Clinical Microbiology and Infection 26 (2020) 35e40

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Clinical Microbiology and Infection

journal homepage: www.clinicalmicrobiologyandinfection.com

Narrative review

When not to start antibiotics: avoiding antibiotic overuse in the

intensive care unit
K.J. Denny 1, 2, *, J. De Wale 3, K.B. Laupland 4, 5, P.N.A. Harris 6, J. Lipman 2, 7, 8
1)
Department of Intensive Care, Gold Coast University Hospital, Gold Coast, QLD, Australia
2)
Burns, Trauma & Critical Care Research Centre, University of Queensland, Herston, QLD, Australia
3)
Department of Critical Care Medicine, Ghent University Hospital, Ghent, Belgium
4)
Department of Intensive Care Services, Royal Brisbane and Womens Hospital and Queensland University of Technology, Herston, QLD, Australia
5)
Department of Medicine, Royal Inland Hospital, Kamloops, BC, Canada
6)
University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital, Herston, QLD, Australia
7)
Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Herston, QLD, Australia
8)
Nimes University Hospital, University of Montpellier, Nimes, France

a r t i c l e i n f o a b s t r a c t

Article history: Background: Most intensive care unit (ICU) patients receive broad-spectrum antibiotics. While lifesaving
Received 23 March 2019 in some, in others these treatments may be unnecessary and place patients at risk of antibiotic-
Received in revised form associated harms.
1 July 2019
Objectives: To review the literature exploring how we diagnose infection in patients in the ICU and
Accepted 4 July 2019
Available online 12 July 2019
address the safety and utility of a ‘watchful waiting’ approach to antibiotic initiation with selected pa-
tients in the ICU.
Editor: C Pulcini Sources: A semi-structured search of PubMed and Cochrane Library databases for articles published in
English during the past 15 years was conducted.
Keywords: Content: Distinguishing infection from non-infectious mimics in ICU patients is uniquely challenging. At
Antibiotic overuse present, we do not have access to a rapid point-of-care test that reliably differentiates between in-
Antibiotic prescribing dividuals who need antibiotics and those who do not. A small number of studies have attempted to
Intensive care compare early aggressive versus conservative antimicrobial strategies in the ICU. However, this body of
Sepsis
literature is small and not robust enough to guide practice.
Watchful waiting
Implications: This issue will not likely be resolved until there are diagnostic tests that rapidly and reliably
identify the presence or absence of infection in the ICU population. In the meantime, prospective trials
that identify clinical situations wherein it is safe to delay or withhold antibiotic initiation in the ICU until
the presence of an infection is proven are warranted. K.J. Denny, Clin Microbiol Infect 2020;26:35
© 2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All
rights reserved.

Introduction Antibiotic-associated harms include adverse drug events, risk of

Prescribing broad-spectrum empiric antibiotics ‘just in case’ is
the norm in the intensive care unit (ICU) [1]. An international point-
prevalence study has demonstrated that, on a given day, 70% of all
patients in ICUs are administered at least one antibiotic [2]. On the
one hand, antibiotics are life-saving therapies in infected patients,
but they do not benefit non-infected patients and place them at risk
for potential antibiotic-associated adverse events.
* Corresponding author. K.J. Denny, Burns, Trauma & Critical Care Research
Centre, University of Queensland, Herston, QLD, Australia.
E-mail address: k.denny@uq.edu.au (K.J. Denny).
secondary opportunistic infections and antimicrobial resistance
[3e6]. Antibiotic-associated adverse drug events are common in
ICU patients, due partly to the underlying critical illness that in-
creases susceptibility to organ injury [4], as well as the multiplicity
of medications that ICU patients receive, which increase the risk of
undesirable drug interactions [5].
The individual and collective ecological harms of antibiotics are
well documented in the ICU [7]. Certain classes of antibiotics
commonly used in the ICU have a propensity to cause ecological
‘collateral damage’ through a loss of microbial diversity and se-
lection for organisms such as Clostridioides difficile and Candida spp.
that can cause secondary infection [8e13]. Further, a significant

https://doi.org/10.1016/j.cmi.2019.07.007
1198-743X/© 2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
36 K.J. Denny et al. / Clinical Microbiology and Infection 26 (2020) 35e40
increase in the carriage of resistant bacteria has been demonstrated
to occur with even brief antibiotic exposure (1e3 days) in ICU pa-
tients [14].
Antibiotic de-escalation has been proposed as a potential
compromise to address the competing goals of rapid and effective
treatment of potential infection and reducing antibiotic overuse
and resultant unnecessary antibiotic harms [15]. However, strong
evidence demonstrating that antibiotic de-escalation is a reliable
strategy in patients in the ICU is lacking, partly because of a lack of a
clear definition of what de-escalation involves. Antibiotic de-
escalation strategies have not yet been shown to be effective in
reducing the carriage of multidrug-resistant bacteria and it may
increase the incidence of secondary infections [16,17].
We therefore propose that the ideal approach, if proven safe,
would be to avoid initiation of antibiotics in the ICU patient until
the treating clinician were convinced of the presence of infection
and its source. The following narrative review aims to explore the
literature that addresses how we diagnose infection in the ICU and
whether clinicians working with ICU patients can confidently
employ a ‘watchful waiting’ strategy, with the resultant benefit of
avoiding unnecessary antibiotic exposure, and hence harms.
There have been previous reviews that have addressed how to
reduce antibiotic exposure in ICU patients [18e21]. Our narrative
review attempts to specifically focus on the question of how to
avoid the initiation of antibiotics in the high stakes environment of
the ICU.
Methods
A literature search using the PubMed and Cochrane Library da-
tabases for published English-language articles within the past
15 years was conducted by one of the authors (KJD). Relevant
additional articles identified ad hoc by all authors were also included.
The following types of articles were included: randomized
controlled trials, meta-analyses, observational (small and large),
expert opinions, and guidelines. Search terms included were
‘intensive care’ AND ‘(antibiotics OR antimicrobials)’ AND (overuse
OR empiric OR delayed OR conservative OR timing OR culture
negative OR biomarkers OR unnecessary OR inappropriate). The
initial search strategy identified 2747 results, those deemed to be
relevant to this narrative review on when not to start antibiotics in
the ICU were included.
Does this patient in the ICU have an infection?
Sepsis is defined as a life-threatening organ dysfunction caused
by a dysregulated response to infection [22]. However, although
identifying organ dysfunction is relatively straightforward, pro-
spectively diagnosing infection as the cause of organ dysfunction is
more challenging. The difficulty in the bedside diagnosis of sepsis
was highlighted by a cohort study in the Netherlands, where of
2579 individuals who presented to the ICU with clinically suspected
sepsis, 13% had a post hoc infection likelihood of ‘none’ and an
additional 30% were ‘possible’ [23].
Diagnosing infectious complications in existing ICU patients is
fraught with problems. Clinical signs (e.g. pyrexia, tachycardia,
vasoplegia) and laboratory findings (e.g. leucocytosis/leucopenia,
hyperlactataemia), which are often attributed to infection, are
commonly associated with non-infectious aetiologies in the ICU
population [24e28]. Even clinical signs that may suggest a specific
source of infection (e.g. lung consolidation, increased sputum
production) may be non-specific in ventilated ICU patients [29].
Microbiological cultures are the current reference standard for
confirming infection and a positive culture, ideally with input from
a clinical microbiologist, facilitates the administration of
appropriate antibiotics. However, current bacterial and fungal cul-
ture techniques take time (typically >24 hours), necessitate good
(and sometimes invasive) sampling techniques, and there is the
potential for patient deterioration while waiting for results. Even
once culture results are obtained, the retrospective diagnosis of
sepsis can be problematic because of contamination, colonization
and ‘culture-negative’ infection. In patients admitted to the ICU,
28%e49% of patients with a syndrome consistent with likely sepsis
have negative cultures [30e34]. Failure to identify an organism may
be a result of the patient receiving antibiotics previously, so
obscuring conventional cultures, poor collection technique, or the
presence of unusual or slow-growing organisms [35,36]. Alterna-
tively, the patient may have a non-infectious cause for their clinical
syndrome. For these reasons, even the retrospective diagnosis of
infection is problematic, as demonstrated in a study by Rhee et al.
[37] in which poor inter-rater reliability (Fleiss's k ¼ 0.21) was
exhibited by critical care clinicians when asked to in diagnose
sepsis using a series of case vignettes.
There has been increasing interest in exploring novel di-
agnostics that can quickly and accurately differentiate between
those patients with and without infection. Diagnostics can be
broadly differentiated into two groups: (i) diagnostics that identify
the presence of microbes, and (ii) biomarkers that identify the host
response to the presence of microbes. Assays that aim to identify
the presence of microbes faster than conventional microbiological
cultures are in various stages of development [38e40]. However,
these assays remain susceptible to the problems of contamination
and colonization, leading to the identification of microorganisms
that are not necessarily responsible for patient deterio-
rationdproblems that may or may not be solved with emerging
next-generation sequencing diagnostic technology [41].
Host biomarkers have shown varying levels of promise in
guiding antibiotic use in the ICU environment [42e44]. Procalci-
tonin has been shown to be helpful in reducing the duration of
antibiotic therapy, albeit this reduction is often modest [45]. Other
proposed biomarkers of sepsis include C-reactive protein [46,47],
various cytokines [48,49], adhesion molecules [50], hormones [51],
receptors [52e55], and surface glycoproteins [56]. There is also
increasing interest in the role of ‘-omic’ technologies (genomics,
metabolomics, transcriptomic, proteomic) in the diagnosis of sepsis
[57]. However, the utility of currently available host biomarkers in
distinguishing between ICU patients with and without infection,
and so guiding antibiotic initiation, remains low [7,44,58e63].
It is hypothesized that, given the biological complexity of sepsis,
a stratification strategy based on a panel of multiple biomarkers
such as gene expression has more potential to meet the needs of an
ideal biomarker-based stratification tool [27,64,65]. Such
biomarker tests remain in their infancy and we await prospective
studies to determine their utility in clinical practice.
Can we afford to ‘watch and wait’ for infection in an ICU patient?
While we wait for improved diagnostic tools that allow us to
more quickly and accurately identify the presence of infection in
patients in the ICU, is it safe to adopt a more conservative approach
to antimicrobial prescribing? Is it safe for the treating clinicians to
delay empiric broad-spectrum antibiotics in an ICU patient until the
likely source of infection or another non-infective diagnosis be-
comes apparent?
The Surviving Sepsis Campaign guidelines recommend that
antibiotics be initiated within 1 hour from recognition of sepsis
[66]. However, data investigating this recommendation have been
inconsistent, particularly in patients without shock, and suffer from
the biases inherent in time-to-intervention trial design (e.g. treat-
ment delay in more complicated patients) [67e72]. Further, many
 K.J. Denny et al. / Clinical Microbiology and Infection 26 (2020) 35e40
studies in this area lack critical information regarding how in-
fections were confirmed, whether antibiotic selection was appro-
priate, and/or when (or whether) source control was achieved.
Initial inappropriate antibiotic therapy has been demonstrated
to be an independent risk factor for mortality in ICU populations
[73e75], where inappropriate was defined retrospectively as
empiric antibiotics that were unlikely to treat the causative path-
ogen. Source control is also vital to preventing increased mortality
[76,77]. In a large prospective observational study by Bloos et al.
[76], there was no mortality benefit from the early initiation of
antimicrobial therapyddefined as antibiotic administration that
occurs within the first hour of the onset of infection-related organ
dysfunction. However, inadequate source control was shown to
increase 28-day mortality from 26.7% to 42.9%. We therefore hy-
pothesize that the importance of timeliness with regards to anti-
biotic administration may be overemphasized, and rather a more
nuanced approach wherein brief delays in antibiotic administration
to allow for source recognition, source control and ensuring anti-
biotic appropriateness may be valid.
Further, it is unclear as to whether we should distinguish between
patients who are admitted to the ICU with likely infection and those
with a critical illness who develop an infection as a secondary
complication. Sepsis is not a homogeneous syndrome; it has a
phenotype that varies based on both characteristics of the culprit
organism and characteristics of the host immune response [78].
Infections acquired in the ICU are associated with microbio-
logical isolates different from those acquired in the community, and
are often associated with resistant organisms [2,79]. This may be, in
part, due to different environmental risk factors (e.g. central
vascular catheters, endotracheal tubes), previous exposure to an-
tibiotics (e.g. antimicrobial prophylaxis for surgery), and an altered
microbiome characterized by a loss of microbial richness and di-
versity [80,81]. The presence of critical illness also results in an
altered immunophenotype, characterized by the concurrent up-
regulation of multiple pro- and anti-inflammatory pathways, with
down-regulation of adaptive immune pathways [82]. Of note, the
immunophenotypes of critical illness, and associated risk of sec-
ondary nosocomial infection, are remarkably similar independent
of whether the initial insult had an infectious or non-infectious
aetiology [82,83].
On the other hand, ICU patients may also have protective fac-
torsdnamely, close monitoring of physiology and one-to-one
nursingdthat may mean that ‘watchful waiting’ in the ICU is a
safer strategy compared with other populations. Hranjec et al. [84]
attempted to address the safety of delayed initiation of antimicro-
bial therapy in a cohort of surgical ICU patients by performing a
quasi-experimental, before-and-after observational cohort study
that compared an aggressive treatment strategy (early antibiotic
treatment for suspected infection) with a conservative one (anti-
microbial treatment only after objective findings confirmed infec-
tion). They concluded that waiting for objective data to diagnose
infection before antimicrobial treatment was not associated with
increased mortality. However, antibiotic appropriateness was low,
with only 62%e74% of patients receiving appropriate antibiotic
regimens, and the case-fatality rate was high. Further, patients
Table 1
Recommendations for daily practice in patients with suspected infection the intensive care unit (ICU) based on expert opinion of the authors
Recommendations for daily practice
Source control in a critically ill patient with sepsis should not be delayed
In the non-shocked ICU patient with suspected infection (and onset >48 hours after ICU admission) consider delaying the initiation of antimicrobial therapy until after
initial investigations aimed at sepsis diagnosis and source identification
In patients with proven infections, do not unnecessarily defer antibiotics
Currently available host biomarkers such as C-reactive protein and procalcitonin have no place in routinely guiding the initiation of antibiotics in the ICU
37
received prolonged courses of antibiotics (12e17 days), which itself
is associated with adverse outcomes [85,86].
In another study, Amaral and Holder [87] investigated whether
delays in antimicrobial therapy increased mortality in a specific
condition in the ICU, ventilator-associated pneumonia. In this
single-centre retrospective study, there was no association be-
tween timing of antibiotics after the identification of a ventilator-
associated complication and patient harm (mortality, super-
infection, or treatment failure) in patients subsequently diag-
nosed with ventilator-associated pneumonia.
However, the above single-centre studies can only be, at best,
hypothesis-generating given their significant and numerous limi-
tations. Future studies are required to determine whether delayed
prescribing strategies for selected patients in the ICU setting are
safe, feasible and beneficial. In the meantime, we have provided
some recommendations for daily practice of antibiotic initiation in
the ICU based on expert interpretation of available evidence
(Table 1).
What future research do we need?
The above narrative review of the literature highlights two key
gaps in the evidence that need to be addressed so that clinicians can
safely and confidently avoid unnecessary antibiotic initiation in the
ICU. First, we need novel diagnostic strategies to help us better
identify the presence of infection and, second, we need high-
quality multi-centre prospective randomized studies to inform us
when ‘watchful waiting’ may be a safe and effective approach in the
ICU. Potential future approaches to address these gaps in the
literature will be discussed in turn.
Improving our ability to identify infection, and distinguish it
from non-infectious mimics, is the ultimate solution to reducing
unnecessary antibiotic initiation in the ICU. We propose that an
ideal diagnostic tool for infection would quickly, accurately and
affordably identify the presence or absence of a specific pathogen,
any antibiotic-resistance genes, and a host response to a pathogen
[78]. Identifying the host response to infection is necessary to
differentiate between colonization or contamination and true
infection. An ideal tool would also be able to monitor the response
to treatment, and facilitate the cessation of antibiotic treatment
[61]. It is essential that any proposed diagnostic tests are evaluated
against clinically important outcome measures (e.g. mortality,
morbidity).
However, until such a diagnostic tool becomes available that has
the sensitivity and specificity to safely distinguish those critically ill
patients who need antibiotics from those who do not, we recom-
mend that additional studies are required that aim to determine
whether a ‘watchful waiting’ approach to antibiotic prescribing is
both safe and beneficial to selected ICU patients.
Clinical researchers additionally need to consider what are the
most practical ICU subgroups in which to trial this approach. We
recommend that studies investigating the safety of delayed pre-
scribing: (i) focus on specific subgroups of patients (e.g. trauma,
burns, or patients with febrile neutropenia); (ii) exclude patients
who are hypotensive because of suspected infection [30]; and, (iii)
38 K.J. Denny et al. / Clinical Microbiology and Infection 26 (2020) 35e40

Fig. 1. Do I need to give antibiotics?

Table 2
Recommended future research strategies and directions aimed at preventing antibiotic overuse in the intensive care unit

Recommended future research strategies and directions

Development of a novel, point-of-care test that accurately identifies both a host response to infection and the causative pathogen to assist in the reliable diagnosis and
treatment of sepsis. A tool that reliably differentiates between infection and non-infectious clinical mimics would also be of importance in other studies that aim to
identify the value of other interventions (e.g. fluids, early vasopressors) in patients with sepsis.
Controlled trials that compare early empiric therapy with a more conservative or delayed antibiotic strategy in intensive care unit subpopulations (e.g. burns, trauma,
febrile neutropenic patients).
All studies investigating the effectiveness of various treatment strategies in sepsis should report on: the appropriateness of antibiotics given; time to source control and
effectiveness of source control; and how/whether infection was confirmed.
Studies to evaluate whether antibiotics are needed at all in conditions where adequate source control has been achieved (i.e. removal of infected catheters with associated
low-virulence organisms).

initially focus on patients who are already in the closely monitored
environment of the ICU who may have developed an infectious
complication (versus an initial presenting complaint of possible
infection). The latter is recommended because the harms of delayed
prescribing in certain populations (e.g. suspected meningococcal
meningitis) are likely to be significantly greater than those of others
(e.g. ventilator-associated pneumonia). We await further evidence
regarding antibiotic initiation in patients in the ICU, but have
summarized a suggested approach to the question ‘Do I Need to
Give Antibiotics?’ in Fig. 1.
Future studies also need to measure and adjust for other
important contributors to treatment failure, including: the appro-
priateness of empiric antibiotic selection [73e75]; the appropri-
ateness of antibiotic dosing based on the unique pharmacokinetic
and pharmacodynamic changes seen in ICU patients [7,88]; and the
timeliness and thoroughness of source control [76,77]. We hy-
pothesize that, for some subgroups of ICU patients, the benefit of
early empiric antimicrobial treatment (versus delayed targeted
antimicrobial treatment) is likely to be minimal if appropriate
antibiotic selection, adequate dosing and efficient source control
are achieved. We have outlined future research strategies and di-
rections in Table 2.
Conclusions
In the future, we will inevitably have the luxury of a rapid
testing and management tool whereby only ICU patients who have
an infection will receive antibiotics. However, at present we must
continue to integrate the available clinical, laboratory and
radiological information to optimize management with nearly all
patients with infections receiving antibiotics while minimizing
these treatments in non-infected patients. This approach relies
heavily on shared decision-making between intensivists and ex-
perts in infectious disease and clinical microbiology. The definitive
answer to the problem of antibiotic overuse in the ICU is the
development of point-of-care diagnostic technologies that will
allow for the quick and reliable diagnosis of infection. In the
meantime, trials that identify when or if it is safe to delay antibiotic
initiation in the ICU until an infection is proven are needed before
this approach can be widely implemented.
Transparency declaration
JdW reports support from Bayer, Pfizer, MSD, Grifols, and
Accelerate outside the submitted work. All other authors have no
conflicts of interest to declare.
Funding
KJD is supported by a Queensland Health Junior Doctor Research
Fellowship.
Authors' contributions
KJD performed the literature search and contributed to manu-
script preparation, editing and revisions. JdW, KBL, PNAH and JL
contributed to the manuscript preparation, editing and revisions.
 K.J. Denny et al. / Clinical Microbiology and Infection 26 (2020) 35e40 39

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