Analytic Review

Journal of Intensive Care Medicine

1-9
Antibiotic Use in the Intensive Care Unit: ª The Author(s) 2018
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Optimization and De-Escalation DOI: 10.1177/0885066618762747
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Maureen Campion, PharmD1, and Gail Scully, MD, MPH1

Abstract
Appropriate antimicrobial therapy is essential to ensuring positive patient outcomes. Inappropriate or suboptimal utilization of
antibiotics can lead to increased length of stay, multidrug-resistant infections, and mortality. Critically ill intensive care patients,
particularly those with severe sepsis and septic shock, are at risk of antibiotic failure and secondary infections associated with
incorrect antibiotic use. Through the initiation of active empiric antibiotic therapy based upon local susceptibilities, daily eva-
luation of signs and symptoms of infection and narrowing of antibiotic therapy when feasible, providers can streamline the
treatment of common intensive care unit (ICU) infections. Optimizing antibiotic dosing through prolonged infusions can be
beneficial in intensive care populations with altered pharmacokinetics. Antimicrobial stewardship teams can assist ICU providers
in managing and implementing these tactics. This review will discuss the current literature on antibiotic use in the ICU applying
antimicrobial stewardship strategies. Based upon the most recent evidence, ICUs would benefit from employing empiric
guidelines for antibiotic use, collecting appropriate specimens and implementing molecular diagnostics, optimizing the dosing of
antibiotics, and reducing the duration of total therapy. These strategies for antibiotic use have the potential to enhance patient
care while preventing adverse outcomes.

Keywords
antimicrobial stewardship, intensive care, antibiotics, antibiotic utilization, critically ill patients, infection

Introduction pharmacokinetics and therefore antibiotic efficacy at the site

Effective antimicrobial therapy is critical for the treatment of
patients in the intensive care unit (ICU), including patients
admitted with severe sepsis, septic shock, and those who
develop health-care-associated infections.1-4 Failure of antibio-
tic therapy can be devastating and can be due to a number of
factors. Empiric therapy that is not active against the infecting
organism, lack of source control, altered volumes of distribution
leading to subtherapeutic serum concentrations of antibiotics,
the development of secondary infections of hospital acquired,
multidrug-resistant microbes, and patient-specific factors such
as immunosuppression are some of the reasons for a poor
response to antibiotic therapy.5-7 Delays in appropriate antimi-
crobial therapy worsen outcomes in critically ill patients.3,8
Multidrug-resistant organisms are increasingly common and are
associated with a longer length of stay, ICU admission, and
higher mortality rates.4,8-10 Providers can take specific steps to
ensure appropriate therapy and limit adverse events. Initiating
effective therapy for infections based upon patients’ risk factors,
collection of appropriate cultures, daily evaluation of clinical
status, and laboratory data, including antibiotic time outs, and
shortened durations of therapy are ways to improve patient out-
comes (see Figure 1).11-16 Special attention should be paid to the
dosing of antimicrobials in the ICU, as fluctuations in fluid
status, organ function, and perfusion can affect antibiotic
of infection.14,17-19 This article reviews the most recent evidence
supporting empiric antibiotic selection, de-escalation strategies,
the importance of optimized antimicrobial doses, and antimicro-
bial stewardships role in the ICU.
Antibiotic Selection and Risk Factors for Resistance in
Critically Ill Patients
Appropriate empiric therapy is key for decreasing the mortality
associated with severe sepsis and septic shock.8,13,14,20 Empiric
antibiotic regimens should be chosen based on local resistance
patterns, the most common pathogens associated with the
known or suspected site of infection and any host factors asso-
ciated with risks of unusual or resistant pathogens.3,21,22
1
Division of Infectious Disease, Department of Medicine, UMass Memorial
Medical Center, Worcester, MA, USA
Received November 15, 2017. Received revised February 07, 2018.
Accepted February 12, 2018.
Corresponding Author:
Gail Scully, Division of Infectious Disease, Department of Medicine, UMass
Memorial Medical Center, 55 lake Ave north Room S7-715, Worcester, MA
01655, USA.
Email: gail.scully@umassmemorial.org
2 Journal of Intensive Care Medicine XX(X)

• Select antibiotics based upon national guidelines and local

susceptibilities

Initiate • Patient specific factors (immunosuppression, indwelling Opmizaon

catheters, allergies)
• Common pathogens for suspected source

• Daily review of clinical signs and symptoms of Ulize

infection
Evaluate • Review of cultures and molecular diagnostics
pharmacokinec/
• Analyze current dosing strategy
pharmacodynamic
principles to
increase cidality

• Narrow therapy based upon cultures

Antimicrobial De-escalate and to minimize adverse events
Stewardship • Consider shorter durations based
upon clinical status

Figure 1. Approach to antibiotic use in the intensive care unit (ICU).

Broad-spectrum therapy should not be confused with empiric
therapy. Broad-spectrum therapy is defined as antibiotic cov-
erage that has extended coverage of gram-negative organisms,
including Pseudomonas subspecies and resistant pathogens,
such as methicillin-resistant Staphylococcus aureus (MRSA).
Administering broad-spectrum therapy is not as important as
administering antimicrobial therapy active against the most
likely pathogens. Hospitals should establish preferred empiric
regimens for specific diseases, taking into consideration local
and national guidelines as well as local antimicrobial suscept-
ibilities.1,2,23 It is recommended to report local susceptibilities
via an antibiogram updated at least yearly and created in col-
laboration with the microbiology laboratory.2 Patient-specific
factors should be considered prior to choosing an antibiotic
regimen. Multiorgan failure, invasive catheters, previous
health-care exposure, antibiotic use, and immunosuppression
may indicate the need for extended organism coverage. 3,24
Sepsis is among the most common reasons for admission to the
ICU and is associated with significant mortality.3,8,25 Although
executing a “sepsis bundle” for timely treatment of sepsis and
prompt administration of antimicrobial therapy has improved
sepsis mortality, appropriate antibiotic choice has shown to be
one of the better predictors of survival.3,8,13,25,26 Simply admin-
istering broad-spectrum antibiotics is not sufficient if the proper
pathogens are not covered based upon suspected location of infec-
tion, previous antibiotic exposure, and the immune-host fac-
tors. 3,27 Antimicrobial therapy should be directed at the
common microbiota of the suspected source of sepsis. Sepsis of
unknown origin requires therapy active against both gram-
negative and gram-positive pathogens. Extended gram-negative
coverage (eg, b-lactam/b- lactamase inhibitors with covering
pseudomonas, third- and -fourth generation cephalosporins and
carbapenems) should be based upon the site of the infection as
well as the patients’ risk factors for resistant gram-negative
organisms, such as exposure to health care, previous antibiotics,
immunosuppressive therapy, and indwelling catheters.21,22,26,28
The need for MRSA coverage is evaluated based upon the site of
infection, specific risk factors, history of MRSA infection, and
rates of MRSA colonization with the institution.2,29,30 Review of
previous inpatient admissions and prior cultures can assist in
determining the most appropriate empiric therapy.7,28
A prospective study conducted on hospitalized septic and
nonseptic community-acquired pneumonia evaluated patients’
length of stay and mortality. Those achieving appropriate anti-
biotic therapy (b-lactam plus a macrolide) and oxygen supple-
mentation within 6 hours had reduced mortality.26 In the 2016
update of the Hospital Associated Pneumonia and Ventilator
Associated Pneumonia guidelines from Infectious Diseases
Society of America and American Thoracic Society, the cate-
gory of health-care-associated pneumonia was removed.
Health-care-associated pneumonia risk factors are overly broad
and misclassify one-third of patients.18,31,32 Instead, prior intra-
venous antibiotic use, poor functional status, and comorbidities
are more likely to be associated with resistant bacterial infec-
tions than nursing home residence alone.30-32 Providers are
encouraged to evaluate these risk factors for multidrug-
resistant organisms rather than determining therapy based
solely on preadmission residence.
For intra-abdominal infections (IAIs), length of hospital stay
or health-care exposure, recent antibiotic use, and postopera-
tive infection are associated with worse outcomes and nosoco-
mial pathogens.33 Intra-abdominal empiric therapy should
cover the most common pathogens, including enteric gram
negatives. Antibiotic regimens should take into account enter-
obacteriaceae resistance patterns.33 Treatment regimens should
include gram-positive coverage; however, most enterococci
and Staphylococcus aureus in intra-abdominal infections are
b-lactam susceptible and multidrug-resistant therapy such as
vancomycin or linezolid may not be needed.34 Anaerobic cov-
erage is not necessarily required for mild–moderate infections
Campion and Scully
involving the biliary tree.35 Most intra-abdominal infections
are polymicrobial and require source control for the best out-
comes.36 In some instances, such as severe or necrotizing pan-
creatitis without documented infection or uncomplicated
diverticulitis, antibiotic therapy may not be required. Recent
studies suggest antibiotic use in these 2 latter instances does not
improve clinical outcomes and should not be done routi-
nely.33,37-39
With the growing concern for gram-negative resistance
and reduced susceptibilities, utilizing 2 antibiotics with dif-
ferent mechanisms of action for empiric treatment of infec-
tion will likely become more important, especially in areas
of higher bacterial resistance.6,24 Dual gram-negative cover-
age typically includes a b-lactam plus an aminoglycoside or
fluoroquinolone. This dual coverage is recommended when
anti-pseudomonal b-lactam agents demonstrate <90% sus-
ceptibility for local isolates.18 Treatment with a b-lactam and
aminoglycoside has been shown to more effectively provide
empiric coverage when compared to b-lactams as monother-
apy or with adjunctive fluoroquinolone use.6 Dual antibiotic
therapy is preferred to empiric carbapenem therapy to pre-
serve carbapenem activity.2,40 A multicenter severe sepsis
analysis conducted in Spain showed the potential benefit of
dual gram-negative coverage in preventing mortality (101
deaths vs 577 survivors, odds ratio [OR]: 1.8 [95% confi-
dence interval: 1.4-2.3; P ¼ <.0001]).41 The majority of
patients received a b-lactam in combination with a fluoro-
quinolone, an aminoglycoside, or azithromycin, respectively.
The greatest benefit for dual therapy is in patients with
nosocomial infections, who are more likely to harbor
multidrug-resistant pathogens.8,13
Initiating appropriate empiric antibiotic therapy based upon
the likely source and typical pathogens as well as patient-
specific risk factors can improve patients’ care in the ICU.
Clinical Evaluation Through Laboratory Diagnostics
Appropriate collection of cultures and the use of biomarkers
can facilitate optimal antibiotic therapy and more effective,
targeted treatment of infections. Gram stain and culture, mole-
cular diagnostics, and procalcitonin are a few tools that can
strengthen providers’ ability to manage antibiotics.
The utility of Gram stains in predicting culture results and
directing therapy is problematic due to inherent concerns
regarding the reproducibility of slide preparation and interpre-
tation. The limited value of the Gram stain has led to empiric
broad-spectrum antibiotic therapy for up to 5 days, as
providers wait for final culture results using routine
techniques.42,43Although Gram stain prediction of pathogenic
organisms is limited, the negative predictive value of the Gram
stain may be useful to providers. In a multicenter randomized-
controlled trial, Albert et al evaluated the relationship between
Gram stain and culture results in endotracheal aspirate and
bronchoalveolar lavage in ventilator-associated pneumonia.
The lack of gram-positive organism visible on Gram stain in
endotracheal aspirates had a 93% negative predictive value
3
(NPV) for gram-positive pneumonia, while the absence of
gram-negative organisms had an 81% negative predictive value
in this study.44 No difference was observed between Gram stain
and culture findings when comparing specimens from endotra-
cheal aspirate and bronchoalveolar lavage. A similar negative
predictive value has been seen in patients admitted after trauma
who develop ventilator-associated pneumonia (Gram-positive
NPV : 83%).45
Molecular diagnostics are a novel and increasingly available
set of tools to reduce time to directed therapy and identify
resistant organisms rapidly. These new technologies analyze
the nucleic acids of bacteria, viruses, and parasites for organ-
ism identification and for common mechanisms of resistance.
Molecular diagnostics are often called “rapid diagnostics,” as
they can report organisms, mechanisms of resistance, and sus-
ceptibility hours to days faster compared to standard microbiol-
ogy testing.9,23,46 Current molecular diagnostics and those in
development have the ability to revolutionize the time to appro-
priate antibiotic therapy in critically ill patients. The diagnos-
tics can be performed on multiple specimen types including
nasal swabs, blood, cerebrospinal fluid, and stool, detecting
both gram-negative and gram-positive pathogens.47 They can
facilitate faster time to the most active therapy for severe
infections, such Staphylococcus aureus bacteremia.48,49 In
gram-negative bacteremia, molecular diagnostics have assisted
providers in escalating therapy when resistance mechanisms
are present.9,50 After the implementation of gram-negative
assays for blood cultures, Walker and colleagues were able to
decrease time to active therapy for extend spectrum producing
b-lactamase organisms from 41.4 hours to 7.3 hours.50 In the
absence of a sputum culture, an MRSA polymerase chain reac-
tion (PCR) of the nares undertaken in the first 48 hours of
hospitalization can help to evaluate the need for empiric
vancomycin or linezolid use in at-risk patients admitted with
pneumonia.29,30,51 The strong negative predictive value of the
MRSA PCR (>90%) greatly diminishes the likelihood that
MRSA is the causative agent of bacterial pneumonia. However,
the positive predictive value of this test is only 35% to 50%.
When compared to standard culture and susceptibility via auto-
mated systems, molecular assays demonstrate concordant
results >90% of the time.46 These techniques combined with
a review of therapy by an antimicrobial stewardship team has
shown a significant decrease in time to directed antibiotic ther-
apy (postmolecular assay: 53 + 41 hours vs premolecular
assay: 82 + 48 hours; P < .001).23 A reduced length of stay
has been demonstrated by some but not all studies using rapid
molecular diagnostic techniques.52,53 It is essential that rapid
diagnostics are combined with stewardship and provider edu-
cation to actively direct therapy. These interventions can be
cost saving through shorter length of ICU stay and decreased
cost of empiric antibiotic regimens.29,30,50
Once appropriate therapy is identified, the biomarker pro-
calcitonin can be used to aid in decisions about duration of
antibiotic therapy. Procalcitonin levels rise in the presence
of bacterial infections but stay relatively normal in the presence
of nonbacterial infections.54 Trending serum procalcitonin
4 Journal of Intensive Care Medicine XX(X)
levels can lead to a decreased length of therapy without increas-
ing the risk of worsening infection or mortality.54,55 The “Stop
Antibiotics on Procalcitonin Guidance Study” was a prospec-
tive, multicenter, randomized study evaluating the use of pro-
calcitonin in the intensive care setting. In the experimental
group, procalcitonin was measured daily while in the ICU or
for 3 days postantibiotic therapy. Providers were encouraged to
discontinue antibiotics if the procalcitonin level had decreased
by 80% from peak value or was <0.5 mg/mL. The experimental
group received fewer defined daily doses (7.5 vs 9.3) on aver-
age compared to the standard group. Mortality was lower in the
procalcitonin group (20% vs 25%, absolute difference 5.4%
[confidence interval, CI: 1.2-9.5; P ¼ .0122]).55 Although pro-
calcitonin can be useful for shortening antibiotic courses, it is
reasonable to weigh the cost of the test against cost savings of
fewer days of antibiotic therapy. The cost of preventing adverse
drugs reactions (eg, acute kidney injury) and less antibiotic
resistance due to these fewer days of antibiotics is more diffi-
cult to evaluate. Utilization of procalcitonin levels in the ICU
setting is only beneficial when the information is used to make
a clinical decision.55 Additional studies have been completed
evaluating procalcitonin’s ability to predict infection and mor-
tality.56 This correlation is limited, and further research is
needed. Collection and daily review of culture and laboratory
data can facilitate more appropriate antibiotic use and perhaps
assist in discontinuing antibiotics for clinically improving
patients.
Optimization and Duration
A pillar of antimicrobial stewardship is deescalation of empiric
antibiotics based upon culture results and daily clinical assess-
ment. As further clinical information develops regarding a
patient in the ICU, thoughts should turn to ways to narrow or
deescalate or indeed stop antibiotic therapy. Longer antibiotic
courses (7-14 days) of overly broad therapy do not necessarily
improve patient outcomes and may well lead to increased risk
of multidrug-resistant organisms, adverse events such as Clos-
tridium difficile infections, and higher health-care costs.57-60
Turza et al reviewed 2658 patients admitted to a surgical
ICU with lung, abdominal, or urinary tract infections. Patients
were retrospectively evaluated for deescalation of therapy
based upon cultures or clinician discretion. Antibiotic deesca-
lation was not associated with increased mortality rates (9%
without deescalation vs 6% in the de-escalation group;
P ¼ .002). Higher mortality was seen in the nondeescalated
group which was likely due to the severity of the underlying
disease and increased comorbidities. For clinically improving,
immunocompetent patients’ deescalation does not seem to
worsen outcomes and may possibly prevent adverse events.61
To better evaluate barriers and consequences to deescalation in
intra-abdominal infections, Montravers et al reviewed post-
operative peritonitis cases in the ICU.12,57 Therapy was tailored
based upon surgical cultures and antibiotic susceptibilities at
approximately day 3 of therapy. Adequate empiric therapy was
most closely associated with the ability to deescalate, while
cultures growing nonlactose-fermenting gram-negative bacilli
and multidrug-resistant bacteria were less likely to be deesca-
lated. There was no appreciable difference in severity of illness
at the time of ICU admission among patients who had deesca-
lation of antibiotic therapy (SOFA score: 7 vs 9, respectively).
Changes in SOFA scores between day 3 and day 7 of ICU stay
were similar between the deescalation group and no-
deescalation group (1 vs 2). Survival rate was similar in
both the groups (Kaplan Meier log-rank test; P ¼ .176).
Although there is limited evidence showing deescalation pre-
vents the emergence of resistant organisms, many studies have
shown narrowing antibiotic therapy does not adversely affect
patient outcomes.53,62,63
In addition to deescalation of antibiotic therapy, duration of
therapy should be limited to reduce adverse events and health-
care-associated infections. Many recent clinical studies and
meta-analyses on common infectious diseases states have
shown that shorter therapy is as efficacious as longer ther-
apy.64-66 These were not all completed in ICUs but do show
the trend of reducing antibiotic therapy for clinically improving
patients. The Short Course Antimicrobial Therapy for Intra-
abdominal Infection (STOP-IT) trial evaluated a predetermined
length of antibiotic therapy versus standard practice for anti-
microbial treatment of intra-abdominal infections. In patients
who had achieved source control through surgical intervention
or noninvasive intervention, there was no difference in out-
comes comparing a 4-day course to usual care (8 days).33,60
The University of Virginia determined intra-abdominal infec-
tions with longer courses of antibiotics had an increased like-
lihood of secondary extra-abdominal infection (EAI; EAI days
of therapy vs no EAI days of therapy: 14 vs 11; P < .01) and
mortality (EAI vs no EAI: 14.9% vs 9.0%; P < .01).67 Chastre
and colleagues completed a prospective randomized trial on
ventilator-associated pneumonia comparing 8 to 15 days of
therapy. Patients receiving shorter courses of therapy were less
likely to have resistant pathogens in recurrent pulmonary infec-
tions; there was no difference in mortality (18.8% with 8 days
vs 17.2% with 15 days, risk difference 1.6 [95% CI: 3.7 to
6.9; P ¼ .41]) or length of ICU stay (30 days for 8-day treat-
ment vs 27.5 days for 15-day treatment; mean between group
difference 2.5 [95% CI: 0.7 to 5.2]).58 In some instances,
therapy as short as 5 days has been used to treat hospital-
associated pneumonia and as short as 3 days for community-
acquired pneumonia.59,65
Providers should be encouraged to reduce total length of
therapy and deescalate antibiotics during the ICU course as
supported by many clinical studies. This evaluation of the treat-
ment has the potential to reduce health-care costs without nega-
tively impacting patient care while also lessening the risk of
adverse drug events.
Pharmacokinetics and Pharmacodynamics
Considerations in Critically Ill Patients
Due to fluid shifts, hyperdynamic state, and multiple other
factors seen in critically ill patients, dosing of antibiotics can
Campion and Scully
be challenging in the ICU. Pharmacokinetics and pharmacody-
namics can fluctuate significantly in ICU patients. A compre-
hensive discussion of the complexity of dosing in critical
illness is beyond the scope of this article but has been discussed
elsewhere.5,14,68 The fluctuation in attainable levels at the site
of infection is influenced by the pharmacokinetic properties
(absorption, distribution, metabolism, and elimination) of the
antimicrobial class. b-lactams and aminoglycosides are hydro-
philic molecules with lower volumes of distribution extracel-
lularly, thus concentrations can significantly change along with
fluid shifts. The levels of lipophilic antibiotics such as fluor-
oquinolones and macrolides are less affected by changes in
fluid status.5 Larger antibiotic doses may be required for
patients with pleural effusions, ascites, large volume fluid ther-
apy, edematous states, postsurgical drains, hypoalbuminemia,
and extracorporeal membrane oxygenation as these reflect
changes in extracellular fluid.5 Active drug abuse, burns,
hyperdynamic states associated with sepsis, and b-agonists
administration (dopamine, dobutamine) can increase clearance
of antimicrobials. Renally eliminated antibiotics will require
adjustment in the setting of poor renal function, dialysis, and
vasopressors. Altered or augmented elimination, both renal and
hepatic, should be taken into account when selecting a
maintenance-dosing regimen.
Optimization of dosing strategies is particularly important to
clinical and microbiological success. 14,24,69 The pharmacody-
namic parameter most closely associated with efficacy of
b-lactam antibiotics is the time the serum level of the drug is
above mean inhibitory concentration (MIC) for an organism.
For fluoroquinolones and aminoglycosides, optimizing a peak
serum level above the MIC is associated with the greatest cid-
ality.19,70 There has been a concentrated effort to develop new
antimicrobials, but none currently in development will be a
clear solution to antimicrobial resistance.71 Therefore, utiliza-
tion of less commonly used antibiotics (eg, colistin) and alter-
nate dosing strategies (eg, extended infusion) of currently
available antibiotics is needed to maintain activity against
resistant pathogens. Studies in ICUs have demonstrated
extended (3-4 hours) or continuous (24 hour) infusions of
b-lactam antibiotics have equivalent or improved outcomes
compared to intermittent (0.5-1 hour) infusions without
increased adverse events.72 Cefepime extended infusions,
administered over 3 to 4 hours, were shown to significantly
decrease mortality (20% in intermittent infusion vs 3% in
extended infusion; P ¼ .03) and ICU length of stay (18.5 days
for intermittent infusion vs 8 days extended infusion; P ¼ .04)
for invasive Pseudomonas aeruginosa infections.73 Patients
treated with piperacillin-tazobactam continuous infusions have
had better clinical response when compared to inpatients
treated with intermittent infusions.74 Cost-effectiveness has
varied between institutions, depending on the frequency of
dosing and cost of drug acquisition.14,74,75
Therapeutic drug monitoring (TDM) can be a beneficial
strategy to more accurately dose antibiotics in critically ill
patients.68 Therapeutic drug monitoring involves measuring
the concentrations of drug in patients to assess achievement
5
of pharmacodynamic goals. It is indicated and commonly per-
formed for drugs such as aminoglycosides and vancomycin that
have narrow therapeutic range and high interindividual phar-
macokinetic variability. Economou and colleagues undertook
therapeutic drug monitoring for all patients receiving b-lactams
in an ICU and undergoing continuous renal replacement ther-
apy. Based upon multiple drug levels taken, 25% of patients
required a decrease in dose and 11% of patients required an
increase in their b-lactam dose or frequency.68 A multidisci-
plinary approach to therapeutic drug monitoring should be
taken when available. Vancomycin and aminoglycoside phar-
macy to dose protocols can reduce adverse events such as renal
toxicity and are recommended when feasible.2,76-78 Drug mon-
itoring is not readily available in all clinical settings except for
certain antimicrobials such as aminoglycosides and vancomy-
cin, largely due to concern for toxicity, but should be consid-
ered for intensive care patients with altered hemodynamics. It
is likely that TDM will become more important to avoid under-
dosing in the setting as higher antibiotic resistance.14
An individualized approach should be taken to dosing anti-
biotics in ICU patients, due to their altered volumes of distri-
bution and elimination as well as the risk of antimicrobial
resistance. When available, providers should utilize intensive
care pharmacist to enhance antibiotic regimens.
Antimicrobial Stewardship in the ICU
Antimicrobial stewardship efforts have had varying success in
the ICU. Stewardship teams, made up of infectious disease
physicians and infectious disease pharmacists, can assist in the
evaluation of patients and provide recommendations on opti-
mizing therapy.2 Different strategies can be utilized including
prospective audit and feedback, restricted formularies, guide-
lines and clinical pathways, and education. It is often a com-
bination of all activities that lead to the greatest success.2,79
A multidisciplinary approach, including intensive care physi-
cians, pharmacists, and nurses in addition to infectious disease
trained individuals should be utilized whenever possible.
Empiric therapy guidelines can be useful in aiding ICU practi-
tioners in antibiotic choice.2 To better facilitate deescalation
and reduce total duration of antimicrobial therapy, antibiotic
time outs (ATO) have been implemented at some institu-
tions.1,60,80 Antibiotic time out is a formal process of reevalu-
ating antimicrobial therapy 48 to 72 hours after initiation of
antibiotics based upon a predesigned checklist or notification.
When a formal ATO is implemented, patients receive shorter
courses of therapy and a decrease in antibiotic cost.1 Imple-
mentation of time outs can be completed through face-to-face
interaction, handout surveys, and electronic prompting.16,80,81
Face-to-face interactions appear to have the greatest effect.81,82
Further evaluation of ATO should be done to assess the benefit
to patient outcomes and prevent adverse events. The most con-
sistent success for antimicrobial stewardship interventions is
reduction in days of antibiotic therapy and overall cost of anti-
biotics.11,83,84 More elusive outcomes, such as mortality, length
of stay, and decrease in resistance have shown mixed results,
6 Journal of Intensive Care Medicine XX(X)
often due to the fact that the studies have been completed over
short time frames and in small patient populations. Challenges
often come with the acceptance of recommendations and
changes in therapy. Cultural changes can take time to imple-
ment and maintain. Antimicrobial stewardship interventions
can improve critical thinking and evaluation of antibiotic ther-
apy by clinicians.15,16
Conclusions
The treatment of infection via appropriate antibiotic choice,
molecular diagnostics, duration of therapy and optimal dosing
is of utmost importance to ensure the best possible outcomes
for patients in the ICU. It is important to provide empiric anti-
biotic treatment that will ensure activity against the most likely
pathogens for patients with severe sepsis and septic shock
while avoiding overly broad antimicrobial therapy. If antipseu-
domonal b-lactam resistance is <10% to local gram-negative
pathogens, coverage with 2 antibiotics with differing mechan-
isms of action may be necessary to improve empiric antibiotic
treatment. Escalation of antibiotic therapy is associated with
worse outcomes compared to treating with active agents at the
initiation of the regimen. Once an empiric antibiotic regimen is
chosen, ongoing characterization of the patients’ clinical status
and review of test results should be done to evaluate antibiotic
regimens for necessary changes. As new molecular methods for
identification and antibiotic susceptibility become more widely
available, this is likely to lead to improved treatment outcomes.
Using the shortest effective course of antibiotic therapy
decreases antibiotic pressure that can lead to resistance,
decreases the risk of adverse effects, and can allow preserva-
tion and recovery of the microbiome. Therapeutic drug moni-
toring is likely to become more important over time as resistant
bacteria become more common and harder to treat. Antimicro-
bial stewardship should be available to the ICU to enhance
antimicrobial therapy. Intelligent use of our antibiotic regimens
could potentially help slow antibiotic resistance that threatens
our ability to care for our patients.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
References
1. CDC. CDC Core Elements of Hospital Antibiotic Stewardship
Programs. US Dep Heal Hum Serv CDC. https://www.cdc.gov/
antibiotic-use/healthcare/implementation/core. Updated February
2017. Accessed September 2017.
2. Barlam TF, Cosgrove SE, Abbo LM, et al. Executive summary:
implementing an antibiotic stewardship program: guidelines by
the infectious diseases society of America and the society for
healthcare epidemiology of America. Clin Infect Dis. 2016;
62(10):1197-1202. doi:10.1093/cid/ciw217.
3. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Cam-
paign: International Guidelines for Management of Sepsis and
Septic Shock: 2016. Vol. 43. Berlin, Heidelberg: Springer; 2017.
4. Elizhauser A, Friedman BSE. Septicemia in U.S. Hospitals, 2009.
HCUP Statistical Brief #122. 2011. http://www.hcup-us.ahrq.gov/
reports/statbriefs/sb122.pdf%0D. Updated October 2011.
Accessed September 2017.
5. Pea F, Viale P, Furlanut M. Antimicrobial therapy in critically Ill
patients altered disposition and pharmacokinetic variability. Clin
Pharmacokinet. 2005;44(10):1009-1034.
6. Micek ST, Welch EC, Khan J, et al. Empiric combination anti-
biotic therapy is associated with improved outcome against sepsis
due to gram-negative bacteria: a retrospective analysis. Antimi-
crob Agents Chemother. 2010;54(5):1742-1748. doi:10.1128/
AAC.01365-09.
7. Shindo Y, Ito R, Kobayashi D, et al. Risk factors for drug-resistant
pathogens in community-acquired and healthcare-associated
pneumonia. Am J Respir Crit Care Med. 2013;188(8):985-995.
doi:10.1164/rccm.201301-0079OC.
8. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension
before initiation of effective antimicrobial therapy is the critical
determinant of survival in human septic shock. Crit Care Med.
2006;34(6):1589-1596. doi:10.1097/01.CCM.0000217961.
75225.E9.
9. Hill JT, Tran KDT, Barton KL, Labreche MJ, Sharp SE. Evalua-
tion of the Nanosphere Verigene BC-GN assay for direct identi-
fication of gram-negative bacilli and antibiotic resistance markers
from positive blood cultures and potential impact for more-rapid
antibiotic interventions. J Clin Microbiol. 2014;52(10):
3805-3807. doi:10.1128/JCM.01537-14.
10. Kaye KS, Pogue JM. Infections caused by resistant gram-negative
bacteria: epidemiology and management. Pharmacotherapy.
2015;35(10):949-962. doi:10.1002/phar.1636.
11. Ramawi RH, Mazer MA, Siraj DS, Gooch MMS CP. Impact of
regular collaboration between infectious diseases and critical care
practitioners on antimicrobial utilization and patient outcome.
Crit Care Med. 2013;41(9):2099-2107. doi:10.1097/CCM.
0b013e31828e9863.
12. Tabah A, Cotta MO, Garnacho-Montero J, et al. A systematic
review of the definitions, determinants, and clinical outcomes
of antimicrobial de-escalation in the intensive care unit. Clin
Infect Dis. 2016;62(8):1009-1017. doi:10.1093/cid/civ1199.
13. Leibovici L, Drucker M, Konigsberger H, et al. Septic shock in
bacteremic patients: risk factors, features and prognosis. Scand J
Infect Dis. 1997;29(1):71-75. doi:10.3109/00365549709008668.
14. Rizk NA, Kanafani ZA, Tabaja HZ, Kanj SS. Extended infusion
of b-lactam antibiotics: optimizing therapy in critically-ill
patients in the era of antimicrobial resistance. Expert Rev Anti
Infect Ther. 2017;15(7):645-652. doi:10.1080/14787210.2017.
1348894.
15. Jones M, Butler J, Graber CJ, et al. Think twice: a cognitive
perspective of an antibiotic timeout intervention to improve anti-
biotic use. J Biomed Inform. 2017;71S:S22-S31. doi:10.1016/j.
jbi.2016.06.005.
Campion and Scully
16. Graber CJ, Jones MM, Glassman PA, et al. Taking an antibiotic
time-out: utilization and usability of a self-stewardship time-out
program for renewal of vancomycin and piperacillin-tazobactam.
Hosp Pharm. 2015;50(11):1011-1024. doi:10.1310/hpj5011-
1011.
17. Pea F, Viale P. Bench-to-bedside review: appropriate antibiotic
therapy in severe sepsis and septic shock—does the dose matter?
Crit Care. 2009;13(3):214. doi:10.1186/cc7774.
18. Kalil AC, Metersky ML, Klompas M, et al. Management of adults
with hospital-acquired and ventilator-associated pneumonia: 2016
clinical practice guidelines by the infectious diseases society of
america and the american thoracic society. Clin Infect Dis. 2016;
63(5): e61-e111. doi:10.1093/cid/ciw353.
19. Ambrose PG, Bhavnani SM, Rubino CM, et al. Pharmacokinetics-
pharmacodynamics of antimicrobial therapy: it’s not just for mice
anymore. Clin Infect Dis. 2007;44(1):79-86. doi:10.1086/510079.
20. Vallés J, Rello J, Ochagavı́a A, Garnacho J, Alcalá MA.
Community-acquired bloodstream infection in critically III adult
patients: impact of shock and inappropriate antibiotic therapy on
survival. Chest. 2003;123(5):1615-1624. doi:10.1378/chest.123.
5.1615.
21. Vasudevan A, Mukhopadhyay A, Goh EYY, Li J, Tambyah PA.
Risk factors for infection/colonization caused by resistant Gram
negative bacilli in critically ill patients (an observational study of
1633 critically ill patients). Prev Med. 2013;(57 Suppl):S70-S73.
doi:10.1016/j.ypmed.2012.12.003.
22. Razazi K, Mekontso Dessap A, Carteaux G, et al. Frequency,
associated factors and outcome of multi-drug-resistant intensive
care unit-acquired pneumonia among patients colonized with
extended-spectrum b-lactamase-producing Enterobacteriaceae.
Ann Intensive Care. 2017;7(1):61. doi:10.1186/s13613-017-
0283-4.
23. Neuner EA, Pallotta AM, Lam SW, et al. Experience with rapid
microarray-based diagnostic technology and antimicrobial stew-
ardship for patients with gram-positive bacteremia. Infect Con-
trol Hosp Epidemiol. 2016;37(11):1361-1366. doi:10.1017/ice.
2016.175.
24. Petrosillo N, Capone A, Di Bella S, Taglietti F. Management of
antibiotic resistance in the intensive care unit setting. Expert Rev
Anti Infect Ther. 2010;8(3):289-302. doi:10.1586/eri.10.7.
25. Rivers E, Nguyen B, Havstad S, et al; Early goal-directed therapy
collaborative group. Early goal-directed therapy in the treatment
of severe sepsis and septic shock. N Engl J Med. 2001;345(19):
1368-1377. doi:10.1056/NEJMoa010307.
26. Menéndez R, Torres A, Reyes S, et al. Initial management of
pneumonia and sepsis: factors associated with improved outcome.
Eur Respir J. 2012;39(1):156-162. doi:10.1183/09031936.
00188710.
27. Septimus EJ, Coopersmith CM, Whittle J, Hale CP, Fishman NO,
Kim TJ. Sepsis national hospital inpatient quality measure
(SEP-1): multistakeholder work group recommendations for
appropriate antibiotics for the treatment of sepsis. Clin Infect Dis.
2017;65(9):1565-1569. doi:10.1093/cid/cix603.
28. Jinno S, Chang S, Donskey CJ. A negative nares screen in com-
bination with absence of clinical risk factors can be used to iden-
tify patients with very low likelihood of methicillin-resistant
7
Staphylococcus aureus infection in a Veterans Affairs hospital.
Am J Infect Control. 2012;40(9):782-786. doi:10.1016/j.ajic.
2011.10.010.
29. Dangerfield B, Chung A, Webb B, Seville MT. Predictive value
of methicillin-resistant Staphylococcus aureus (MRSA) nasal
swab PCR assay for MRSA pneumonia. Antimicrob Agents Che-
mother. 2014;58(2):859-864. doi:10.1128/AAC.01805-13.
30. Chalmers JD, Rother C, Salih W, Ewig S. Healthcare-associated
pneumonia does not accurately identify potentially resistant
pathogens: a systematic review and meta-analysis. Clin Infect Dis.
2014;58(3):330-339. doi:10.1093/cid/cit734.
31. Shorr AF, Zilberberg MD, Micek ST, Kollef MH. Prediction of
infection due to antibiotic resistant bacteria by select risk factors
for health care-associated pneumonia. Arch Intern Med. 2008;
168(20):2205-2210. doi:10.1001/archinte.168.20.2205.
32. Attridge RT, Frei CR, Pugh MJ, et al. Health Care associated
pneumonia in the intensive care unti: guideline-concordant anti-
biotics and outcomes. J Crit Care. 2016;36:265-271.
33. Mazuski JE, Tessier JM, May AK, et al. The surgical infection
society revised guidelines on the management of intra-abdominal
infection. Surg Infect (Larchmt). 2017;18(1):1-76. doi:10.1089/
sur.2016.261.
34. De Waele J, Lipman J, Sakr Y, et al. Abdominal infections in the
intensive care unit: characteristics, treatment and determinants of
outcome. BMC Infect Dis. 2014;14(1):420. doi:10.1186/1471-
2334-14-420.
35. Westphal JF BJ. Biliary tract infections: a guide to drug treatment.
Drugs. 1999;57(1):81-91.
36. Dupont H. The empiric treatment of nosocomial intra-abdominal
infections. Int J Infect Dis. 2007;11(suppl 1):S1-S6. doi:10.1016/
S1201-9712(07)60001-0.
37. Jiang K. Present and future of prophylactic antibiotics for severe
acute pancreatitis. World J Gastroenterol. 2012;18(3):279. doi:
10.3748/wjg.v18.i3.279.
38. de Vries AC, Besselink MGH, Buskens E, et al. Randomized
controlled trials of antibiotic prophylaxis in severe acute pancrea-
titis: relationship between methodological quality and outcome.
Pancreatology. 2017;7(6-5):531-538. doi:10.1159/000108971.
39. de Korte N, Kuyvenhoven JP, van der Peet DL, Felt-Bersma RJ,
Cuesta MA, Stockmann HBAC. Mild colonic diverticulitis can be
treated without antibiotics. A case–control study. Color Dis.
2012;14(3):325-330. doi:10.1111/j.1463-1318.2011.02609.x.
40. Rahal JJ, Urban C, Segal-Maurer S. Nosocomial antibiotic resis-
tance in multiple gram-negative species: experience at one hos-
pital with squeezing the resistance balloon at multiple sites. Clin
Infect Dis. 2002;34(4):499-503. doi:10.1086/338639.
41. Martı́nez JA, Cobos-Trigueros N, Soriano A, et al. Influence of
empiric therapy with a b-lactam alone or combined with an ami-
noglycoside on prognosis of bacteremia due to gram-negative
microorganisms. Antimicrob Agents Chemother. 2010;54(9):
3590-3596. doi:10.1128/AAC.00115-10.
42. Samuel LP, Balada-Llasat JM, Harrington A, Cavagnolo R. Mul-
ticenter assessment of gram stain error rates. J Clin Microbiol.
2016;54(6):1442-1447. doi:10.1128/JCM.03066-15.
43. Blot F, Raynard B, Chachaty E, Tancrède C, Antoun S, Nitenberg
G. Value of gram stain examination of lower respiratory tract
8 Journal of Intensive Care Medicine XX(X)
secretions for early diagnosis of nosocomial pneumonia. Am J
Respir Crit Care Med. 2000;162(5):1731-1737. doi:10.1164/
ajrccm.162.5.9908088.
44. Albert M, Friedrich JO, Adhikari NKJ, Day AG, Verdant C, Hey-
land DK. Utility of gram stain in the clinical management of
suspected ventilator-associated pneumonia. Secondary analysis
of a multicenter randomized trial. J Crit Care. 2008;23(1):
74-81. doi:10.1016/j.jcrc.2008.01.004.
45. Davis KA, Eckert MJ, Reed RL II, et al. Ventilator-associated
pneumonia in injured patients: do you trust your gram’s stain?
J Trauma-Injury Infect Crit Care. 2005;58(3):462-467.
46. Marschal M, Bachmaier J, Autenrieth I, Oberhettinger P, Will-
mann M, Peter S. Evaluation of the accelerate PhenoTM system for
fast identification and antimicrobial susceptibility testing from
positive blood culture in Gram-negative bloodstream infection.
J Clin Microbiol. 2017;55(7):2116-2126. doi:10.1128/JCM.
00181-17.
47. Administration F and D. Nucleic Acid Based Test. https://www.
fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitro
Diagnostics/ucm330711.htm. Accessed December 11, 2017.
48. Romero-Gómez MP, Cendejas-Bueno E, Garcı́a Rodriguez J,
Mingorance J. Impact of rapid diagnosis of Staphylococcus aur-
eus bacteremia from positive blood cultures on patient manage-
ment. Eur J Clin Microbiol Infect Dis. 2017;36(12):2469-2473.
doi: https://doi.org/10.1007/s10096-017-3086-5.
49. Clerc O, Prod’hom G, Senn L, et al. Matrix-assisted laser deso-
rption ionization time-of-flight mass spectrometry and PCR-
based rapid diagnosis of Staphylococcus aureus bacteraemia. Clin
Microbiol Infect. 2014;20(4):355-360. doi:10.1111/1469-0691.
12329.
50. Walker T, Dumadag S, Lee CJ, et al. Clinical impact after labora-
tory implementation of the Verigene gram-negative bacteria
microarray for positive blood cultures. J Clin Microbiol. 2016;
54(7):1789-1796. doi:10.1128/JCM.00376-16.
51. Minejima E, Lou M, Nieberg P, Wong-Beringer A. Patients pre-
senting to the hospital with MRSA pneumonia: differentiating
characteristics and outcomes with empiric treatment. BMC Infect
Dis. 2014;14(1):252. doi:10.1186/1471-2334-14-252.
52. Roshdy DG, Tran A, LeCroy N, et al. Impact of a rapid
microarray-based assay for identification of positive blood cul-
tures for treatment optimization for patients with streptococcal
and enterococcal bacteremia. J Clin Microbiol. 2015;53(4):
1411-1414. doi:10.1128/JCM.00104-15.
53. Sango A, McCarter YS, Johnson D, Ferreira J, Guzman N, Jan-
kowski CA. Stewardship approach for optimizing antimicrobial
therapy through use of a rapid microarray assay on blood cultures
positive for enterococcus species. J Clin Microbiol. 2013;51(12):
4008-4011. doi:10.1128/JCM.01951-13.
54. Bouadma L, Luyt C-E, Tubach F, et al. Use of procalcitonin to
reduce patients’ exposure to antibiotics in intensive care units
(PRORATA trial): a multicentre randomised controlled trial.
Lancet. 2017;375(9713):463-474. doi:10.1016/S0140-6736(09)
61879 -1.
55. de Jong E, van Oers JA, Beishuizen A, et al. Efficacy and safety of
procalcitonin guidance in reducing the duration of antibiotic treat-
ment in critically ill patients: a randomised, controlled, open-label
trial. Lancet Infect Dis. 2016;16(7):819-827. doi:10.1016/S1473-
3099(16)00053-0.
56. Heredia-Rodrı́guez M, Bustamante-Munguira J, Lorenzo M, et al.
Procalcitonin and white blood cells, combined predictors of infec-
tion in cardiac surgery patients. J Surg Res. 2017;212:187-194.
doi:10.1016/j.jss.2017.01.021.
57. Montravers P, Augustin P, Grall N, et al. Characteristics and out-
comes of anti-infective de-escalation during health care-
associated intra-abdominal infections. Crit Care. 2016;20(1):83.
doi:10.1186/s13054-016-1267-8.
58. Chastre J, Wolff M, Fagon J-Y, et al. Comparison of 8 vs 15 days
of antibiotic therapy for ventilator-associated pneumonia in
adults. Jama. 2003;290(19):2588. doi:10.1001/jama.290.19.2588.
59. Pugh RJ, Cooke RPD, Dempsey G. Short course antibiotic ther-
apy for gram-negative hospital-acquired pneumonia in the criti-
cally ill. J Hosp Infect. 2010;74(4):337-343. doi:10.1016/j.jhin.
2009.10.009.
60. Sawyer RG, Claridge JA, Nathens AB, et al. Trial of short-course
antimicrobial therapy for intraabdominal infection. N Engl J Med.
2015;372(21):1996-2005. doi:10.1056/NEJMoa1411162.
61. Turza KC, Politano AD, Rosenberger LH, Riccio LM, McLeod
M, Sawyer RG. De-escalation of antibiotics does not increase
mortality in critically ill surgical patients. Surg Infect (Larchmt).
2016;17(1):48-52. doi:10.1089/sur.2014.202.
62. Daneman N, Rishu AH, Xiong W, et al. Bacteremia antibiotic
length actually needed for clinical effectiveness (BALANCE):
study protocol for a pilot randomized controlled trial. Trials.
2015;16(1):173. doi:10.1186/s13063-015-0688-z.
63. Pasquau J, de Jesus ES, Sadyrbaeva S, Aznarte P, Hidalgo-
Tenorio C. The reduction in duration of antibiotic therapy as a
key element of antibiotic stewardship programs. J Antimicrob
Agents. 2015;1(1):1-6. doi:10.4172/2472-1212.1000103.
64. Havey TC, Fowler RA, Daneman N. Duration of antibiotic ther-
apy for bacteremia: a systematic review and meta-analysis. Crit
Care. 2011;15(6): R267. doi:10.1186/cc10545.
65. el Moussaoui R. Effectiveness of discontinuing antibiotic treat-
ment after three days versus eight days in mild to moderate-severe
community acquired pneumonia: randomised, double blind study.
Bmj. 2006;332(7554):1355.. doi:10.1136/bmj.332.7554.1355.
66. Hayashi Y, Paterson DL. Strategies for reduction in duration of
antibiotic use in hospitalized patients. Clin Infect Dis. 2011;
52(10):1232-1240. doi:10.1093/cid/cir063.
67. Riccio LM, Popovsky KA, Hranjec T, et al. Association of exces-
sive duration of antibiotic therapy for intra-abdominal infection
with subsequent extra-abdominal infection and death: a study of
2,552 consecutive infections. Surg Infect (Larchmt). 2014;15(4):
417-424. doi:10.1089/sur.2012.077.
68. Economou CJP, Wong G, McWhinney B, Ungerer JPJ, Lipman J,
Roberts JA. Impact of b-lactam antibiotic therapeutic drug mon-
itoring on dose adjustments in critically ill patients undergoing
continuous renal replacement therapy. Int J Antimicrob Agents.
2017;49(5):589-594. doi:10.1016/j.ijantimicag.2017.01.009.
69. Fish DN, Ohlinger MJ. Antimicrobial resistance: factors and out-
comes. Crit Care Clin. 2006;22(2):291-311. doi:10.1016/j.ccc.
2006.02.006.
Campion and Scully
70. Craig WA. State-of-the-art clinical article: pharmacokinetic/phar-
macodynamic parameters: rationale for antibacterial dosing of
mice and men. Clin Infect Dis. 1998;26(1):1-10. doi:10.1086/
516284.
71. Boucher HW, Talbot GH, Benjamin DK, et al. 10 x ‘20 Progress–
development of new drugs active against gram-negative bacilli:
an update from the infectious diseases society of America. Clin
Infect Dis. 2013;56(12):1685-1694. doi:10.1093/cid/cit152.
72. Teo J, Liew Y, Lee W, Kwa AL-H. Prolonged infusion versus
intermittent boluses of b-lactam antibiotics for treatment of acute
infections: a meta-analysis. Int J Antimicrob Agents. 2017;43(5):
403-411. doi:10.1016/j.ijantimicag.2014.01.027.
73. Bauer KA, West JE, O’Brien JM, Goff DA. Extended-infusion
cefepime reduces mortality in patients with Pseudomonas aeru-
ginosa infections. Antimicrob Agents Chemother. 2013;57(7):
2907-2912. doi:10.1128/AAC.02365-12.
74. Grant EM, Kuti JL, Nicolau DP, Nightingale C, Quintiliani R.
Clinical efficacy and pharmacoeconomics of a continuous-
infusion piperacillin-tazobactam program in a large community
teaching hospital. Pharmacotherapy. 2002;22(4):471-483. doi:10.
1592/phco.22.7.471.33665.
75. Goff DA, Nicolau DP. When pharmacodynamics trump costs: an
antimicrobial stewardship program’s approach to selecting opti-
mal antimicrobial agents. Clin Ther. 2013;35(6):766-771. doi:10.
1016/j.clinthera.2013.05.004.
76. Marquis KA, DeGrado JR, Labonville S, Kubiak DW, Szumita
PM. Evaluation of a pharmacist-directed vancomycin dosing and
monitoring pilot program at a tertiary academic medical center.
Ann Pharmacother. 2015;49(9):1009-1014. doi:10.1177/
1060028015587900.
77. Momattin H, Zogheib M, Homoud A, Al-Tawfiq JA. Safety
and outcome of pharmacy-led vancomycin dosing and
9
monitoring. Chemotherapy. 2016;61(1):3-7. doi:10.1159/
000440607.
78. Bond CA, Raehl CL. Clinical and economic outcomes of
pharmacist-managed aminoglycoside or vancomycin therapy.
Am J Heal Pharm. 2005;62(15):1596 LP-1605. http://www.
ajhp.org/content/62/15/1596.abstract.
79. Mertz D, Brooks A, Irfan N, Sung M. Antimicrobial stewardship
in the intensive care setting – a review and critical appraisal of the
literature. Swiss Med Wkly. 2015;(December):1-10. doi:10.4414/
smw.2015.14220.
80. Lee TC, Frenette C, Jayaraman D, Green L, Pilote L. Antibiotic
self-stewardship: trainee-led structured antibiotic time-outs to
improve antimicrobial use. Ann Intern Med. 2014;161(10 suppl):
S53-S58. doi:10.7326/M13-3016.
81. Weiss CH, DiBardino D, Rho J, Sung N, Collander B, Wunderink
RG. A clinical trial comparing physician prompting with an
unprompted automated electronic checklist to reduce empirical
antibiotic utilization. Crit Care Med. 2013;41(11):2563-2569.
doi:10.1097/CCM.0b013e318298291a.
82. Lesprit P, Landelle C, Girou E, Brun-Buisson C. Reassessment of
intravenous antibiotic therapy using a reminder or direct counsel-
ling. J Antimicrob Chemother. 2010;65(4):789-795. doi:10.1093/
jac/dkq018.
83. DiazGranados CA.Prospective audit for antimicrobial steward-
ship in intensive care: impact on resistance and clinical outcomes.
Am J Infect Control. 2017;40(6):526-529. doi:10.1016/j.ajic.
2011.07.011.
84. Elligsen M, Walker SA, Pinto R, Simor A, Mubareka S, Rachilis
ADN. Audit and feedback to reduce broadspectrum antibiotic use
among intensive care unit patients: a controlled interrupted time
series analysis. Infect Control Hosp Epidemiol. 2012;33(4):
354-361. doi: 10.1086/664757.