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Antibiotics and palliative care

Article  in  European Journal of Palliative Care · January 2006

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Antibiotics and palliative care
Lukas Radbruch, Martina Pestinger, Annekatrin Müller and Frank Elsner
examine the use of antibiotics in terminally ill patients
I
nfections are common in patients with
advanced cancer or other incurable
diseases. The incidence ranges from 5% to
55% of patients.1–3
Various disease-related and therapy-induced
factors make cancer patients susceptible to
infection. The malignant disease may facilitate
infection via several mechanisms. The
inflammatory milieu around the tumour may
suppress immune activities, such as recognition
of tumour-associated antigens or activation of
immune cells or cytolysis. Cytokines,
prostaglandins and oxidants may contribute to
this inflammation-associated immune
suppression.4 Transforming growth factor (TGF-
beta) seems to play a central role in tumour-
related immunosuppression, but other
cytokines such as interleukin-2 (IL-2) or tumour
necrosis factor (TNF-alpha) are also involved.5,6
Immune cell function may be compromised by
destruction of bone marrow from malignant
infiltration. Cachexia with progressive disease
will be associated with reduced humoral
immune response from hypoglobulinaemia.
Chemotherapy- or radiotherapy-induced
neutropenia is a frequent cause of infection.
However, in a palliative care setting, treatments
with less side-effects and complications are used
and consequently neutropenia would be
expected to play a minor role but this will vary
since local referral criteria and patterns differ. In
a Canadian palliative care unit, it was identified
in only one of 100 patients.1 Chemotherapy and
radiotherapy can facilitate infections such as
skin irritations, radio- or chemotherapy-induced
mucositis or immunosuppressive effects.
Pharmacological treatment can also facilitate
infections. Immunosuppression is a common
result of treatment with corticosteroids. It has
been reported to a lesser extent for opioids7 and
cannabinoids.8 Intravenous (IV) lines, catheters
and drains are gates for infectious agents.
Palliative non-cancer patients also are
susceptible to infections in a high degree.
Patients with HIV/AIDS have a reduced immune
response and are at risk of different
EUROPEAN JOURNAL OF PALLIATIVE CARE, 2006; 13(1)
C l i n i c a l m a n a ge m e n t
opportunistic infections throughout their
disease process. Neurological patients often
suffer from impaired respiratory function.
Patients with advanced amyotrophic lateral
sclerosis usually develop respiratory failure.
Recurrent pneumonia is a frequent problem.
Symptom burden of infection
Terminally ill patients usually suffer from
multiple symptoms caused by the cancer itself,
cancer treatment or comorbidities. Infections
increase the burden related to these symptoms
and further reduce quality of life. There is Terminally ill
evidence that patients with infections suffered patients usually
from psychological distress as well as from suffer from
disabling symptoms.3 multiple
The predominant symptom is fever which can symptoms
aggravate other symptoms of progressive cancer caused by
such as fatigue9 or dehydration. Fever and the cancer
dehydration often lead to confusion and itself, cancer
disorientation10 and so it is important to treatment or
consider the presence of fever and infection comorbidities
when assessing the causes of confusion and of
fatigue. Infection is also one of the factors
contributing to lymphedema, and recurrent
inflammation may require prophylactic
antibiotics to prevent continuous deterioration.11
The nature of symptoms as well as the burden
to the patient will depend on the affected organ
systems. The most frequent infection sites are
the urinary tract, the respiratory tract, skin and
subcutaneous tissues, and blood.1,3
Urinary tract infections are related to long-
term urinary catheterisation. Symptoms are
Key points
● Infections are common in patients with advanced cancer or
other incurable diseases.
● The appropriateness of diagnostic procedures, and of
antibiotic therapy are influenced by stage of disease and
estimated life expectancy.
● More research is needed before outcome criteria or
algorithms for decision-making can be developed.
5
C l i n i c a l m a n a ge m e n t
usually mild. In non-catheterised patients,
bladder function may be impaired by the
infection causing urinary incontinence.
Respiratory tract infections frequently cause
dyspnoea and increased mucous secretions that
induce coughing and rattling respirations.
Diagnosis of infections
Fever and leucocytosis are red flag indicators of
an infection. Clinical assessment is necessary to
identify the infection site and the affected
organ system. Pathogen identification may
SCIENCE PHOTO LIBRARY
require analysis of urine, blood, sputum,
infected catheter tips or other specimens.
Deciding on the appropriate extent of
investigations for a palliative care patient may
be difficult. Using a case vignette with a patient
with pneumonia, participants of a focus group
had difficulties in deciding whether progressive
dyspnoea and mucous obstruction were
symptoms of pneumonia or indicators of
disease progression.12 Clinical practice often
does not include diagnostic measures or regular
laboratory or radiological assessments of disease
extent in order not to overburden the patient.
Diagnosing is often done clinically and
followed over the next days and weeks, thus
Fever and making an ongoing causal differentiation of the
leucocytosis causal pathology of symptoms.12
are red flag
indicators of Treatment of infections
an infection Antibiotic choice should depend on
microbiologic assessment and identification of
the pathogen organisms. As this is not available
in most palliative care patients and high
symptom burden necessitates fast relief,
treatment is often initiated blindly. For
uncomplicated infections, oral administration
of antibiotics is usually adequate. For severe
infection or sepsis, IV administration may be
required. Topical or rectal administration is also
possible. Antibiotics licensed for subcutaneous
use are only available in France.13 Intramuscular
injections should be used avoided.
Cotrimoxazole or gyrase-inhibitors can be
used for uncomplicated urinary infections.
Pneumonia and other infections will be treated
with aminopenicillins, preferably in
combination with a beta-lactamase-inhibitor or
second-generation cephalosporin. Antibiotic
therapy should be augmented with other drug
and non-drug interventions.
Persistent or recurrent infections will require
secondline antibiotics such as aminoglycosides,
macrolide antibiotics, specific penicillins or
6 EUROPEAN JOURNAL OF PALLIATIVE CARE, 2006; 13(1)
Antibiotic choice should depend on microbiologic
assessment and identification of the pathogen organisms
cephalosporins. Antimycotic drugs may be
required for mycosis of the oral cavity or the
genital region, and rarely also for other mycotic
infections. Antiviral therapy with acyclovir is
required for herpes zoster infections.
A survey of drug usage in German palliative
care units revealed that the most frequently
used antibiotics were amoxicillin, ciprofloxacin
and metronidazole.14 However, antibiotics were
neither among the ten most frequently used
drug classes nor were any antibiotic drugs
among the most frequently used drug list.
In a comparison of frequency and types of
antibiotics prescribed in the last week of life in
three palliative care settings, namely an acute
care hospital, a tertiary palliative care unit, and
a hospice, marked variability was found in the
number and type of antibiotics prescribed in
the last week of life.15 Antibiotics were
prescribed for 58% of the patients in the acute
hospital setting and for 52% in the tertiary
palliative care unit, compared to 22% in the
hospice setting. In the acute care and tertiary
palliative care settings, the most frequent route
of antibiotic administration was IV and, in the
hospice setting, oral administration.
In a hospice, infections were diagnosed in
31% of the patients on admission, and
antibiotic treatment was commenced within
48 hours of admission in 60% of these
patients. Overall antibiotic response and
symptom control of infections was observed to
be a minimum of 40%.3 In a Canadian
palliative care unit, 72% of the infections were
treated with antibiotics.1 Reasons for not
treating infections were very poor general
condition, imminent death, patients were

unable to take oral antibiotics and refused
parenteral application.1
Usually, antibiotics are well tolerated. The
most frequent side-effects are allergic reactions,
which are often mild with fever, exanthema or
urticaria. In a few cases, severe complications
such as anaphylactic shock may develop.
Penicillins and cephalosporins can produce
neurotoxic side-effects such as hallucinations,
psychotic reactions, depression or seizures.
Cephalosporins may cause nephrotoxicity and
aminoglycosides may cause oto- and
nephrotoxicitiy. Some antibiotics may cause
cardiac side-effects, others can impair hepatic
function. Most antibiotics can cause
gastrointestinal side-effects, usually diarrhoea,
and rarely may induce pseudomembranous
colitis that has to be treated with vancomycin.
Withholding/withdrawing antibiotics
Central to palliative care is individual
adjustment of the treatment regimen balancing
symptom control and improved quality of life
on one side and additional burden on the other
side for the patient. This also applies to the
diagnosis of infections and antibiotic treatment.
The site of infection and/or the organ system
involved will influence the impact of infection
on a patient’s life and the need to consider
treatment of the infection. In clinical practice,
the decision about whether to initiate or
discontinue treatment in an individual patient
is usually made by the physician. Other
professions may evaluate the impact of
infections differently, depending on the type of
infection. For example, an urinary tract
infection may be considered to require
treatment by relatives and nursing staff but not
by physicians who may not perceive reduction
in the quality of life from this infection.
Pneumonia causing dyspnoea, however, may
induce obvious and comprehensible complaints
and thus lead to antibiotic therapy. The
decision on treatment or omission is influenced
by the doctor’s assessment of the patient’s
performance status and life expectancy. In
accordance with the palliative care philosophy,
it might be better to use the multiprofessional
palliative care team for these decisions.
However, in clinical practice, this could be
impractical and time-consuming.12
There is consensus that in the final phase of
illness and in dying patients, antibiotic therapy
should not be initiated.12 High use of IV
antibiotics and the large number of patients
EUROPEAN JOURNAL OF PALLIATIVE CARE, 2006; 13(1)
C l i n i c a l m a n a ge m e n t
who were still receiving antibiotics at the time
of death have even been described as indicators
of overtreatment.15 Antibiotic therapy has also
been used as an indicator for aggressive
treatment in patients with end-stage dementia.16
Decision-making may be harder in the earlier
disease stages and no consensus exists for the
use of antibiotics in this group of patients.
Although there is an argument that treatment
relieves symptoms,3 there are cases where
antibiotics should be withheld.
The balance of benefits and disadvantages
from antibiotic therapy is influenced by the
route of administration. If placing an IV line
will only increase the burden for the patient,
then either oral administration or no antibiotic
treatment may be appropriate.
Ideally, economic aspects related to expensive
antibiotic therapy in patients with a short life
expectancy should not play a part in the
decision process. However, antibiotic drugs can
be an increasing item in budgets and concern
has been expressed that decisions on
withholding or discontinuing antibiotics could The balance of
be influenced by this. In 2004, antibiotics were benefits and
one of the most expensive drug classes in our disadvantages
own unit, accounting for 10% of the from antibiotic
pharmaceutical budget. On the other hand, the therapy is
fear of possible legal consequences might lead influenced by
physicians to administer antibiotics, even if they the route of
are not required from a clinical indication.12 administration
Lack of knowledge and experience may
influence a physician’s prescribing habits. In a
survey of 418 German general physicians, 7%
categorised withdrawal of antibiotic treatment
for pneumonia incorrectly as active euthanasia.17
Competence and comfort with end-of-life issues
is only acquired with high levels of training.
Medical students expressed greater concern for
violating medical practice standards than junior
doctors when withdrawing parenteral antibiotics
from a severely demented patient with sepsis at
the request of his legal guardian, whereas more
experienced junior doctors showed a greater
concern for the violation of personal religious or
ethical beliefs.18
There is controversy in the literature about the
efficacy of antibiotics used in palliative care. In a
prospective survey, urinary tract infections were
more commonly associated with a positive
outcome than other indications.19 The authors
found no association between outcome and age
of the patient, underlying diagnosis or reason
for admission. However, positive outcomes were
more common in terminal- and stable-phase
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C l i n i c a l m a n a ge m e n t
patients than deteriorating- or acute-phase
patients. The authors concluded that in specific
circumstances there is a beneficial role for the
use of parenteral antibiotics.
Chen et al reported that withholding
antibiotic therapy in hospice patients with fever
is correlated with a shorter survival time and a
higher three-day-mortality.20 However, longer
survival times may not always be a benefit, but
can be seen as a prolongation of the dying
process and may add to the patient’s distress.21
Another study found no correlation between
survival time and presence of bacterial
infection, irrespective of whether a positive
culture isolate was obtained.3
Decision-making
Clinical decision-making requires consideration
of the advantages and disadvantages of
treatment options and evaluation of the need
for informed consent, identification of the
patient’s needs and wishes. Consequences of
withholding or discontinuing antibiotics seem
to have less influence on survival time or
quality of life than other treatment decisions.
However, decision-making about initiating
antibiotic treatment is not easy. A focus group
of participants from German and Austrian
palliative care units tried to identify problem
areas and criteria for decision-making. By
analysing case reports with critical appraisal,
hypotheses on the decision process for
initiating antibiotic treatment were generated
(Box 1).12 Different attitudes and values
attached to antibiotics became evident
(Figure 1).
Informed consent
Assessment of the patient’s needs and
determination of therapeutic goals in close
communication with the patient and family are
essential. Decisions on withholding, initiating
or discontinuing antibiotic therapy require
informed consent from the patient. Ahronheim
et al22 and Goodlin et al23 have demonstrated
that dying patients with an incurable disease
often receive systemic antibiotic therapy in
hospital, often on the basis of a diagnosis based
on clinical examination. The subjects included
patients who wanted symptom control, but not
resuscitation. White et al came to the
conclusion that many of these patients had
they been given the choice and been involved
in the decision-making process, would have
declined antibiotic therapy.24
8 EUROPEAN JOURNAL OF PALLIATIVE CARE, 2006; 13(1)
Box 1. Hypotheses on decision making for antibiotic
therapy in palliative care12
● As prognostic criteria for assessment of the individual life
expectancy are not sensitive enough, decision-making strongly
depends on the subjective evaluation of a patient’s functional status.
● Type of infection (pneumonia versus urinary tract infection) influences
the decision on antibiotic treatment. Symptoms from some infections
are more strongly associated with the need for antibiotics .
● Antibiotics are used even though their efficacy in palliative care is
not clear because physicians carry standards from previous care
settings such as oncology forward to palliative care. Fear of legal
consequences of withholding or discontinuing antibiotic therapy is
an additional motivation.
lack of informed consent
Application forms Aims of therapy
Costs
conflict of different expectations
Antibiotics in
specific symptoms lead
to stronger associations
palliative care Indication use of antibiotics?
Stress-correlated
symptoms Adverse effects
omission of
Absence of unique Anticipated Empirical diagnosis
burdening methods
definitions of the several lead to uncertainty
expectancy of life
phases of progression Absence of unique
outcome criteria
Figure 1. Problem Antibiotic therapy may symbolise ongoing
areas related to treatment efforts and discontinuation may be
the use of
antibiotics seen as taking away hope. Discussion is needed
identified by a for informed consent. This should not lead to
focus group12 unilateral treatment decisions ignoring the
views of patient and family. A balance needs to
be struck between the information given to the
patient to allow them to make a decision and
the amount of information requested. This
process is continuous and requires constant
reflection between patient and staff.
Many patients with infection suffer from
cognitive impairment. Fever and concomitant
dehydration are among the most frequent
causes of cognitive impairment. In these
patients, informed consent may not be an
option. Advanced directives offer an
alternative option for decision-making.
However, only very few patients will include
statements on antibiotic therapy in their
advanced directives, as they do not realise that
treatment decisions could involve antibiotics.
Other information included in advanced
directives may be helpful to assess the patients’
preferences and values and to evaluate the
presumed intention of the patient.
Appointment of a substitute decision-maker
may be a better option.

Outcome criteria
In other areas of medicine, outcome criteria for
antibiotic treatment are well defined, but there
are no clear criteria in palliative care.12
Alleviation of fever and reduced number of
leucocytes are clear indicators of treatment
efficacy, but are not necessarily useful in
palliative care. It has been suggested that
outcomes can be classified as helpful (general
condition improved or symptoms improved) or
not helpful (symptoms not improved) as
suggested by Clayton et al.19 This may not be
useful in clinical practice either, as it depends
predominantly on the physician’s attitude.
Morant and Senn suggested that improvement
in quality of life and of patient–family
interaction should be an outcome measure of
antibiotic therapy.25 However, they did not
address the problems related to assessment and
evaluation of these. These studies show the
difficulties in identifying relevant outcome
parameters. Inadequate documentation
discipline impedes evaluation of the clinical
decision-making process. Pereira et al reported
that in 21 untreated cases of infection the reason
for abandoning treatment was documented in
only ten cases.1 This data supports the findings
of other studies that documentation in palliative
care is regarded as suboptimal.2
Life expectancy
The appropriateness of antibiotic therapy is
influenced by stage of disease and estimated life
expectancy. There is broad consent that
diagnostic procedures and antibiotic therapy
should not be performed in the terminal phase
of life. However, for the time before the
terminal phase, no clear consensus can be
found. The discussion is burdened with the
uncertain definition of dying. Definitions of
the terminal phase and its starting point vary
and depend on ethical and medical concepts.
Prognosis scores estimating survival times
have been the focus of recent research.26
Scoring sytems such as the Prognostic Palliative
Score27 or the Prognostic Palliative Index28 could
be used to facilitate decision-making, as low
scores indicating shorter life expectancy would
weaken the indication for antibiotics. However,
the sensitivity of the existing tools is not good
enough to use them as sole indicators.
Conclusion
We believe that currently the use of antibiotics
in palliative medicine is beyond consensus and
EUROPEAN JOURNAL OF PALLIATIVE CARE, 2006; 13(1)
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C l i n i c a l m a n a ge m e n t
that it is impossible to develop robust
guidelines for clinical practice. More research is
needed before outcome criteria or algorithms
for decision-making can be developed.
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Lukas Radbruch, job title; Martina Pestinger, job title;
Annekatrin Müller, job title; Frank Elsner, job title,
Department of Palliative Medicine, RWTH Aachen
University, Germany
9