A n t i m i c ro b i a l S t e w a rd s h i p

A p p ro a c h e s i n t h e
In t en si ve C are U n it
a, b
Sarah B. Doernberg, MD, MAS *, Henry F. Chambers, MD

KEYWORDS
 Antimicrobial stewardship  Antibacterial resistance  Rapid diagnostics
 Clostridium difficile infection  Prospective audit and feedback
 Formulary restriction  Computerized decision support

KEY POINTS
 Antibiotic resistance is a major and growing problem, and antimicrobials are a limited
resource. Antimicrobial stewardship is an approach to improving and monitoring the
use of existing antimicrobials.
 The intensive care unit (ICU) is a unique and high-stakes setting for antimicrobial use that
presents distinct challenges for antimicrobial stewardship programs. This article outlines
approaches to antimicrobial stewardship with a focus on the ICU setting.
 Opportunities for antimicrobial stewardship exist during the diagnosis, empirical treat-
ment, and definitive antimicrobial choice. General approaches and ICU-specific applica-
tion are discussed.
 Both process and outcome measures should be monitored as antimicrobial stewardship
initiatives are implemented in the ICU to demonstrate effectiveness and ensure safety.

CASE PRESENTATIONS
 A 75-year-old man who underwent a Whipple procedure for pancreatic cancer
1 month prior with a rocky postoperative course, including respiratory failure,
shock, upper gastrointestinal bleed, and surgical site infection, develops a new
fever, need for reintubation, and pressor requirement. Blood and urine cultures
are negative and chest radiograph demonstrates bilateral infiltrates, stable

Disclosure Statement: SBD has received research funding from Merck, Genentech, Cerexa, and
Cubist Pharmaceuticals and serves as a consultant to Actelion. HFC has received grant support
from Allergan and Genentech.
a
Division of Infectious Diseases, Department of Medicine, University of California, 513 Parnas-
sus Avenue, Box 0654, San Francisco, CA 94143, USA; b Division of Infectious Diseases, Depart-
ment of Medicine, Zuckerberg San Francisco General Hospital, University of California, Room
3400, Building 30, 1001 Potrero Avenue, San Francisco, CA 94110, USA
* Corresponding author.
E-mail address: sarah.doernberg@ucsf.edu

Infect Dis Clin N Am - (2017) -–-

http://dx.doi.org/10.1016/j.idc.2017.05.002 id.theclinics.com
0891-5520/17/ª 2017 Elsevier Inc. All rights reserved.
2 Doernberg & Chambers

from prior. How should this patient’s antibiotics be managed initially? What tests
are useful to help direct therapy? What antibiotic stewardship strategies are
helpful in this situation?
 A 19-year-old trauma patient is admitted with multiple fractures and a subarach-
noid hemorrhage, now has a fever 4 days after admission. How does one deter-
mine whether this patient has an infectious cause for fever? Does this patient
need antibiotics?
 A 60-year-old lung transplant recipient is admitted from the community with sep-
tic shock. How can one rapidly determine the cause? When is it safe to deesca-
late antibiotics? When can antibiotics be stopped?

BACKGROUND

More than 2 million illnesses and 23,000 deaths occur each year in the United States
due to infections caused by antimicrobial-resistant pathogens, a large burden of which
occur in the intensive care unit (ICU) setting.1,2 Since the discovery of penicillin, there
has been a clear temporal relationship between the introduction of antibiotics into clin-
ical practice and development of resistance.3 Though the antibiotic pipeline has
improved in recent years, new drugs have not kept pace with threatening antibiotic-
resistant organisms.4–6 Antimicrobial stewardship has emerged as a strategy to pre-
serve existing drugs, as well as newly developed drugs, so that these remain effective.
Antimicrobial stewardship refers to an organized program designed to monitor,
improve, and measure the responsible use of antibiotics.7 Though there are many
approaches to antimicrobial stewardship, fundamental strategies include develop-
ment and implementation of facility-specific treatment guidelines, restriction of certain
types of high-risk antibiotics, and review of antibiotic therapy by an infectious disease
(ID) expert (physician or pharmacist) with feedback to providers.8 These programs are
often led by an interdisciplinary team composed of an ID and/or stewardship-trained
physician and pharmacist, who oversee the core actions, monitor antibiotic use, and
provide education for their facility in conjunction with key stakeholders, including cli-
nicians, the microbiology laboratory, hospital infection control, information technology
(IT), quality groups, and executive leadership. First described as far back as the 1970s,
antimicrobial stewardship has grown immensely in past years due to a combination of
increasing attention to patient safety, increasing reports of antibiotic resistance, and
regulatory mandates.9–12 The underlying goal for stewardship programs is to improve
clinical outcomes in individual patients, through improved treatment of infection and
prevention of adverse events, while limiting selective pressure for antimicrobial resis-
tance for the population as a whole and, to the extent possible, decreasing costs.
The ICU is a unique and high-stakes setting for antimicrobial use. Antimicrobial
resistance rates are high, resulting in poor clinical outcomes and high cost.2,13 Inad-
equate initial antimicrobial therapy in the ICU setting is associated with worse out-
comes, which given the prevalence of antimicrobial resistance often results in use
of very broad-spectrum agents in critically ill patients, even when risk factors for resis-
tance are not present.14–17 On the flip side, inappropriate antimicrobial therapy ac-
counts for approximately 30% of prescriptions in the ICU setting, most frequently
for treatment of colonization or contamination, treatment of noninfectious or viral in-
fections, or too-long or too-broad treatment.18,19 The combination of the acuity of
illness in the ICU setting mixed with the high stakes of inadequate initial therapy can
push providers to use antibiotics in inappropriate ways, such as treatment of
community-acquired infections or organisms with very low likelihood of resistance
with overly broad-spectrum agents.20
 Antimicrobial Stewardship Approaches in the ICU 3

The goal of this review article is to provide an overview of strategies and opportu-
nities for stewardship in the ICU setting, from the diagnosis and empirical therapy
for suspected infection to management of confirmed and documented infection.
Although it touches on core elements of stewardship in general, the focus is on appli-
cations specific to the ICU setting.

GENERAL ANTIMICROBIAL STEWARDSHIP APPROACHES

Basic elements of antimicrobial stewardship programs (ASPs) include having a dedi-

cated institutional policy, an interdisciplinary team, members (ideally both MD and
PharmD degrees) with training in antimicrobial stewardship or ID, and monitoring
and reporting of activities (Fig. 1). Core actions of ASPs include7,8
 Facility-specific guidelines based on national guidelines, local antibiogram, and
formulary availability. These can be for particular syndromes such as pneumonia,
individual infections such as Clostridium difficile, or based on certain antimicro-
bials such as guidance on appropriate vancomycin use.
 Prior authorization or restricted formulary (eg, restrictive program): Requirement
that approval is given by the ASP team before release of an antimicrobial.
Restricted agents are generally chosen based on spectrum, cost, and risks of
side effects such as nephrotoxicity.
 Prospective audit and feedback (PAF; eg, persuasive program): Review of pa-
tients on antimicrobials by the ASP with feedback to providers recommending
changes or discontinuation if appropriate. For larger facilities where comprehen-
sive review is impractical, criteria for review can include specific units, certain tar-
geted antimicrobials, or selected diagnoses.
 Automatic stop orders: Having a set date for discontinuation of antimicrobials
that would require an additional order for the drug to be continued.

Pharmacy and
therapeucs
commiee

Quality and
Pharmacy
Safety

ASP
Informaon
Clinical
technology
Services
systems

Hospital
epidemiology
and Infecon
Control

Fig. 1. Structure of an ASP.

4 Doernberg & Chambers

 Antibiotic time-out: A prompt to providers to review antimicrobial use at a certain

time point after initiation (generally 48 hours) to assess diagnostic test results,
need for ongoing treatment, and appropriate choice of agent.
 Automatic pharmacy interventions to improve antibiotic use and safety: Interven-
tions include intravenous to oral conversions, dose adjustment for renal dysfunc-
tion, therapeutic drug monitoring, pharmacodynamic or pharmacokinetic
optimization, and notification of duplicative agents or agents with drug
interactions.
 Education to providers on antimicrobial use and stewardship principles.
 Though not generally considered a core stewardship activity, embedding an ASP
physician or pharmacist on rounds or requiring routine consultation in ICU pa-
tients started on antimicrobials are other approaches that have been reported
in the literature.21–23
 Integration of IT into these activities or use of IT to aid with stewardship is another
emerging field that is likely to gain increasing attention.
These approaches to stewardship can be tailored to the institution and the phase of
care, and data of varying quality exist to support each approach. See later discussion
of application of these general approaches to the ICU setting. This discussion is
framed around the natural phases of suspected infection, from diagnostic testing to
empirical therapy to definitive therapy (Fig. 2).

DIAGNOSIS

As a corollary to the common use of inappropriate antimicrobial therapy in the ICU

setting for noninfectious or nonbacterial syndromes, or treatment of colonization or
contamination, more accurate and timely diagnosis of infection should result in
improved antimicrobial use.18,19 Goals of diagnostics for infection include
 Establishing an infection as the cause of the presenting syndrome; discrimination
of bacterial infection from noninfectious syndrome
 Discrimination of bacterial from nonbacterial infections
 Rapidly identifying a microbial pathogen, if present, to direct therapy
 Providing timely information about drug susceptibility of the pathogen.

Fig. 2. Opportunities for antimicrobial stewardship interventions.

 Antimicrobial Stewardship Approaches in the ICU 5

Currently available approaches that fulfill some of these goals include markers of
bacterial infection, including biomarkers such as procalcitonin, and characterization
of the host immune response, as well as rapid identification of bacteria or other path-
ogens from clinical samples.

Host Response to Infection

For a deeper discussion of procalcitonin in the ICU setting. (See David N. Gilbert’s
article, “Role of Procalcitonin in the Management of Infected ICU Patients,” in this
issue.) The bottom line for this biomarker is that it generally does not decrease initia-
tion of antibiotics in the ICU but can help with de-escalation and discontinuation of
therapy.24,25 Identification of a host immune genetic expression (eg, transcriptome)
to identify specific responses to bacterial infections has been another recent prom-
ising focus of investigation, though the application of these classifiers to clinical
care needs further study.26–29 In particular, whether the good but imperfect sensitivity
will be enough to confidently allow for discontinuation of antimicrobials in the critically
ill and improve outcomes in a real-world setting remains unclear. As precision medi-
cine and molecular diagnostics are introduced into clinical practice, there will likely
be refinements and advances in use of host biomarkers and protein and gene expres-
sion to discriminate bacterial infections from nonbacterial infections and noninfectious
syndromes.
Discussion of utility of combinations of clinical markers or scoring systems (eg, clin-
ical pulmonary infection score [CPIS]) for accurate diagnosis of infection is beyond the
scope of this article, but there is significant literature regarding this topic.30–34 For
instance, the CPIS has been studied as a tool for antimicrobial stewardship in the
setting of suspected ventilator-associated infection (VAP) and was shown to decrease
antibiotic duration by more than 6 days without adverse clinical consequences.35
Commentators note, however, that in the absence of a CPIS scoring system, clinical
judgment of patients with suspected VAP by the ASP provider might accomplish the
same outcomes.33

The Role of Traditional Microbiology Testing

Before launching into further discussion of advanced molecular methods for diagnosis
of microbes, a review of the utility of traditional clinical laboratory and microbiology
testing is important. Traditional testing includes
 Gram stain and culture of various specimen sites
 Urinalysis (UA) and urine microscopy
 Cellular analysis of bodily fluids (eg, bronchoalveolar lavage fluid, cerebrospinal
fluid, ascitic fluid)
 In vitro drug susceptibility testing through disk diffusion testing, antimicrobial
gradient methods, or broth microdilution, including automated systems.
The first step of analysis of a clinical culture is performance of a Gram stain to
identify the staining pattern and shape of the bacteria, if present, which can help
to direct therapy. Particularly from respiratory specimens, Gram stains have the po-
tential to aid in decision-making about antibiotic therapy. VAP is a good example of
the utility of a negative Gram stain. Without a gold standard, VAP is a notoriously
difficult diagnosis to make.36 Although a positive respiratory Gram stain or culture
needs to be interpreted with caution given the strong possibility of colonization, a
negative Gram stain from an invasively obtained sputum culture was found to
have a negative predictive value of 91% in the setting of a VAP prevalence of
20% to 30% and thus can be useful in the decision to stop antibiotics.37 A positive
6 Doernberg & Chambers

Gram stain, on the other hand, has only fair concordance with culture and poor pos-
itive predictive value, making this a poor test to use for clinical decision-making in
general.37,38
Identification of a pathogen from a clinical specimen from the ICU can take be-
tween 48 and 96 hours, and susceptibility testing generally takes another 48 to
72 hours. Thus, by the time full susceptibility is available, patients have often been
on empirical therapy for several days. In a multicenter point prevalence study of
empirical antimicrobial use in the ICU, 50% of subjects were still on empirical therapy
(ie, did not meet definitions for confirmed infection with directed therapy) at 72 hours,
reflecting at least in part the delay in confirmation of infection.39 In another multi-
center study of subjects in the ICU with suspected nosocomial infections, antibiotics
were continued for at least 72 hours in 69% of subjects and 5 days in 59% of sub-
jects with negative cultures.40 Despite the trends suggesting that prolonged empir-
ical therapy is common, small studies suggest that stopping antibiotics in ICU
patients with suspected pneumonia and negative cultures, even at 24 to 48 hours,
can be safe.41,42
A negative UA can be useful in the decision not to send a urine culture and/or treat
for possible urinary tract infection (UTI).43 Although the UA has a poor positive pre-
dictive value for true UTI, especially in catheterized patients, a negative UA has been
shown to have 100% negative predictive value in the febrile trauma ICU patient,
though the utility of a negative UA is controversial in some populations.44,45 Epstein
and colleagues46 report an interrupted time-series analysis of an ICU intervention at
their institution that mandated a positive UA (defined as >10 white blood cells per
high-powered field) before urine culture performance, though oncology and trans-
plant patients were excluded and providers could override. Although they did not
examine antimicrobial use, they did find a significant decrease in urine culture rate,
which could reduce inappropriate treatment of asymptomatic bacteriuria. Further
studies are needed to determine whether decreasing reporting of positive urine cul-
tures in the setting of likely asymptomatic bacteriuria (eg, with negative UA) affects
antibiotic use.
The way in which microbiology tests are reported can also affect antimicrobial use.
One common approach, known as cascade or selective reporting, involves releasing
susceptibility information for broad-spectrum antibiotics to clinicians only when there
is resistance to more narrow-spectrum agents. The Infectious Diseases Society of
America (IDSA) supports this practice, and the Clinical and Laboratory Standards
Institute provides guidance on how to actually perform the reporting.7 There are
limited data supporting use of cascade reporting in the inpatient setting. In 1 health
system that implemented cascade reporting for Enterobacteriaceae, there was a
decrease in the use of anti-pseudomonal beta-lactams for definitive treatment of
cefazolin-susceptible organisms isolated from blood cultures from 26% to 0% of
cases in a population made up of 23% ICU patients.47 Interestingly, this improvement
in appropriate de-escalation occurred in the setting of a very high rate of ID consulta-
tion: 81% in the baseline group. At another hospital implementing cascade reporting
for gram-negative bacilli, there were notable decreases in resistance of Enterobacter
and Proteus species to third-generation cephalosporins coupled with changes in anti-
microbial usage and decreased C difficile rates, though resistance to other antibiotics
paradoxically increased over time.48 Still another group reported inappropriate use of
rifamycins for primary treatment of staphylococcal infections after their laboratory
began reporting susceptibilities to these drugs routinely, underscoring the importance
of continued surveillance for unintended consequences of changes in laboratory
reporting.49
 Antimicrobial Stewardship Approaches in the ICU 7

Coupling of antimicrobial stewardship interventions to specific culture results has

also been shown to improve antimicrobial use and clinical outcomes.7 Several studies
examining routine antimicrobial stewardship program (ASP) review of positive blood
cultures coupled with bundled interventions have demonstrated improvements in
appropriate antibiotic use as well as clinical benefit, including decreased mortal-
ity.50–52 These studies highlight the importance of expert guidance in treatment of
serious infectious syndromes, many of which are managed in the ICU setting.

Rapid Microbial Identification and Susceptibility Testing

Because the turnaround time for traditional microbiology testing is on the order of
days, there has been significant interest in and focus on more rapid diagnostic testing
for pathogen identification and drug susceptibility information. More rapid information
can lead to more rapid and appropriate antibiotic decisions, which can result in
improved clinical outcomes and decreased antibiotic use. In recent years, many rapid
test methods have emerged, including53
 Nucleic acid amplification tests, such as multiplex polymerase chain reaction
(PCR) for respiratory viruses and real-time PCR to detect genes for
vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus
aureus (MRSA), and beta-lactamase producing gram-negative rods from positive
cultures
 Latex agglutination testing for penicillin-binding protein 2a for detection of MRSA
directly from culture
 Matrix-associated laser desorption or ionization time-of-flight mass spectrom-
etry, which can rapidly identify organisms and also may be able to detect
resistance
 Rapid detection of bacterial cell lysis after incubation with an antibiotic
 Whole-genome sequencing.
The IDSA recommends use of rapid diagnostic testing in combination with support
in interpretation by an ASP and use of rapid viral testing for respiratory pathogens.7
(See James M. Walter and Richard G. Wunderink’s article, “Severe Respiratory Viral
Infections: New Evidence and Changing Paradigms,” in this issue.) Several studies
have demonstrated that antimicrobial stewardship enhances the benefits of rapid di-
agnostics. For instance, in a study of rapid multiplex PCR testing of positive blood
cultures, Banerjee and colleagues54 demonstrated that 24% of subjects in the rapid
testing plus stewardship arm had de-escalation of therapy compared with only 15%
in the rapid testing alone group and 12% in the control group. Interestingly, the
involvement of the stewardship team mainly affected time to de-escalation, whereas
the results of the multiplex PCR affected time to appropriate escalation regardless of
whether the subject was in the stewardship arm or not. It is possible that having the
stewardship team support to de-escalate in addition to the rapid test results pro-
vided more confidence for the providers facing complex clinical scenarios. This
may be even more important in critically ill ICU patients for whom providers may
be reticent to narrow antimicrobials, even when an organism has been identified
and susceptibilities reported. Several other observational studies have shown clinical
benefit of rapid diagnostics for assorted infections combined with antimicrobial stew-
ardship to varying degrees, though these studies are uncontrolled so that the degree
of impact of adding stewardship is difficult to quantify.55–62 Further research is
needed to quantify the benefit of rapid testing in the ICU setting and the degree to
which stewardship programs are needed to assist with interpretation and manage-
ment based on the results.
8 Doernberg & Chambers

Diagnostic Testing Take-Home Points

 Accurate identification of bacterial infection and rapid identification and suscep-
tibility testing can improve antibiotic use and clinical outcomes.
 Negative test results can assist providers with stopping antibiotics when no alter-
native infections have been identified.
 Cascade reporting of antibiotics may improve appropriate selection of antibiotics
for documented bacterial infections.
 ASPs are important adjuncts to help providers with interpretation of rapid iden-
tification and susceptibility technologies, particularly in de-escalation of
antibiotics.

EMPIRICAL THERAPY

While awaiting results of a work-up for a suspected infection, antimicrobial therapy

will likely be administered to the ICU patient. Because inadequate empirical
antibiotic therapy, or empirical antibiotics that do not cover the ultimate identified
pathogen, accounts for an estimated 39% to 51% of excess mortality in ICU pa-
tients with various infectious syndromes, initiation of broad empirical therapy in a
patient with high suspicion for infection is appropriate.15,16,63,64 However, de-
escalation can be initiated promptly after a specific diagnosis is made and empir-
ical therapy should only last for 48 to 72 hours. Conversely, overly broad therapy
should not be encouraged given the well-documented adverse effects of
antibiotics.65–69
In general, goals for empirical therapy in the ICU setting include
 Assurance of a high probability of covering commonly recovered organisms for
the patient population being treated based on local microbiology
 Promoting timely delivery of antibiotics
 Avoidance of overly broad antibiotics or redundant spectra of activity
 Selection of antimicrobials that are effective at the site of suspected infection (eg,
peritoneum, cerebrospinal fluid).
The next sections cover antimicrobial stewardship approaches to guide empirical
therapy selection.

Guidelines
Because empirical therapy is, by definition, therapy given without specific knowledge
of the infectious organism, guidelines can be an effective method to influence anti-
biotic choice.7,70 Recently updated consensus guidelines for empirical antibiotic ther-
apy in specific syndromes relevant to the ICU setting include those for complicated
intra-abdominal infections, hospital-acquired pneumonia or VAP, and skin or soft tis-
sue infections.71–73 These can and should be adapted to each institution based on
local antibiograms, patient population, and drug availability. Most studies examining
the effectiveness of guideline implementation have been single-center, pre-post anal-
ysis, and often are coupled with a concomitant educational campaign. For instance,
Worrall and colleagues74 reported improvements in appropriateness of empirical an-
tibiotics and therapy de-escalation along with decreased duration of antibiotics after
implementation of a pneumonia guideline in their trauma ICU. Though not statistically
significant on uncontrolled analyses, in a multivariate analysis controlling for severity
of illness and isolation of MRSA or Pseudomonas aeruginosa, the investigators re-
ported decreased hospital and ICU length-of-stay and ventilator days after guideline
implementation. Others have reported that implementation of a guideline for VAP
 Antimicrobial Stewardship Approaches in the ICU 9

management focusing on quantitative bronchoscopy, local antibiograms, and appro-

priate duration of therapy resulted in improvements in appropriate therapy and
1.3 days shorter duration of therapy without changes in mortality.75 Yet another group
implementing a VAP guideline in the medical ICU that focused on very broad initial
coverage with focused de-escalation reported statistically significant increases in
appropriate empirical therapy with decreased duration of total therapy from 14.8 to
8.6 days on average without changes in clinical outcomes.76 The investigators also re-
ported significantly fewer secondary VAPs, although changes in antimicrobial suscep-
tibility or whether de-escalation occurred after initial broad-spectrum empirical
coverage were not described.
Choice of empirical antibiotic regimen is easier when a specific infectious syn-
drome is presumed than when the source of a suspected infection is unclear.
Much attention has been placed recently on the definitions of sepsis, with a main
goal of early recognition and treatment.77–79 These definitions and guidelines rightly
emphasize sensitive definitions for sepsis with aggressive early antimicrobial therapy,
and the Centers for Medicaid and Medicare Services has recently made manage-
ment of sepsis a core measure.80,81 Given this mandate, resultant initial antibiotic
management often is very broad. Because of evidence supporting the importance
of adequate initial antibiotic therapy, there has been interest in whether addition of
empirical antifungal agents and/or additional antibacterial agents to cover resistant
gram-negative rods results in better clinical outcomes. Two recent studies on use
of empirical antifungals in the ICU setting help to clarify appropriateness of these
agents when diagnosis is uncertain.82,83 The Empirical Antifungal Treatment in
ICUs (EMPIRICUS) study was a multicenter, randomized, blinded study of empirical
micafungin treatment of patients in the ICU colonized with candida but without clear
focus of fungal infection who had unresolved sepsis despite broad-spectrum
antibiotics.83 In this population of nonimmunocompromised but critically ill patients,
there were no significant differences in mortality detected, even in those patients with
the highest suspicion for candidal infection. Another recent study showed no benefit
of early empirical therapy for patients with suspected candida peritonitis compared
with those who had antifungals started only when fungal peritonitis was confirmed,
though delay in systemic antifungals for 6 or more days may lead to worse out-
comes.82 Taken together, these 2 studies suggest that routine empirical antifungal
therapy in the ICU setting is not beneficial, even in high-risk populations with sepsis,
especially as diagnostics become more rapid and lead to fewer delays in identifica-
tion of patients with fungal infection.

Computerized Decision Support to Assist with Empirical Antibiotic Choice

In addition to evidence-based guidelines for specific syndromes, computerized deci-
sion support (CDS) at the time of initiation of empirical antibiotic initiation can be
another tool to support appropriate antibiotic choice.7 For example, in a multicenter,
cluster, randomized trial of a sophisticated CDS tool guiding selection of empirical
antibiotics in patients with suspected infection, wards with CDS trended toward hav-
ing higher rates of appropriate antibiotic usage.84 In those subjects whose providers
followed the CDS advice, the odds of having appropriate antibiotics started were
3.4-fold higher than control subjects (95% confidence interval, 2.3–5.1, in a model
accounting for location and clustering). This type of decision support can also be
used by antimicrobial stewardship teams to provide advice and feedback to pro-
viders, such as dual coverage of gram-negative organisms.85 Though relatively inex-
pensive to implement, a limitation to the use of decision support or electronic
checklists is alert fatigue.86
10 Doernberg & Chambers

Formulary Restriction
Requiring prior authorization for release of certain antimicrobials is a proven strategy
to limit initiation of unnecessary or inappropriate broad-spectrum antibiotic use
safely.87,88 Benefits include decreased resistance and lower costs. Though most
studies of formulary restriction have focused on institutions as a whole, several
have concentrated on critical care specifically. For instance, Lewis and colleagues89
report on the impact of implementation of ciprofloxacin restriction in the intermediate
and ICU units of a large tertiary care center. They found that significant decreases in
ciprofloxacin usage were associated with significant decreases in percentages and
rates of both ciprofloxacin and carbapenem-resistant isolates of P aeruginosa. Addi-
tionally, they observed a concomitant increase in use of carbapenems, highlighting the
importance of monitoring countermeasures when implementing selected antimicro-
bial restrictions. In fact, after restriction of cephalosporins, 1 institution reported an
increase in imipenem use, which was associated with a 69% increase in imipenem-
resistant P aeruginosa isolates.90 Though these 2 institutions enacted focused restric-
tions in response to outbreaks of organisms resistant to particular antibiotics, many
institutions introduce formulary restrictions for a broader list of antimicrobials. White
and colleagues87 reported that on implementation of a program to restrict antipseudo-
monal agents from multiple classes, use of nonrestricted antibiotics increased
concomitantly to a decrease in the restricted antibiotics, but the nonrestricted agents
were all narrower spectrum. As a result, significant improvements in gram-negative
bacterial susceptibilities were noted, including 18% decreases each in ceftazidime-
resistant Escherichia coli and imipenem-resistant P aeruginosa, specifically in the ICU.
Drawbacks of formulary restriction with prior authorization include7
 Shift to nonrestricted antibiotic use and resultant downstream effects
 Focus on empirical use when there are often limited microbiological and clinical
data available
 Concern for limits on prescriber autonomy
 Potential delays in therapy
 Variation in approval practice based on approver background and information
provided by the prescriber
 Need for on-call approver
 Prescriber manipulation and gaming of information presented to the approver or
bypass of the system (eg, learning the approval codes).
Because both restricted formulary with prior authorization and PAF are resource-
intensive interventions for the ASP, these 2 approaches have been compared in
several studies.91–93 Tamma and colleagues91 performed a crossover trial comparing
the 2 approaches with several internal medicine teams and found that the formulary
restriction with prior authorization group had a median of 2 days more antibiotic ther-
apy compared with the PAF group. However, Mehta and colleagues92 reported oppo-
site results from an interrupted time series study after their ASP moved from a
restricted formulary to use of PAF. Tamma and colleagues91 posited that these differ-
ences may have been due to unmeasured temporal trends, the limited scope of the
PAF in the latter study, and unaccounted for outpatient prescriptions.91 In a Cochrane
Database of Systematic Reviews assessment of antimicrobial stewardship ap-
proaches, there was benefit of both restrictive and persuasive (enabling) interventions,
which often were reported together.93 It should be noted that restrictive interventions
included cascade reporting, automatic stop orders, and therapeutic substitution,
whereas persuasive interventions included education and reminders, which are known
 Antimicrobial Stewardship Approaches in the ICU 11

to have limited effectiveness.7 Taken together, these findings highlight the importance
for multiple interventions to improve antimicrobial prescribing.
Allergy Testing
Being labeled as having a penicillin allergy has been linked to poor clinical out-
comes, including longer lengths of stay, more readmissions, and higher rates of
C difficile infection, MRSA, andVRE compared with matched controls.94,95 In pa-
tients with a beta-lactam allergy and gram-negative bacteremia, those patients
receiving a non–beta-lactam antibiotic had a 17% increase in risk of inappropriate
antibiotics, as well as an 11% increased risk of clinical failure.96 In contrast there
are only approximately 150 deaths from drug-induced anaphylaxis annually in the
United States.97 Because between 8% and 12% of patients report a penicillin al-
lergy and antibiotic use in the hospital is so common, the risks of mislabeling
have a huge impact.98
Penicillin skin testing and then rechallenge is safe in the ICU and results in clearance
of the allergy in most patients, with change in antibiotic management in 48% to 88% of
patients.99,100 The corollary to this is expected to be decreased antibiotic resistance,
failure, and costs, though these warrant further study. In addition to skin testing,
partnership between ID, pharmacy, and allergists can improve appropriate use of
beta-lactam antibiotics in patients with reported beta-lactam allergies. Though not
specifically implemented in the ICU setting, King and colleagues101 report on a
bundled guideline and educational intervention aimed at encouraging test doses
and appropriate use of beta-lactams in patients with low likelihood of cross-
reactivity. Without any increases in antibiotic adverse events, the investigators
observed a 31% decrease in vancomycin and 12% decrease in fluoroquinolone use
with a concomitant increase in use of beta-lactam antibiotics. An approach of eluci-
dating penicillin allergy history combined with the option for skin testing and/or graded
challenge would likely improve appropriate use of beta-lactams with downstream clin-
ical and microbiological benefit.7,102
Antimicrobial Stewardship Strategies to Guide Empirical Therapy Take-Home Points
 Appropriate antibiotic therapy improves outcomes, but use of overly broad
spectrum agents carries risk of resistance, adverse events, and C difficile
infection
 Approaches to improve choice of empirical therapy include
 Local guideline development and implementation
 CDS at the time of prescription
 Formulary restriction with prior authorization
 Beta-lactam allergy pathways, including skin testing, graded challenge, and
multidisciplinary evaluation.

DEFINITIVE THERAPY

Once the patient has been stabilized with empirical antimicrobials and diagnostic
testing results return, a clinical and/or microbiological diagnosis often, though not al-
ways, can be made. At this point, goals of therapy become
 Choosing the narrowest and most potent agent for identifying the syndrome and
microbes and treating for minimal effectiveness
 Optimizing pharmacodynamics and pharmacokinetics
 Avoiding adverse consequences of antimicrobial use while ensuring cure of
infection.
12 Doernberg & Chambers

Prospective Audit and Feedback

In addition to having a restricted formulary with requirement for prior authorization of
certain antimicrobials, PAF is among the foundations of most ASPs. PAF entails review
of patients on antimicrobials by the ASP pharmacist or physician, with feedback to
prescribers on appropriate choice, dose, and/or duration. Depending on the goals, re-
sources, and size of the ASP, the patients reviewed may range from a comprehensive
list of all patients on antimicrobials to targeting specific populations (eg, patients in
certain units), conditions (eg, positive blood cultures), or drugs (eg, broad-spectrum
agents). PAF can be complementary to facility-specific treatment guidelines, reinforc-
ing knowledge about and adherence to these guidelines.
In the ICU setting, PAF has been shown to decrease utilization of inappropriate
broad-spectrum antibiotics, rates of bacterial resistance, and C difficile infections
while maintaining similar mortality and length-of-stay outcomes.103,104 Because PAF
occurs after antimicrobials are started, benefits include having additional clinical infor-
mation on response to treatment, work-up for source of infection, and laboratory re-
sults. In addition, data suggest that there is an educational component to PAF with
1 study suggesting transfer of similar decrease in antimicrobial utilization on other
units staffed by the same physicians as the sole unit where PAF was performed but
not on units without overlap in staffing.105
Drawbacks to PAF include7
 Resource-intensive: Can require a significant amount of time to review targeted
patients.106 Computerized tools can help with this process but are costly.85
 For patients doing poorly, providers may be disinclined to deescalate, whereas
for patients responding to current therapy, providers may opt to continue the
successful therapy.
 Choice to follow recommendations is optional.
 Success of the program depends on who and how the feedback is delivered.107–110

Antibiotic Time-Out
Given the resource-intensive nature of PAF programs, there has been a push to iden-
tify methods by which prescribers could be prompted to perform their own PAF, other-
wise known as an antibiotic time-out, at 48 to 72 hours after initiating antibiotics.7,8 In
the ICU setting, approach to a time-out has mainly been use of checklists along with a
prompt if the items on the checklist were not addressed.111,112 Compared with pa-
tients whose physicians had a checklist embedded in the electronic medical record
without prompting, Weiss and colleagues111 found that those with in-person prompt-
ing to address antibiotic use had a 7% decrease in the proportion of days in which
empirical antibiotics were administered, and they even noted a risk-adjusted increase
in mortality for each additional day of empirical antibiotics. The marginal benefit of
having an unprompted checklist in the ICU is unclear.

Infectious Disease Physician Embedding Within the Intensive Care Unit Rounding
Structure
Though resource intensive, routine ASP or ID rounding on ICU patients with suspected
or documented infections can improve clinical outcomes and decrease inappropriate
or unnecessary antimicrobial use.21–23 For instance, Gilbert22 reported on outcomes
associated with routine inclusion of an ID physician on ICU multidisciplinary rounds
in a 23-bed ICU in a community teaching hospital. When compared with days when
the ID physician was not present, there was a significant difference of 0.35 decreased
days of antibiotic therapy per patient between the start and end of rounds. Similarly,
 Antimicrobial Stewardship Approaches in the ICU 13

Cairns and colleagues21 describe daily ICU-ASP rounds at their tertiary care center
with a 45-bed ICU, which were timed to directly follow the standard ICU ward rounds.
Though they do not report antibiotic use before their intervention, there was a high
acceptance rate of recommendations for antibiotic change, including discontinuing
antibiotics 36% of the time and de-escalation 12% of the time when antibiotic deci-
sions were made. Likewise, Butt and colleagues23 implemented a program in a
noncardiac ICU at a large tertiary care hospital in Abu Dhabi, UAE, which involved
dedicated ASP rounds daily and presence at the ICU work rounds at least weekly.
Though not statistically significant, there were numerical decreases in antibiotic cost
per patient, length-of-hospital and ICU stay, and mortality after this intervention
started. The impact of routine ID physician consultation in the ICU has also been
assessed with similar results.113–115

Studies of Duration
Many of the interventions described above, including guideline development, PAF,
antibiotic time-outs, use of biomarkers, and negative predictive value of negative
testing, can result in a significantly shorter duration of antibiotic exposure. In general,
studies of various infectious syndromes treated in the ICU, including VAP, pyelone-
phritis, and intraabdominal infection, have all demonstrated that shorter duration of
therapy is safe and decreases antibiotic exposure.116–119 As ASPs develop ap-
proaches to definitive therapy, knowledge of these types of studies can be useful in
implementing programs aimed to give the shortest effective duration of therapy.

Dosing Strategies
Due to altered hemodynamics, fluid balance, and organ function, as well as frequent
use of organ replacement therapies, antibiotic dosing in the ICU is challenging.120
Among the low-hanging fruits of ASPs are programs aimed at improving dosing stra-
tegies for various antibiotics. In the ideal situation, these strategies (generally phar-
macy run) improve clinical outcomes by optimizing pharmacokinetic properties but,
at the least, they can decrease antibiotic costs without affecting overall clinical out-
comes.121,122 In addition to global benefit from having pharmacists review patients
in the ICU on antibiotics, specific interventions aimed at drugs with narrow therapeutic
window have proven beneficial. For instance, in the time when aminoglycosides were
frequently chosen as primary therapy for gram-negative infections, several studies
showed clinical benefit or decreased adverse events related to pharmacist-directed
dosing, though these results were not always reproducible.123–125 Similar programs
for vancomycin dose monitoring and adjustment have generally found improved target
attainment, decreased adverse events, and lower costs while maintaining comparable
clinical endpoints.126,127
Recent data suggest that beta-lactam dosing may be inadequate in many ICU pa-
tients.128 Based on pharmacodynamic principles, extended-infusion or continuous-
infusion strategies for beta-lactam antibiotics have been studied with the goals of
improving outcomes and decreasing costs, though a recent large multicenter, ran-
domized, controlled trial did not find clinical benefit.129–132 Regardless, it can be a
cost-saving measure because the dosing strategies often result in lower overall dosing
of the beta-lactam antibiotic.7

Antimicrobial Stewardship Strategies to Guide Definitive Therapy Take-Home Points

 PAF is a mainstay of tailoring therapy for definitive management of infection.
 Other less resource-intensive but still effective approaches include CDS and
clinician self-stewardship via antibiotic time-outs.
14 Doernberg & Chambers

 Strategies to improve antibiotic dosing in this complex population are also impor-
tant and can be easy wins for an ASP.
 Attention to duration of therapy, whether via PAF or guideline development, may
be a way to decrease unnecessary antimicrobials in the ICU setting.

DEMONSTRATING EFFECTIVENESS

As with any quality improvement program, ASPs must track outcomes to focus efforts,
demonstrate successes, and ensure no unexpected countermeasures. In general,
ASPs should monitor both process and outcome measures.7 This includes measures
of antimicrobial usage (eg, days of therapy) normalized to census, costs, antibiotic
resistance, uptake of recommendations, and clinical outcomes such as adverse
events, secondary infections, mortality, and length-of-stay.

SUMMARY

Antimicrobial stewardship in the ICU setting can improve quality of care and
decrease antimicrobial resistance without compromising patient outcomes.
Though low-level evidence supports individual aspects of stewardship, there is lit-
tle information about which particular interventions have the most impact.133 Two
structured reviews of antimicrobial stewardship in the ICU setting have
found modest benefit, though studies tend to be small and uncontrolled, with
lack of emphasis on patient-centered outcomes, as previously noted.113,134 Individ-
ual institutions need to consider their own needs, resources, and priorities
when designing an ASP, and it is critical to monitor outcomes and adjust interven-
tions. Further high-quality research is needed to define which bundles of inter-
ventions might lead to the best outcomes without requiring overly onerous
resources.

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