause harm to other patients.
23
Ethical decisions regarding use
of antimicrobial treatment in a potentially futile situation are
problematic and may require considering both duty to the indi-
vidual patient as well as minimizing antimicrobial resistance
globally.
24
Given our findings, we suggest that clinicians
carefully consider appropriate indications for antimicrobial
use at the end of life.
Several limitations to our study exist, including its retro-
spective nature, the heterogeneity of the sample with regard
to cancer diagnoses (leukemia vs solid tumors), and an inability
to associate antimicrobial use with symptomatic benefits or
adverse outcomes. Despite these shortcomings, our findings
provide important additional confirmation of the frequent and
potentially unnecessary use of broad-spectrum antimicrobials
among cancer patients at the end of life.
Additional research is needed into the factors contributing to
aggressive use of antimicrobials at the end of life. Beliefs
about the benefit of antimicrobials may outweigh evidence, and
understanding the values that drive decision making among
physicians, families, and patients specifically with regard to
antimicrobial use should be examined prospectively.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship,
and/or publication of this article.
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