European Journal of Clinical Microbiology & Infectious Diseases (2022) 41:29–36

https://doi.org/10.1007/s10096-021-04325-z

ORIGINAL ARTICLE

Antibiotic stewardship program (ASP) in palliative care: antibiotics,

to give or not to give
Kai Chee Hung1 · Lai Wei Lee1 · Yi Xin Liew1 · Lalit Krishna2 · Maciej Piotr Chlebicki3 · Shimin Jasmine Chung3 ·
Andrea Lay‑Hoon Kwa1,4,5

Received: 9 March 2021 / Accepted: 26 July 2021 / Published online: 20 August 2021
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021

Abstract
Antimicrobial therapy in terminally ill patients remains controversial as goals of care tend to be focused on optimizing
comfort. International guidelines recommend for antibiotic stewardship program (ASP) involvement in antibiotic deci-
sions in palliative patients. The primary objective was to evaluate the clinical impact of ASP interventions made to stop
broad-spectrum intravenous antibiotics in terminally ill patients. This was a retrospective chart review of 459 terminally ill
patients in Singapore General Hospital audited by ASP between December 2010 and December 2018. Antibiotic duration,
time-to-terminal discharge for end-of-life care, time-to-mortality, and mortality rates of patients with antibiotics ceased or
continued upon ASP recommendations were compared. A total of 283 and 176 antibiotic courses were ceased and contin-
ued post-intervention, respectively. The intervention acceptance rate was 61.7%. The 7-day mortality rate (47.3% vs 61.9%,
p = 0.003) was lower in the ceased group, while 30-day mortality rate (76.0% vs 81.2%, p = 0.203) and time-to-mortality post-
intervention (3 [0–24] vs 2 [0–27] days, p = 0.066) did not differ between the ceased and continued groups. After excluding
the 57 patients who had antibiotics continued until death within 48 h of intervention, only time-to-mortality post-intervention
was statistically significantly shorter in the ceased group (3 [0–24] vs 4 [0–27], p < 0.001). Of the 131 terminally discharged
patients, antibiotic duration (4 [0–17] vs 6.5 [1–14] days, p = 0.001) and time-to-terminal discharge post-intervention (6
[0–74] vs 10.5 [3–63] days, p = 0.001) were shorter in the ceased group. Antibiotic cessation in terminally ill patients was
safe, and was associated with a significantly shorter time-to-terminal discharge.

Keywords Antibiotic stewardship · Palliative care · Retrospective study

Introduction

Kai Chee Hung and Lai Wei Lee share co-authorship.
* Andrea Lay‑Hoon Kwa
andrea.kwa.l.h@sgh.com.sg
1
Department of Pharmacy, Singapore General Hospital,
Outram Road, Singapore 169608, Singapore
2
Division of Supportive and Palliative Care, National Cancer
Centre Singapore, 11 Hospital Drive, Singapore 169610,
Singapore
3
Department of Infectious Diseases, Singapore General
Hospital, Outram Road, Singapore 169608, Singapore
4
Emerging Infectious Diseases, Duke-National
University of Singapore Medical School, 8 College Rd,
Singapore 169857, Singapore
5
Singhealth Duke-NUS Medicine Academic Clinical
Programme, 8 College Road, Level 4, Singapore 169857,
Singapore
Up to 44.9% of hospitalized terminally ill patients in Singa-
pore receive antibiotics in the last 24 h of life [1], ostensi-
bly to prolong survival or relieve symptoms [2]. Typically,
patients at end-of-life have a prognosis of 6 months as a
result of a late-stage life-limiting illness [3]. Antibiotics use
in this group of patients is controversial as clinical benefits
have not been clearly established [4–6]. Growing calls to
respect patient choices at the end-of-life have placed these
complex ethical and care determinations firmly in the spot-
light [7, 8], particularly when these treatments often require
inpatient hospital care which have significant ramifications
upon end-of-life decisions and the preferred place of care
[9, 10].
In Singapore, 82% of patients have stated that their pre-
ferred place of death is at home rather than at an institution
[9]. In the home setting, intravenous antibiotic therapy is

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30 European Journal of Clinical Microbiology & Infectious Diseases (2022) 41:29–36
not possible as central venous access is required for outpa-
tient parenteral antimicrobial therapy. Insertion of a central
venous catheter would deviate from the intent of optimizing
comfort as the primary goal of palliative care. Therein lies
the conundrum. While the patient and family may desire to
go home for end-of-life care, or otherwise termed as termi-
nal discharge, they may have difficulty accepting the notion
of withdrawing treatment, resulting in an inertia to discon-
tinue intravenous antibiotics [11, 12]. This results in the pro-
longation of intravenous antibiotic therapy, which may go
against the patients’ wishes, hindering the transition home
for end-of-life care. Their length of hospitalization will be
unnecessarily prolonged, with increased healthcare costs,
potential discomfort from venipuncture, and significant side
effects from antibiotics such as Clostridium difficile diarrhea
[2, 13].
From a public health perspective, use of antibiotics
amongst terminally ill patients is increasingly seen as pos-
ing a risk to the development of resistant bacterial strains
[14, 15]. With an emerging aging population, the ecological
implications of antibiotics use in these patients will intensify
in the coming decades. Thus, it is imperative to use antibiot-
ics judiciously in the terminally ill patient as recommended
by international antibiotic stewardship guidelines [16]. Anti-
biotic stewardship has been shown to reduce resistance rates
in several studies [17], and has been envisaged to similarly
help curb growing antibiotic resistance in the terminally ill.
The antibiotic stewardship program (ASP) at Singapore
General Hospital (SGH) extends the audit of broad-spectrum
intravenous antibiotics to those who are terminally ill. In this
retrospective study, we aimed to evaluate the clinical impact
of ASP interventions placed to stop antibiotics in terminally
ill patients. The clinical impact that we assessed were the
mortality rates, time-to-mortality, and time-to-terminal dis-
charge of these patients. We hypothesized that the mortality
rates in the antibiotics ceased group (where interventions
were accepted) would be similar to the antibiotics continued
group (where interventions were rejected), and that patients
were able to be terminally discharged earlier in the ceased
group.
Methods
Study design
The study was conducted as a retrospective chart review of
patients audited by the ASP team at SGH, a 1700 bed public
tertiary care hospital, from December 2010 to December
2018.
The ASP team, consisting of clinical pharmacists and
infectious disease physicians, audits patients prescribed
with broad-spectrum intravenous antibiotics including
13
carbapenems (meropenem, doripenem, imipenem, ertap-
enem), piperacillin-tazobactam, and fluoroquinolones (cip-
rofloxacin, levofloxacin). These newly initiated antibiotics
were audited within the next working day. Trained ASP clin-
ical pharmacists performed the primary review and screened
cases for antibiotic appropriateness in terms of choice, dura-
tion, dose, and route, with consideration of extent of care in
terminally ill patients. Cases flagged for potential interven-
tions were discussed at a second review with the ASP infec-
tious disease physician before therapeutic recommendations
were made to the primary team. The final decision to accept
or reject these recommendations was left to the discretion of
the primary team. The ASP team was not directly involved
in the patient care and served as an independent assessor of
antibiotic appropriateness.
Patients were included in this study if an ASP interven-
tion was issued to the primary care team for antibiotic dis-
continuation, where the patient was deemed to be terminally
ill. Terminally ill patients were identified by decisions made
by the primary team in this current admission to be,
• at end-of-life,
• for optimal comfort palliative measures,
• not for further blood takings or reinsertion of intravenous
cannulas, and
• not for resuscitation and escalation of therapy such as
mechanical ventilation or inotropic support.
These patients tend to have end-stage metastatic cancers
or are elderly with multiple comorbidities. The standard
intervention note would indicate that the patient was for
comfort measures, and if the primary team does not consider
that antibiotics will help improve symptoms of the patient,
antibiotics discontinuation is recommended. A recommen-
dation was accepted if antibiotics were ceased within 48 h
of the ASP recommendation, and the patient was still alive.
Rejection was defined as continuation of antibiotics beyond
48 h after receiving the ASP recommendation, or if anti-
biotics were ceased due to patient’s death within 48 h of
receiving the ASP recommendation. If interventions were
rejected, the reason for rejection would be determined by
the ASP pharmacist via clinical note review or by com-
munication with the primary team. The following potential
reasons for rejection were available for selection; “physi-
cian’s personal preference,” “patient’s death within 48 h,”
“clinical improvement,” “sudden clinical deterioration,” or
“others (including family’s decision).” The ASP workflow
schematic is included in Fig. 1. There was no significant
change in ASP workflow during this study period of 8 years.
Only index hospitalization cases were included, and in the
event where multiple interventions were made to discontinue
antibiotics during the hospitalization, only the first interven-
tion would be included. A post hoc subgroup analysis was
European Journal of Clinical Microbiology & Infectious Diseases (2022) 41:29–36
Fig. 1  ASP workflow
performed after excluding patients whose antibiotics were
continued until death within 48 h of intervention, as the pri-
mary team may not have sufficient opportunity to respond
to the intervention.
Data collection
Patient demographics such as age, gender, previous hospi-
talization stay, previous antibiotic use, and department were
collected and compared. Primary clinical outcomes of 7-day
and 30-day mortality rates, as well as secondary clinical
outcomes of antibiotic duration, 30-day mortality cause,
time-to-mortality, and time-to-terminal discharge were col-
lected. Nurses made a post-discharge call within a month to
follow up on the patient’s progress, and document mortality
in the event that it occurs. All data were extracted from the
ASP database.
Definitions
The 7-day and 30-day mortalities were defined as death of
patient within 7 or 30 days, respectively, after the start of ASP
audit, regardless if the patient remained hospitalized. Termi-
nal discharge refers to discharge for end-of-life care. Time-to-
terminal discharge was defined as duration of stay in patients
who were alive on discharge, from the date of intervention.
Time-to-mortality was measured from the date of interven-
tion to death, for patients who died within 30 days post-audit.
Of the rejection reasons, “physician’s personal preference”
31
referred to a decision solely made by the primary physician’s
clinical judgment that was otherwise not explainable by a sud-
den deterioration or an improvement in patient’s status while
on antibiotics.
Ethics
Approval from the SingHealth Centralised Institutional
Review Board (CIRB) was obtained for this study (CIRB
Ref: 2010/114/E). Informed consent was not required as only
anonymized data were analyzed.
Statistical analysis
Continuous variables were expressed as medians with ranges,
and analyzed using non-parametric statistics with Mann–Whit-
ney U test. For categorical discrete variables, they were
expressed as proportions and analyzed using χ2 test or Fis-
cher’s exact test, where appropriate. All tests for significance
were 2-tailed, with p < 0.05 considered significant. All statis-
tical analyses were performed using IBM SPSS version 20.
Results
Patient demographics
A total of 459 patients were included in the study. There
were no statistical differences in age, gender, previous
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32 European Journal of Clinical Microbiology & Infectious Diseases (2022) 41:29–36

hospitalization, previous antibiotic use, type of antibiotic
used, department, or infection site between the ceased group
and the continued group. The median age of patients was
73 years in the antibiotic ceased group and 76 years in the
continued group. The most common site of infection was the
lower respiratory tract, amounting to 39.9% in the ceased
group and 52.3% in the continued group. The most common
antibiotic use was piperacillin-tazobactam, with 67.5% in the
ceased group and 63.6% in the continued group, followed by
meropenem, with 28.3% in the ceased group and 31.8% in
the continued group. The internal medical department was
the most common admitting department, with 48.4% in the
ceased group and 58.5% in the continued group, followed by
hematology/oncology, with 39.6% in the ceased group and
32.4% in the continued group. (Table 1).
Interventions and rejection reasons
There were 459 interventions made to discontinue antibi-
otics for palliative reasons over a period of 8 years. The
overall acceptance rate by physicians was 61.7%. A total of
283 courses of antibiotics were ceased and 176 courses of
antibiotics were continued. The most common reason for
rejection was due to physician’s personal preference (45.5%),

Table 1  Patient demographics Antibiotics ceased Antibiotics contin- p ­valuea

and mortality outcomes (n = 283) ued (n = 176)

Demographics
Age—years, median (min–max) 73 (23–100) 76 (28–102) 0.070
Male gender 137 (48.4%) 90 (51.1%) 0.631
Previous hospitalization in last 90 days 197 (69.6%) 114 (64.8%) 0.305
Previous antibiotic use in last 90 days 209 (73.9%) 137 (77.8%) 0.373
Antibiotic ­auditeda
Piperacillin-tazobactam 191 (67.5%) 112 (63.6%) 0.053
Meropenem 80 (28.3%) 56 (31.8%)
Ertapenem 8 (2.8%) 1 (0.6%)
Ciprofloxacin 3 (1.1%) 3 (1.7%)
Imipenem 1 (0.4%) 0
Levofloxacin 0 4 (2.3%)
Department
Medical 137 (48.4%) 103 (58.5%) 0.106
Hematology/oncology 112 (39.6%) 57 (32.4%)
Surgical 34 (12.0%) 16 (9.1%)
Type of ­infectionb
Lower respiratory tract 113 (39.9%) 92 (52.3%) 0.187
Unspecified sepsis 70 (24.7%) 32 (18.2%)
Gastrointestinal 40 (14.1%) 17 (9.7%)
Multiple infections 18 (6.4%) 15 (8.5%)
Skin and soft tissue 16 (5.7%) 7 (4.0%)
Urinary tract 13 (4.6%) 6 (3.4%)
Bloodstream 6 (2.1%) 6 (3.4%)
Febrile neutropenia 4 (1.4%) 1 (0.6%)
Central nervous system 2 (0.7%) 0
Ear, nose, throat, or mouth 1 (0.4%) 0
Mortality outcomes
Overall 7-day mortality rate 134 (47.3%) 109 (61.9%) 0.003
Overall 30-day mortality rate 215 (76.0%) 143 (81.2%) 0.203
30-day mortality due to ­infectionc 53 (24.7%) 55 (38.5%) 0.007
Time-to-mortality—days, median (min–max)c 3 (0–24) 2 (0–27) 0.066
a
Bolded values are statistically significant
b
Figures do not total to 100% due to rounding
c
Thirty-day mortality cause and time-to-mortality were calculated for 358 patients who died within 30 days
of audit, with 215 in the ceased group and 143 in the continued group

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European Journal of Clinical Microbiology & Infectious Diseases (2022) 41:29–36 33

Table 2  Intervention rejection reasons
Intervention
Physician’s personal preference
Patient’s death within 48 h
Clinical improvement
Sudden clinical deterioration
Others (including family’s decision)
a
Figures do not total to 100% due to rounding
followed by patient’s death (32.4%). The remaining rejection
reasons consisted of clinical improvement (9.1%), sudden
clinical deterioration (9.1%), and others which included fam-
ily’s decision (4.0%) (Table 2).
who died within 30 days of audit, mortality due to infection
Frequency a (24.7% vs 33.7%, p = 0.110) was non-significantly differ-
ent, while time-to-mortality was significantly shorter in the
80/176 (45.5%) ceased group (3 [0–24] vs 4 [0–27], p < 0.001) (Table 3).
57/176 (32.4%)
16/176 (9.1%) Duration of antibiotic therapy and time‑to‑terminal
16/176 (9.1%) discharge in terminally discharged patients
7/176 (4.0%)
A total of 131 patients were terminally discharged. Duration
of antibiotic therapy in the ceased group was statistically
significantly shorter by approximately 2.5 days (4 [0–17]
vs 6.5 [1–14] days, p = 0.001). Time-to-terminal discharge
post-intervention was also significantly shorter in the ceased
group by 4.5 days (6 [0–74] vs 10.5 [3–63] days, p = 0.001)
as compared to the continued group. (Table 4).

Mortality rates and time‑to‑mortality

The 7-day mortality rate post-audit was significantly lower in
the ceased group than the continued group (47.3% vs 61.9%,
p = 0.003). Meanwhile, the 30-day mortality rate post-audit
was not statistically different between the two groups (76.0%
vs 81.2%, p = 0.203). Amongst the 358 patients who died
within 30 days of audit, mortality due to infection was
significantly higher in continued group (24.7% vs 38.5%,
p = 0.007), while time-to-mortality was not significantly dif-
ferent (3 [0–24] vs 2 [0–27] days, p = 0.066) (Table 1).
After excluding the 57 patients whose antibiotics were
continued until death within 48 h, 7-day mortality (47.3%
vs 45.4%, p = 0.718) and 30-day mortality (76.0% vs 72.3%,
p = 0.435) were not significantly different between the
ceased and continued groups. Amongst the 301 patients
Discussion
This study was conducted to investigate the clinical impact
of ASP interventions made to discontinue antibiotics in
end-of-life patients. Our results showed that cessation of
antibiotics after ASP interventions was not associated with
an increase in 7-day or 30-day mortality. In patients who
were terminally discharged, cessation of antibiotics was
associated with a shorter duration of antibiotics and time-
to-terminal discharge.
Though this observational study was not designed to
determine cause-and-effect, the most plausible explanation
for the lower 7-day mortality rate when antibiotics were
ceased was that this group of patients appeared to not be
actively dying at the point of intervention. Furthermore,

Table 3  Mortality outcomes Antibiotics ceased Antibiotics continued p ­valuea

after excluding patients whose (n = 283) (n = 119)
antibiotics were continued
until death within 48 h of Overall 7-day mortality rate 134 (47.3%) 54 (45.4%) 0.718
intervention
Overall 30-day mortality rate 215 (76.0%) 86 (72.3%) 0.435
30-day mortality due to ­infectionb 53 (24.7%) 29 (33.7%) 0.110
Time-to-mortality—days, median (min– 3 (0–24) 4 (0–27) < 0.001
max)b
a
Bolded value is statistically significant
b
Thirty-day mortality cause and time-to-mortality were calculated for 301 patients who died within 30 days
of audit, with 215 in the ceased group and 86 in the continued group

Table 4  Outcomes for patients Antibiotics ceased Antibiotics contin- p ­valuea

who were terminally discharged (n = 87) ued (n = 44)

Duration of therapy—days, median (min–max) 4 (0–17) 6.5 (1–14) 0.001

Time-to-terminal discharge post-intervention—days, 6 (0–74) 10.5 (3–63) 0.001
median (min–max)
a
Bolded values are statistically significant

13
34 European Journal of Clinical Microbiology & Infectious Diseases (2022) 41:29–36
after excluding the patients whose antibiotics were con-
tinued until death within 48 h of intervention, no differ-
ence in 7-day mortality was seen. Physicians may face an
inertia to withdraw treatment in a dying patient, due to
the ethical challenges presented. It was observed in our
study that the principal reason for intervention rejection,
and hence antibiotic continuation, was due to physician’s
personal preference. A survey done in a group of physi-
cians highlighted that physicians may not be confident in
determining when the patient is facing imminent death,
and that they preferred to avoid giving the perception of
“giving up” on the patient [18]. Also, many doctors are
more willing to continue antibiotics if they believed that
antibiotics may help relieve the patients’ symptoms [18].
While there are studies showing the use of antibiotics in
reducing symptomatic burden in urinary tract infections,
data in pneumonia is less clear [5, 6, 19]. There is even
evidence suggesting that antibiotics can potentially lead
to a paradoxical worsening of symptoms amongst nursing
home residents with dementia and pneumonia [20]. A pos-
tulation is that serious infections may produce sedation,
leading to a peaceful death, whereas the administration
of antibiotics can prolong the process of dying, thereby
worsening the experience of suffering [21]. As a result of
this dilemma, a common practice seen is to give patients a
trial of antibiotics before deciding if antibiotics should be
discontinued. However, our results showed that the 30-day
mortality rate was similar at approximately 80% regardless
if antibiotics were continued or not, in the presence of a
life-limiting illness. This information may aid physicians
in their discussion with patients and their family on the
overall goals of care, preferences, and advanced directives,
as treatment with antibiotics may likely be futile.
In patients who were terminally discharged, the antibiotic
duration was significantly shorter by 2.5 days in the ceased
group. Patients tended to remain hospitalized for a number
of days after stopping antibiotics, which could be for rea-
sons such as ensuring hemodynamic stability and providing
caregiver training prior to discharge. Overall, we observed
that stopping antibiotics was associated with a shorter time-
to-terminal discharge of 4.5 days. A recent study in older
adults with advanced cancer transitioned to comfort meas-
ures similarly showed that antibiotics were associated with
a significantly longer length of stay [22]. Shortened stays
have ramifications upon patients and their families. Earlier
discharge allows families to meet their filial obligations of
caring for their loved ones at end-of-life, in keeping with
dominant Confucian centric practices in Singapore [11, 12,
23]. The reduction in both antibiotic duration and length
of stay produces benefits such as reduction in line-related
complications, antibiotic-related adverse effects, and acqui-
sition of nosocomial multidrug-resistant infections [2, 13,
13
24]. Shortened stays may also reduce unnecessary healthcare
expenditure, for both patients and the government as health-
care costs are often shared in the local context.
There was a trend towards significance for time-to-mor-
tality in patients who died within 30 days of audit, with
the median being marginally higher at 3 days in the ceased
group vs 2 days in the continued group. In the subgroup
analysis that excluded patients whose antibiotics were con-
tinued until death within 48 h of intervention, time-to-mor-
tality was statistically significantly shorter by 1 day in the
ceased group. Available data on the prolongation of survival
with antibiotics is mixed [19]. Two studies done on antibi-
otic use in hospice patients, primarily with advanced can-
cer, showed no difference in survival [25, 26]. Meanwhile,
other studies found that antibiotics prolonged survival from
days to weeks [20, 27–29]. Though antibiotics may prolong
survival, the question on whether the prolongation of life
by a few days confers a greater benefit over risk ratio is
contentious. These few days might be beneficial by allowing
time for the patient’s family to say their goodbyes, improv-
ing bereavement outcomes [30]. Conversely, the symptom
burden of the patient may be overwhelming and pose great
discomfort to the patient.
Our study has several limitations. Firstly, as this was a
retrospective study, we were unable to clearly elucidate the
impetus for antibiotic continuation in this population, and
studies on the mental models of doctors in the local context
might be useful. For instance, physicians’ chief concerns
could be further attributed to reasons such as a fear of being
seen as giving up on the patient, consequential legal and
professional liabilities, or an underestimation of the detri-
mental adverse effects of antibiotics. Secondly, we have a
lack of data on the symptomology of patients in both groups
to address the possibility of symptom relief with antibiotics.
Other limitations are the absence of data on desired place of
care, the overall goals of the patients and the family, medica-
tion use, performance status, and the comorbidities affecting
the patient; thus, correlation of ASP impact on the above-
mentioned factors cannot be made. Moving forward, stud-
ies should include these variables to better account for the
complex interacting relationship that exists between them.
Conclusion
Our results demonstrated the utility of ASP in providing
reminders to review antibiotic use in palliative care patients
at end-of-life. We showed that antibiotic cessation by ASP
was safe. In some instances, the reduced duration of intra-
venous antibiotic therapy and hospitalization, as well as
facilitated transition of care from hospital to home, would
be invaluable to patients.
European Journal of Clinical Microbiology & Infectious Diseases (2022) 41:29–36
Author contribution Kai Chee Hung, Lai Wei Lee, Yi Xin Liew: con-
ception and design of study, acquisition of data, analysis and inter-
pretation of data, drafting of article and/or critical revision, and final
approval of the manuscript. Lalit Krishna, Maciej Piotr Chlebicki,
Shimin Jasmine Chung, and Andrea Lay-Hoon Kwa: analysis and
interpretation of data, drafting of article and/or critical revision, and
final approval of the manuscript.
Funding This work was supported in part by the National Medical
Research Council, Singapore (NMRC/CG/C005/2017, NMRC/CG/
M011/2017).
Declarations
Conflict of interest The authors declare no competing interests.
Ethics approval This study was approved by the SingHealth Central-
ised Institutional Review Board (CIRB Ref: 2010/114/E).
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