cancers

Article
Antibiotic Treatment in End-of-Life Cancer
Patients—A Retrospective Observational Study
at a Palliative Care Center in Sweden
Maria Helde-Frankling 1,2 , Jenny Bergqvist 3,4 , Peter Bergman 2 and Linda Björkhem-Bergman 1,2, *
1 ASIH Stockholm Södra, Långbro Park, Palliative Home Care and Hospice Ward, Bergtallsvägen 12,
125 59 Älvsjö, Sweden; maria.helde-frankling@sll.se
2 Department of Laboratory Medicine, Division of Clinical Microbiology,
Karolinska Institutet and Karolinska University Hospital, Huddinge, 141 86 Stockholm,
Sweden; peter.bergman@ki.se
3 Breast Centre, Department of Surgery, Capio St. Gorans Hospital, 112 81 Stockholm, Sweden;
Jenny.Bergqvist@capiostgoran.se
4 Department of Oncology/Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden
* Correspondence: linda.bjorkhem-bergman@ki.se; Tel.: +46-70-484-66-55; Fax: +46-8-585-813-05

Academic Editor: Samuel C. Mok

Received: 3 June 2016; Accepted: 1 September 2016; Published: 6 September 2016

Abstract: Background: The aim of this study was to elucidate whether palliative cancer patients
benefit from antibiotic treatment in the last two weeks of life when an infection is suspected. Method:
We reviewed medical records from 160 deceased palliative cancer patients that had been included
in previous studies on vitamin D and infections. Patients treated with antibiotics during the last
two weeks of life were identified and net effects of treatment (symptom relief) and possible adverse
events were extracted from medical records. Results: Seventy-nine patients (49%) had been treated
with antibiotics during the last two weeks in life. In 37% (n = 29), the treatment resulted in evident
symptom relief and among these 50% had a positive bacterial culture, 43% had a negative culture and
in 7% no culture was taken. Among the patients with no or unknown effect of antibiotics, 50% had
a positive culture. When the indication for antibiotic treatment was to avoid or treat sepsis, symptom
relief was achieved in 50% of the patients (n = 19). Only 4% (n = 3) of the patients experienced adverse
events of the treatment (diarrhea, nausea). Conclusions: Treating infections with antibiotics in the
last weeks of life may improve the quality of life for palliative cancer patients, especially if sepsis
is suspected or confirmed. According to our results, the beneficial effects outweigh the potentially
negative outcomes.

Keywords: infections; antibiotics; palliative care; hospice care; cancer; CRP; immune system;
vitamin D

1. Introduction
According to the WHO-definition of palliative care, early identification and assessment of physical
symptoms in the palliative patient aim to prevent and relieve suffering. The overall goal is to improve
quality of life in patients facing the problems associated with life-threatening illness. Therefore it is
important that the side effects of any medical treatment do not outweigh possible beneficial effects.
In light of this basic principle the question whether suspected infections should be treated or not
arises. Infections might give the patient bothering symptoms, such as fatigue, pain and discomfort.
Especially symptoms of sepsis lead to distress. At the same time, non-restricted use of antibiotics in
the dying patient may be questioned due to potential risks of allergic reactions, antibiotic-associated
diarrhea and emergence of multi-drug resistant bacteria [1]. It is also possible that antibiotics may not

Cancers 2016, 8, 84; doi:10.3390/cancers8090084 www.mdpi.com/journal/cancers

Cancers 2016, 8, 84 2 of 10

be effective due to physiological alterations in the dying patient, such as decreased tissue perfusion,
increased distribution volume and an impaired immune-system. Another practical implication of
antibiotic-use in this patient-group is the increased need for use of invasive devices.
Infection in the dying patient is common. In an autopsy study from an inpatient hospice ward
(n = 38) including both cancer and non-cancer patients, pneumonia was evident in 79% of cases and
the leading cause of death in 44% of cases [2]. However, the clinical evidence for using or not using
antibiotics in the end-of-life period is scarce and the results are divergent [3–6]. The frequency of
antibiotic use in the dying cancer patient also varies greatly [1,7–9]. In a systematic review of studies
of antimicrobial use in palliative care, the prevalence ranged from 4% to 84% [10].
There are no written guidelines regarding the use of antibiotics in the dying cancer patient and
to treat or not to treat these patients needs ethical considerations. The difficulty of making sound
treatment decisions in palliative patients have been addressed in several publications discussing such
philosophical and ethical issues [11–13]. In a recent editorial, Furuno et al. argues that decisions
on antibiotic use in hospice care should be made on a case-by-case basis and be consistent with the
individuals goals of care [14].
In this study we set out to elucidate if cancer patients in the end-of-life situation experienced any
benefit from antibiotic treatment when infections were suspected and whether antibiotic treatment had
a positive or negative effect on patients’ symptoms. We wanted to test the hypothesis that antibiotics
seldom do any harm in the end-of-life cancer patients and sometimes may improve quality of life.
To this end, we retrospectively extracted data from medical records of 160 deceased cancer patients
who had participated in previously performed studies related to vitamin D status and infections.

2. Methods

2.1. Study Cohort

To elucidate the effect of using antibiotics in the end of life we collected data from deceased
cancer patients that had participated in two observational studies on vitamin D status and infections
in palliative care; one study is completed and published [15], and one is still ongoing. The aim of
the studies was to test the hypothesis that low vitamin D levels are associated with higher opioid
dose, higher infectious burden and impaired quality of life in palliative cancer patients. One was
a cross-sectional study to investigate the vitamin D levels and in the ongoing study patients with
low vitamin D-levels are supplemented with vitamin D. Palliative cancer patients were recruited
from ASIH Stockholm Södra, Långbro Park Advanced Palliative Home Care Team and Hospice Ward.
The patients were recruited consecutively, i.e., they did not have any specific infections at inclusion
and patients with any type of cancer were included. In these two studies 163 patients had deceased at
the end of April 2016. Three patients had moved from Stockholm or had changed care-givers, which
precluded access to the medical records (missing data). In total, n = 160 patients were included in the
final analysis.

2.2. Data Extraction

We identified all patients with any antibiotic treatment in their last two weeks of life. For these
patients, data were collected from the medical records regarding type of infection, microbiological
cultures, pathogens, type of antibiotics and indication of treatment divided into five groups:
(1) treatment or prevention of sepsis; (2) respiratory tract symptoms; (3) urinary tract symptoms;
(4) GI-tract symptoms; (5) skin infections. In general, when no obvious infectious focus was evident
but the patient had fever, elevated CRP and an impaired general condition the indication for antibiotic
use was “prevention of sepsis”. Data on positive effects of treatment, such as different forms of
symptom relief or increased quality of life stated in the medical or nursing records was collected.
Examples of “positive effects” were reduced fatigue, resolution of fever or that the patient gained
energy to do things of their choice that were not possible before antibiotic treatment was initiated.
Cancers 2016, 8, 84 3 of 10

If no positive effects were mentioned in the medical record the effect was classified as “no effect” or
“unknown”. In addition, possible adverse reactions to the antibiotic treatment stated in 3 of 10 
Cancers 2016, 8, 84  the medical
records were also collected. The assessment of the effects of antibiotics was performed by two
In addition, possible adverse reactions to the antibiotic treatment stated in the medical records were 
independent reviewers (MHF and LBB). If there were divergent opinions the case was discussed and
also  collected.  The  assessment  of  the  effects  of  antibiotics  was  performed  by  two  independent 
a consensus decision was taken.
reviewers (MHF and LBB). If there were divergent opinions the case was discussed and a consensus 
Demographic data regarding age, sex and cancer diagnosis had already been collected previously.
decision was taken. 
The latest CRP and
Demographic  albumin
data  levels were
regarding  collected.
age,  sex  and No values
cancer  were older
diagnosis  than 3 been 
had  already  weeks before death.
collected 
Vitamin D was measured as 25-hydroxyvitamin D and only levels measured less than 60 days before
previously. The latest CRP and albumin levels were collected. No values were older than 3 weeks 
before death. Vitamin D was measured as 25‐hydroxyvitamin D and only levels measured less than 
death was included in the analysis, since the half-life of 25-hydroxvitamin D is 3–4 weeks and values
60 days before death was included in the analysis, since the half‐life of 25‐hydroxvitamin D is 3–4 
older than 2 month were considered to be non-representative of the current vitamin D status.
weeks and values older than 2 month were considered to be non‐representative of the current vitamin 
D status. 
2.3. Statistical Analysis
2.3. Statistical Analysis 
Statistical analyses were performed using Graph Pad Prism vs. 6.0. Since some of the data
did not show a Gaussian distribution we present median levels and ranges. When comparing
Statistical analyses were performed using Graph Pad Prism vs. 6.0. Since some of the data did 
not  show 
demography parameters,a  Gaussian  distribution 
CRP, albumin we andpresent  median  levels Dand 
25-hydroxyvitamin ranges. 
levels, When  comparing 
Mann-Whitney U-test was
demography parameters, CRP, albumin and 25‐hydroxyvitamin D levels, Mann‐Whitney U‐test was 
used. When comparing the distribution of “positive”, “negative” or “no culture” and “antibiotic
used.  When  comparing  the  distribution  of  “positive”,  “negative”  or  “no  culture”  and  “antibiotic 
effects” in different cancer forms, Chi2 -test was used. When comparing “positive” or “no effect of
effects” in different cancer forms, Chi2‐test was used. When comparing “positive” or “no effect of 
antibiotic treatment” in sepsis or urinary tract infections, Fisher’s exact test was used (Figure 1).
antibiotic treatment” in sepsis or urinary tract infections, Fisher’s exact test was used (Figure 1). 

 
Figure 1. Effect of antibiotics at different infection indications in end‐of‐life cancer patients. Positive 
Figure 1. Effect of antibiotics at different infection indications in end-of-life cancer patients. Positive
effect  (pos)  or  unknown/no  effect  (neg)  are  presented.  Sepsis  means  to  treat  or  avoid  sepsis. 
effect (pos) or unknown/no effect (neg) are presented. Sepsis means to treat or avoid sepsis. Percentage
Percentage  of  positive  effect  of  all  treatment  in  that  specific  infections  indication  is  stated.  When 
of positive effect of all treatment in that specific infections indication is stated. When comparing the
comparing the outcome of treatment of sepsis and urinary tract infections it was more likely to have 
outcomea positive effect when treating sepsis, OR 5.0; 95% CI 0.96–25.9 (p = 0.05). 
of treatment of sepsis and urinary tract infections it was more likely to have a positive effect
when treating sepsis, OR 5.0; 95% CI 0.96–25.9 (p = 0.05).
2.4. Ethic Statement 
2.4. Ethic Statement
The  original  studies  were  approved  by  the  local  Ethical  Committee  at  Karolinska  Institutet, 
Stockholm, Sweden (Dnr: 2014/455‐31/4 and 2015/776‐31) and was performed in accordance with the 
Thedeclaration of Helsinki. Written informed consent was obtained from all patients before inclusion in 
original studies were approved by the local Ethical Committee at Karolinska Institutet,
Stockholm, Sweden (Dnr: 2014/455-31/4 and 2015/776-31) and was performed in accordance with the
the original study which enabled us to follow the outcome of the patients, as registered in the medical 
records regarding infections, pain and quality of life. 
declaration of Helsinki. Written informed consent was obtained from all patients before inclusion in
the original study which enabled us to follow the outcome of the patients, as registered in the medical
3. Results 
records regarding infections, pain and quality of life.
3.1. Demography, Antibiotics and Infections 
3. Results
The demography of all patients is shown in Table 1. Of the 160 patients in this cohort, 79 (48%) 
had  been  treated 
3.1. Demography, with and
Antibiotics any Infections
antibiotic  during  the  last  week  in  life.  The  mean  CRP‐values  were 
significantly higher in antibiotic treated patients than in non‐treated patients (p < 0.001). There were 
Theno significant differences in albumin levels, age or gender distribution between the two groups (Table 
demography of all patients is shown in Table 1. Of the 160 patients in this cohort, 79 (48%) had
been treated with any antibiotic during the last week in life. The mean CRP-values were significantly
higher in antibiotic treated patients than in non-treated patients (p < 0.001). There were no significant
differences in albumin levels, age or gender distribution between the two groups (Table 1). Of the
Cancers 2016, 8, 84 4 of 10

79 patients who were treated, evident symptom relief was achieved in 37% (n = 29). Notably, only 4%
(n = 3) of the patients experienced any adverse event (diarrhea in two cases, nausea in one case)
(Table 1). Among the patients with a positive effect of the treatment, only 50% had a positive culture,
43% had a negative culture and in 7% no culture had been taken (Figure 2). Among the patients
Cancers 2016, 8, 84  4 of 10  with
no or unknown effect of antibiotics, 50% had a positive culture, 30% had a negative culture and in
1). Of the 79 patients who were treated, evident symptom relief was achieved in 37% (n = 29). Notably, 
20% no only 4% (n = 3) of the patients experienced any adverse event (diarrhea in two cases, nausea in one 
culture had been taken (Figure 2). There was no statistically significant difference between the
distribution of positive and negative cultures between the groups.
case) (Table 1). Among the patients with a positive effect of the treatment, only 50% had a positive 
culture,  43%  had  a  negative  culture  and  in  7%  no  culture  had  been  taken  (Figure  2).  Among  the 
Table 1. Demographic data of the study cohort of 160 end-of-life cancer patients. Effect of antibiotic
patients with no or unknown effect of antibiotics, 50% had a positive culture, 30% had a negative 
treatment; positive
culture  and  effect
in  20%  no (Pos effect)
culture  had orbeen 
unknown/no effect2). 
taken  (Figure  (No effect);
There  was isno 
presented. Reference
statistically  range
significant 
according to Clinical Chemistry Dept. of Karolinska University Hospital: CRP <3 mg/L, Vit. D
difference between the distribution of positive and negative cultures between the groups. 
75–250 nmol/L, Albumin 36–48 nmol/L. * CRP-levels among the antibiotic treated patients were
Table 1. Demographic data of the study cohort of 160 end‐of‐life cancer patients. Effect of antibiotic 
significantly higher than for non-treated patients, p < 0.05. There were no other statistical significant
treatment; positive effect (Pos effect) or unknown/no effect (No effect); is presented. Reference range 
differences between the groups. NA = not applicable.
according to Clinical Chemistry Dept. of Karolinska University Hospital: CRP <3 mg/L, Vit. D 75–250 
nmol/L, Albumin 36–48 nmol/L. * CRP‐levels among the antibiotic treated patients were significantly 
Age CRP mg/L Vit. D nmol/L Albumin g/L Adverse Culture Pos
higher than for non‐treated patients, p < 0.05. There were no other statistical significant differences 
Men %
Median Median Median Median Event % Taken % Culture
(n)
between the groups. NA = not applicable. 
(Range) (Range) (Range) (Range) (n) (n) % (n)
All Age CRP mg/L Vit. D nmol/L Albumin Adverse  Culture  Pos
71 (18–95) 43% (69)Men %  61 (1–597) 36 (8–133) 24 (11–39) NA NA NA
(n = 160)   Median  Median  Median  g/L Median  Event %  Taken %  Culture 
(n) 
No Antibiotics (Range)  (Range)  (Range)  (Range)  (n)  (n)  % (n) 
72 (32–95) 42% (34) 44 * (1–283) 39 (8–133) 25 (16–39) NA NA NA
(n = 81)All (n = 160)  71 (18–95)  43% (69)  61 (1–597)  36 (8–133)  24 (11–39)  NA  NA  NA 
Antibiotics
No Antibiotics   
68 (18–90) 44% (35)
72 (32–95)  124 * (1–597)
42% (34)  44 * (1–283)  33 (8–120)
39 (8–133)  22 (11–37)
25 (16–39)  3.8% (3) NA 85% (67)NA  52% (41)
NA 
(n = 79) (n = 81) 
Pos effectAntibiotics   
69 (36–90) 34% (10)
68 (18–90)  44% (35) 76 (7–319)
124 * (1–597) 37 (10–112)
33 (8–120)  22 (14–31) 3.8% (3) 
22 (11–37)  3.4% (1)85% (67) 
93% (27) 52% (15)
52% (41) 
(n = 29) (n = 79) 
No effect
Pos effect (n = 29)  69 (36–90)  34% (10)  76 (7–319)  37 (10–112)  22 (14–31)  3.4% (1)  93% (27)  52% (15) 
68 (18–86) 50% (25) 141 (1–597) 32 (8–120) 22 (11–37) 4% (2) 80% (40) 52% (26)
(n = 50)
No effect (n = 50)  68 (18–86)  50% (25)  141 (1–597)  32 (8–120)  22 (11–37)  4% (2)  80% (40)  52% (26) 

 
Figure 2. Distribution of number of positive and negative cultures among end‐of‐life cancer patients 
Figure 2. Distribution of number of positive and negative cultures among end-of-life cancer patients
in  patients  who  had  positive  (Pos  effect)  or  unknown/no  effect  (No  effect)  of  antibiotic  treatment. 
in patients
There who
was had positive (Pos
no  statistically  effect)
significant  or unknown/no
difference  between  the effect (No effect)
distribution  of antibiotic
of  positive  treatment.
and  negative 
There was no statistically significant
cultures between the groups (Chi 2 difference between the distribution of positive and negative
‐test, p = 0.22). 
cultures between the groups (Chi2 -test, p = 0.22).
When  “prevention  or  treatment  of  sepsis”  was  the  indication  for  antibiotic  treatment,  a 
statistically significant association with symptom relief was observed in 50% of the patients (n = 19). 
When “prevention or treatment of sepsis” was the indication for antibiotic treatment, a statistically
In  contrast,  when  a  urinary  tract  infection  was  suspected  and  used  as  an  indication  for  antibiotic 
significant association with symptom relief was observed in 50% of the patients (n = 19). In contrast,
treatment only 17% (n = 2) experienced symptom relief (Fishers exact test showed OR 5.0; 95% CI 
when a 0.96–25.9; p = 0.05) (Figure 1). 
urinary tract infection was suspected and used as an indication for antibiotic treatment only
experienced symptom relief (Fishers exact test showed OR 5.0; 95% CI 0.96–25.9; p = 0.05)
17% (n = 2) The most common antibiotic used was ceftriaxone (27%), followed by piperacillin/tazobactam 
(Figure (20%) 
1). and  cefotaxime  (13%).  The  majority  had  a  parental  route  of  administration  (77%)  and  the 
remainder had oral antibiotics (23%). 
The most common antibiotic used was ceftriaxone (27%), followed by piperacillin/tazobactam
Bacterial cultures were taken in 67 patients and the different pathogens found in the 41 patients 
(20%) and cefotaxime (13%). The majority had a parental route of administration (77%) and the
with positive bacterial cultures are presented in Table 2. Staphylococcus aureus was the most common 
remainder had oral antibiotics (23%).
pathogen found. Two of the bacterial cultures revealed E. coli expressing extended spectrum beta‐
Bacterial cultures were taken in 67 patients and the different pathogens found in the 41 patients
lactamase (ESBL). There was no positive culture for methicillin resistant S. aureus (MRSA). 
with positive bacterial cultures are presented in Table 2. Staphylococcus aureus was the most common
 
pathogen found. Two of the bacterial cultures revealed E. coli expressing extended spectrum
beta-lactamase (ESBL). There was no positive culture for methicillin resistant S. aureus (MRSA).
Cancers 2016, 8, 84 5 of 10

Table 2. Pathogens in the positive cultures (n = 41 patients).

Cultures Pos Effect, n = 15 (15 Cultures) No Effect, n = 26 (32 Cultures)

7 8
S. epidermidis 3 S. epidermidis 4
Enterococcus species 1 Enterococcus species 1
Blood
Corynebacterium species 1 Enterobacter species 1
Klebsiella species 1 S. aureus 1
S. marscecens 1 Klebsiella species 1
14
E. coli 7
4 Klebsiella species 1
Urine E. coli 2 S. aureus 1
Klebsiella species 2 Enterococcus species 3
Enterobacter species 1
Legionella species 1
5
Skin 0 S. aureus 4
E. faecialis 1
1 3
Sputum
Bacillus species 1 S. aureus 3
1
Feces 0
C. difficile 1
2
Nasopharynx 0 M. catharralis 1
S. aureus 1
1
Synovial fluid 0
S. aureus 1
1
Pleura fluid 0
S. epidermidis 1

3.2. Type of Cancer

To study if the use or response to antibiotics varied between different cancer types we grouped
the patients into 14 different cancer types presented in Table 3.

Table 3. Type of cancer in the whole cohort and among those with antibiotic treatment. In column 3 and
4 patients with positive effect (Pos effect) or unknown/no effect (No effect) of the antibiotic treatment is
presented and percentage intends of those with that specific cancer form receiving antibiotics (column 2).
NA = not applicable.

Type of Cancer All (n = 160) Antibiotics (n = 79) Pos Effect (n = 29) No Effect (n = 50)
1
Brain tumor 4 1 0
100%
3 7
Breast cancer 19 10
30% 70%
4 5
Gynecological 16 9
44% 56%
5 8
GI-cancer 29 13
38% 62%
2 1
Gallbladder 6 3
67% 33%
2 2
Head-Neck cancer 8 4
50% 50%
2 1
Hematologic mal. 8 3
67% 33%
Cancers 2016, 8, 84 6 of 10

Table 3. Cont.

Type of Cancer All (n = 160) Antibiotics (n = 79) Pos Effect (n = 29) No Effect (n = 50)
1 1
Kidney 3 2
50% 50%
6 13
Lung cancer 32 19
32% 68%
Malignant Melanoma 3 0 NA NA
1
Mesotelioma 2 1 0
100%
2 4
Pancreas 14 6
33% 67%
1 7
Prostate cancer 13 8
12% 88%
Other 3 0 NA NA

The most common cancer was lung cancer, followed by gastrointestinal cancer and breast cancer.
There was no statistically significant difference between the different cancer forms regarding treatment
with antibiotics or whether the antibiotic use had any beneficial effect on symptoms or not (Chi2 test,
p = 0.99 and p = 0.73). The lowest effect of antibiotics was found in prostate cancer where only 12%
had a positive effect of the treatment. However, when comparing these patients with the rest of the
cohort no statistically significant difference was observed (Fishers exact test, p = 0.25).

3.3. Vitamin D and Effect of Antibiotics

Vitamin D status is important for host immunity against various infections [16–18] and has
also been suggested to play a role in the quality of life of palliative cancer patients [15,19].
Thus, we evaluated whether the vitamin D status of the patients was related to antibiotic-use or
with response to treatment. Representative vitamin D levels were available for 123 patients, i.e., levels
measured less than 60 days before death (Table 1). There was no association found between vitamin D
levels and antibiotic use (p = 0.20) or with response to treatment (p = 0.32). In the cohort there were only
17 patients with “sufficient” vitamin D levels, defined as 25-hydroxyvitamin D levels > 75 nmol/L.
Of these 17 patients six received antibiotics (35%) compared to 55% for those with lower vitamin
D-levels (p = 0.19). Among the six patients with sufficient vitamin D levels, four responded (67%) to
antibiotics and two (33%) did not respond, compared to 33% responders and 67% non-responders
among those with insufficient levels. However, this difference did not reach statistical significance,
as Fischer’s exact test showed p = 0.17.

4. Discussion
Here we show that antibiotic treatment resulted in improved symptoms in 37% of the patients
in this cohort of palliative cancer patients. Interestingly, also in cases with negative cultures the
administration of antibiotics appeared to have beneficial effects and, importantly, the prevalence of
adverse events was not common (<4%).
The clinical evidence for using or not using antibiotics in the end-of-life period is scarce, and there
are no written guidelines [20]. Results from previous studies are divergent. Our findings are in line
with the study by Vitetta et al. (n = 102), where it was shown that 40% of terminally ill patients
achieved symptom control after antibiotic treatment [6]. Furthermore, a nationwide survey evaluated
282 patients treated with antibiotics in both hospice and outpatient settings and 56% of the patients
were evaluated as having “good” or “very good” clinical effect of antibiotics [5]. In a university hospital
with a mean duration of 31 days between admission and death, a total of 84% of patients were treated
with antibiotics during admission, and 63% at time of death. Symptomatic improvement was achieved
in only 15% of the patients, but 48% of the patients with fever experienced an improvement [4].
Another single-centre retrospective study from an inpatient hospice ward registered antibiotic use in
Cancers 2016, 8, 84 7 of 10

85% of febrile episodes in a population with a median survival of 15 days after initiation of antibiotic
treatment. Resolution of fever was achieved in 54% of patients in the treatment group and in 2% of
patients not treated with antibiotics (p = 0.004) [3].
In contrast to our results a study including 255 patients showed that the use of antibiotics was
associated with symptom relief for urinary tract infections, but it was less effective for other infections
including bacteremia and sepsis [21]. However, symptom relief from urinary tract infections might be
underestimated in our cohort since this is more seldom documented in the records than relief from
septic symptoms.
Also in non-cancer patients there is controversy regarding the effect of antibiotic treatment in the
last days and weeks of life, since data from different epidemiological studies vary. One study including
559 palliative non-cancer patients with pneumonia revealed that antibiotic treatment decreased
discomfort even when death was imminent [22]. In contrast, another study (n = 225) showed that
antibiotic treatment did not improve symptoms in terminally ill patients with pneumonia although
the survival time was increased [23]. It is noteworthy that serious infections may produce sedation
leading to a peaceful death, whereas the administration of antibiotics can prolong the process of dying
and thereby paradoxically increase the experience of suffering [24].
The conflicting results from previous epidemiological studies might reflect how difficult it is to
assess if a patient is dying or suffering from a temporary deterioration due to an infection. In addition
to that, the immune system in terminally ill patients is probably impaired and the effectiveness of
antibiotics might be reduced. For example, it has been shown that there is a dysregulation of innate
immune responses in the aging body leading to more inflammatory response, sometimes called
“inflammaging” [25]. Notably, CRP increases in the end-of-life in cancer patients also in the absence of
infections. Indeed, elevated CRP has been shown to be a good prognostic marker for estimation of
the time of death [15,26]. However, this increase in CRP is often misinterpreted as an infection and
treatment is initiated—although bacterial cultures later are found to be negative and the patient dies.
Our study reports a large proportion of intravenously administered antibiotics (77%), reflecting
current practice at our site, where a majority of patients have an intravenous line (picc-line or
subcutaneous venous access device). The practice of using intravenously administered drugs in
the end-of-life patients might vary largely between different countries but is common in palliative
wards in Sweden.
S. aureus and E. coli were the two most common pathogens in our patient cohort, well in line with
previous studies [4,5,21,27]. Treatment against S. aureus was only associated with symptom relief when
the bacterium was found in synovial fluid (one patient), suggesting that S. aureus often is a colonizer
and not always causes a clinically relevant infection. Likewise, antibiotic treatment of bacteria found
in various wound cultures was not associated with improvement of symptoms in this patient-group.
However, skin cultures are not specific for active infection. In addition, it should be noted that positive
a urine culture does not necessary indicate urinary tract infection, since asymptomatic bacteriuria is
common among frail patients.
Notably, there was a high frequency of S. epidermidis in blood cultures (7/15), raising suspicion
of contamination, but it might also reflect the high prevalence of invasive devices in the patients in
this particular cohort. Multidrug-resistant organisms (MDROs) were found in 2/41 cultures (ESBL).
This correlates well with the comparatively low frequency of MDROs in the Swedish population
(http://ecdc.europa.eu/en/healthtopics/antimicrobial_resistance/database) and differs from results
from other cohorts where MDROs were found in 1 /4 of cultures in patients who died during hospital
admission [1].
In our study 48% of terminally ill cancer patients were treated with antibiotics in the last week of
life, placing our single center experience near the middle of the range (4%–84%) of the prevalence of
antimicrobial treatment as shown in a systematic review including studies from different countries [10].
Differences in patients’, families’ and health care professionals’ attitudes [11–13] as well as differences
in the organization and financing of health care systems might explain the diverging results regarding
Cancers 2016, 8, 84 8 of 10

the frequency of antibiotics treatment near the end of life. Comparing US and Asian experiences
demonstrate large differences in current practice. A nationwide US survey showed that 14% of patients
admitted to hospice with cancer as primary diagnosis were treated with antibiotics in the last week
of life [28]. In two different US cohorts from academic hospitals, cancer patients who transitioned to
comfort focused care remained on antimicrobial treatment in 20% and 35% of cases [8,9]. In contrast,
a small study from a Chinese palliative care unit showed that 18/21 patients with hematological
malignancies received i.v. antibiotics during the last week of life [7]. In a Korean cohort of deceased
patients (75.6% with solid tumors) who had been treated in general medicine wards in acute care
hospitals, 87.5% had received antibiotic treatment lasting more than 24 h [1].
There a several limitations of this study. Most importantly, this is a retrospective study where our
assessment of the potential response to antibiotics is based solely on the medical- and nursing records.
Thus, cases with symptom relief may be underestimated since this is not always mentioned in the
records. This might explain the divergence between the positive effects for septic symptoms in contrast
to urinary tract infections. It should also be mentioned that the true source of infection is often hard to
determine. For example, a positive urine or sputum culture does not necessarily indicate urinary tract
infection or pneumonia, respectively. Thus, data on the source of infections must be interpreted with
caution. Another limitation is the relatively small sample size. Especially, the few cases for each cancer
type make this subgroup analysis less reliable. On the other hand, studies on the effect of antibiotics in
the end-of-life cancer patients are scarce and this study supports the hypothesis that antibiotics seldom
do any harm in these patients. This is also the first study where the response to antibiotics in the dying
patient is correlated with vitamin D status of the patients. Our findings show that there is no clear
association between vitamin D status and antibiotic response in the dying patient, although there was
a trend towards a better outcome for patients with sufficient vitamin D levels (p = 0.17).

5. Conclusions
In conclusion, treating infections in the last weeks of life may contribute to improving the quality
of life for palliative cancer-patients, especially if sepsis is suspected or confirmed. According to our
results, beneficial effects are generally more common than harmful effects. However, the efficacy of
antibiotics might not be optimal in the dying patient. The decision to treat or not to treat suspected
infection in the terminally ill patient is complex and requires an individual approach and ethical
considerations. If possible the decision should preferably be taken together with the patient and the
relatives, which is a recommendation that aligns with recent publications in the field [14].

Acknowledgments: We are most grateful to all patients that have participated in the studies. The authors have
no conflict of interest to declare. Financial support was provided through the Regional agreement on training and
clinical research (ALF) between Karolinska Institutet and Stockholm County Council, The Swedish Cancer Society,
Magnus Bergwall Foundation, Karolinska Institutet and the Swedish Research Council.
Author Contributions: M.H.-F., J.B., P.B. and L.B.-B. designed the study. M.H.-F. and L.B.-B. collected and
analyzed the data. M.H.-F. and L.B.-B. wrote the first-draft of the manuscript. M.H.-F., J.B., P.B. and L.B.-B.
contributed to the writing and finalized the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.

References
1. Kwak, Y.G.; Moon, C.; Kim, E.S.; Kim, B.N. Frequent Prescription of Antibiotics and High Burden of
Antibiotic Resistance among Deceased Patients in General Medical Wards of Acute Care Hospitals in Korea.
PLoS ONE 2016, 11, e0146852. [CrossRef] [PubMed]
2. Abdel-Karim, I.A.; Sammel, R.B.; Prange, M.A. Causes of death at autopsy in an inpatient hospice program.
J. Palliat. Med. 2007, 10, 894–898. [CrossRef] [PubMed]
3. Chen, L.K.; Chou, Y.C.; Hsu, P.S.; Tsai, S.T.; Hwang, S.J.; Wu, B.Y.; Lin, M.H.; Chen, T.W. Antibiotic
prescription for fever episodes in hospice patients. Support. Care Cancer 2002, 10, 538–541. [CrossRef]
[PubMed]
Cancers 2016, 8, 84 9 of 10

4. Oh, D.Y.; Kim, J.H.; Kim, D.W.; Im, S.A.; Kim, T.Y.; Heo, D.S.; Bang, Y.J.; Kim, N.K. Antibiotic use during the
last days of life in cancer patients. Eur. J. Cancer Care 2006, 15, 74–79. [CrossRef] [PubMed]
5. Stiel, S.; Krumm, N.; Pestinger, M.; Lindena, G.; Nauck, F.; Ostgathe, C.; Radbruch, L.; Elsner, F. Antibiotics
in palliative medicine—Results from a prospective epidemiological investigation from the HOPE survey.
Support. Care Cancer 2012, 20, 325–333. [CrossRef] [PubMed]
6. Vitetta, L.; Kenner, D.; Sali, A. Bacterial infections in terminally ill hospice patients. J. Pain Symptom Manag.
2000, 20, 326–334. [CrossRef]
7. Cheng, B.H.; Sham, M.M.; Chan, K.Y.; Li, C.W.; Au, H.Y. Intensive palliative care for patients with
hematological cancer dying in hospice: Analysis of the level of medical care in the final week of life.
Am. J. Hosp. Palliat. Care 2015, 32, 221–225. [CrossRef] [PubMed]
8. Merel, S.E.; Meier, C.A.; McKinney, C.M.; Pottinger, P.S. Antimicrobial Use in Patients on a Comfort Care
Protocol: A Retrospective Cohort Study. J. Palliat. Med. 2016. [CrossRef] [PubMed]
9. Thompson, A.J.; Silveira, M.J.; Vitale, C.A.; Malani, P.N. Antimicrobial use at the end of life among
hospitalized patients with advanced cancer. Am. J. Hosp. Palliat. Care. 2012, 29, 599–603. [CrossRef]
[PubMed]
10. Rosenberg, J.H.; Albrecht, J.S.; Fromme, E.K.; Noble, B.N.; McGregor, J.C.; Comer, A.C.; Furuno, J.P.
Antimicrobial use for symptom management in patients receiving hospice and palliative care: A systematic
review. J. Palliat. Med. 2013, 16, 1568–1574. [CrossRef] [PubMed]
11. Chiu, T.Y.; Hu, W.Y.; Huang, H.L.; Yao, C.A.; Chen, C.Y. Prevailing ethical dilemmas in terminal care for
patients with cancer in Taiwan. J. Clin. Oncol. 2009, 27, 3964–3968. [CrossRef] [PubMed]
12. Ford, P.J.; Fraser, T.G.; Davis, M.P.; Kodish, E. Anti-infective therapy at the end of life: Ethical decision-making
in hospice-eligible patients. Bioethics 2005, 19, 379–392. [CrossRef] [PubMed]
13. Marcus, E.L.; Clarfield, A.M.; Moses, A.E. Ethical issues relating to the use of antimicrobial therapy in older
adults. Clin Infect. Dis. 2001, 33, 1697–1705. [CrossRef] [PubMed]
14. Furuno, J.P.; Noble, B.N.; Fromme, E.K. Should we refrain from antibiotic use in hospice patients? Expert Rev.
Anti. Infect. Ther. 2016, 14, 277–280. [CrossRef] [PubMed]
15. Bergman, P.; Sperneder, S.; Höijer, J.; Bergqvist, J.; Björkhem-Bergman, L. Low vitamin D levels are associated
with higher opioid dose in palliative cancer patients—Results from an observational study in sweden.
PLoS ONE 2015, 10, e0128223. [CrossRef] [PubMed]
16. Bergman, P.; Norlin, A.C.; Hansen, S.; Björkhem-Bergman, L. Vitamin D supplementation to patients with
frequent respiratory tract infections: A post hoc analysis of a randomized and placebo-controlled trial.
BMC Res. Notes 2015, 8, 391. [CrossRef] [PubMed]
17. Hewison, M. Antibacterial effects of vitamin D. Nat. Rev. Endocrinol. 2011, 7, 337–345. [CrossRef] [PubMed]
18. Hewison, M. Vitamin D and immune function: An overview. Proc. Nutr. Soc. 2012, 71, 50–61. [CrossRef]
[PubMed]
19. Björkhem-Bergman, L.; Bergman, P. Vitamin D and patients with palliative cancer. BMJ Support. Palliat. Care
2016, 6, 287–291. [CrossRef] [PubMed]
20. Juthani-Mehta, M.; Malani, P.N.; Mitchell, S.L. Antimicrobials at the End of Life: An Opportunity to Improve
Palliative Care and Infection Management. JAMA 2015, 314, 2017–2018. [CrossRef] [PubMed]
21. White, P.H.; Kuhlenschmidt, H.L.; Vancura, B.G.; Navari, R.M. Antimicrobial use in patients with advanced
cancer receiving hospice care. J. Pain Symptom Manag. 2003, 25, 438–443. [CrossRef]
22. Van Der Steen, J.T.; Pasman, H.R.; Ribbe, M.W.; van der Wal, G.; Onwuteaka-Philipsen, B.D. Discomfort in
dementia patients dying from pneumonia and its relief by antibiotics. Scand. J. Infect. Dis. 2009, 41, 143–151.
[CrossRef] [PubMed]
23. Givens, J.L.; Jones, R.N.; Shaffer, M.L.; Kiely, D.K.; Mitchell, S.L. Survival and comfort after treatment of
pneumonia in advanced dementia. Arch. Intern. Med. 2010, 170, 1102–1107. [CrossRef] [PubMed]
24. Ahronheim, J.C.; Morrison, R.S.; Baskin, S.A.; Morris, J.; Meier, D.E. Treatment of the dying in the acute care
hospital. Advanced dementia and metastatic cancer. Arch. Intern. Med. 1996, 156, 2094–2100. [CrossRef]
[PubMed]
25. Kollmann, T.R.; Levy, O.; Montgomery, R.R.; Goriely, S. Innate immune function by Toll-like receptors:
Distinct responses in newborns and the elderly. Immunity 2012, 37, 771–783. [CrossRef] [PubMed]
Cancers 2016, 8, 84 10 of 10

26. Beleigoli, A.M.; Boersma, E.; Diniz Mde, F.; Vidigal, P.G.; Lima-Costa, M.F.; Ribeiro, A.L. C-reactive protein
and B-type natriuretic peptide yield either a non-significant or a modest incremental value to traditional
risk factors in predicting long-term overall mortality in older adults. PLoS ONE 2013, 8, e75809. [CrossRef]
[PubMed]
27. Albrecht, J.S.; McGregor, J.C.; Fromme, E.K.; Bearden, D.T.; Furuno, J.P. A nationwide analysis of antibiotic
use in hospice care in the final week of life. J. Pain Symptom Manag. 2013, 46, 483–490. [CrossRef] [PubMed]
28. Dwyer, L.L.; Lau, D.T.; Shega, J.W. Medications that Older Adults in Hospice Care in the United States Take,
2007. J. Am. Geriatr. Soc. 2015, 63, 2282–2289. [CrossRef] [PubMed]

© 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC-BY) license (http://creativecommons.org/licenses/by/4.0/).