REVIEW

CURRENT
OPINION Antibiotics and adverse events: the role of
antimicrobial stewardship programs in
‘doing no harm’
Karri A. Bauer a, Ravina Kullar a,, Mark Gilchrist b, and Thomas M. File Jr. c,d

Purpose of review
Antimicrobial resistance (AMR) is a global threat worldwide, with deaths associated with AMR infections
projected to exceed 10 million per year by the year 2050. The overuse and misuse of antibiotics is the
primary driver of this resistance, with up to 50% of antibiotics prescribed in the hospital setting being either
unnecessary or inappropriate. Antimicrobial stewardship (AMS) programs (ASPs) can mitigate some of this
resistance, with the benefits well recognized; however, if we are to truly advance the state of AMS, the
principles and practices should align with patient safety.
Recent findings
In a recent evaluation, among 1488 adult patients receiving systemic antibiotic therapy, 298 (20%)
experienced at least one antibiotic-associated adverse drug event (ADE). Fifty-six (20%) nonclinically
indicated antibiotic regimens were associated with an ADE. It is also well recognized that besides ADEs,
the inappropriate use of antibiotics is associated the development of multidrug-resistant infections and
Clostridium difficile infection.
Summary
Currently, there is a significant gap in ASPs correlating initiatives with patient safety goals, including
reductions in antibiotic-associated ADEs and multidrug-resistant infections. Therefore, in this article, we
provide the rationale for why ASPs are best suited to lead a collaborative effort to prevent antibiotic-
associated ADEs and multidrug-resistant infections.
Keywords
adverse event, antibiotic, antimicrobial stewardship, multidrug-resistant infection

INTRODUCTION and the level of interventions is variable. Currently,

The globalization of antimicrobial stewardship most ASPs’ efforts have focused on optimized anti-
(AMS) programs (ASPs) is necessary in the fight biotic use, improved clinical and microbiological
against antimicrobial resistance (AMR) with deaths outcomes in hospital settings, and reduced antibi-
attributed to resistant infections projected to exceed otic costs [4–6]. However, if we are to truly advance
10 million/year by 2050 [1]. All antibiotic use, of the state of AMS, efforts should focus on principles
which approximately 50% is overuse and misuse, is and practices that align with patient safety,
the primary driver of antibiotic resistance [2,3]. The
United Nations issued a call to action for countries
a
to implement AMS to address AMR and overuse of MRL, Merck & Co., Inc., Kenilworth, New Jersey, USA, bImperial College
antibiotics. While the benefits of AMS in the health- Healthcare NHS Trust, Charing Cross Hospital, London, UK,
c
Department of Internal Medicine, Northeast Ohio Medical University,
care environment have received increasing recogni- Rootstown and dDivision of Infectious Diseases, Summa Health, Akron,
tion, there remains an opportunity to enhance the Ohio, USA
importance of ASPs by focusing on patient safety. Correspondence to Karri A. Bauer, MRL, Merck & Co., Inc., 2000
AMS has emerged as one of the key strategies Galloping Hill Road, Kenilworth, NJ 07033, USA.
employed to minimize the development of resis- Tel: +1 614 530 9973; e-mail: [email protected]
tance to preserve antibiotic efficacy considering 
Current address: Expert Stewardship, Inc.; Newport Beach, California,
dwindling candidates in the pipeline. However, USA.
there are significant challenges in assessing the Curr Opin Infect Dis 2019, 32:553–558
achievements of ASPs globally as data are limited, DOI:10.1097/QCO.0000000000000604

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Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Antimicrobial agents

patients, 118 (17.1%) experienced ADEs, including

KEY POINTS gastrointestinal (6.4%), hepatobiliary (4.2%), der-
 AMR is a global threat worldwide, with deaths matologic (2.5%), and renal (2.3%) manifestations.
associated with AMR infections projected to exceed Finally, a recent analysis evaluated the Food and
10 million per year by the year 2050. Drug Administration (FDA) Adverse Event Report
System to determine the association between C.
 ASPs can mitigate some of this resistance, with the &
difficile infection (CDI) and antibiotic classes [10 ].
benefits well recognized; however, if we are to truly
advance the state of AMS, the principles and practices A total of 5187 CDI reports were considered. Linco-
should align with patient safety. samides (e.g., clindamycin) had the greatest propor-
tion of CDI reports. CDI reporting odds ratios for the
 Recent findings have demonstrated the prevalence of antibiotic classes were: lincosamides 46.95 (39.49–
antibiotic-associated adverse events.
55.82), monobactam 29.97 (14.60–61.54), penicil-
 Currently, there is a significant gap in ASPs correlating lin combinations 20.05 (17.39–23.12), carbape-
initiatives with patient safety goals, including reductions nems 19.16 (15.52–23.67), and cephalosporins
in antibiotic-associated ADEs and multidrug-resistant 15.33 (12.60–18.65).
infections.

 In this article, we provide the rationale for why ASPs

are best suited to lead a collaborative effort to prevent ROLE OF ANTIMICROBIAL STEWARDSHIP
antibiotic-associated ADEs and multidrug-resistant PROGRAMS IN ‘DOING NO HARM’
infections. The Institute of Medicine’s (IOM) first Quality
Chasm report, To Err is Human: Building a Safer
Health System stated that medication-related errors
were a significant cause of morbidity and mortality
including reductions in antibiotic-associated and accounted for more than 7000 deaths annually
adverse drug events (ADEs) and multidrug-resistant [11]. Building on this work and previous IOM
infections. Therefore, in this article we provide the reports, the IOM put forth a report on medication
rationale for why ASPs’ efforts should also focus on safety, Preventing Medication Errors. This report
patient safety by leading collaborative efforts to emphasized the importance of reducing medication
prevent antibiotic-associated ADEs and multidrug- errors, continuing monitoring for errors, and pro-
resistant infections. viding clinicians with decision-support and infor-
mation tools. Among the most common classes of
medications cited in the report due to their associa-
SIGNIFICANT PROBLEM OF ANTIBIOTIC- tion with ADEs were antibiotics. In a recent evalua-
ASSOCIATED ADVERSE EVENTS tion, among 1488 adult patients receiving systemic
The administration of antibiotics when they are not antibiotic therapy, 298 (20%) patients experienced
indicated is associated with unintended consequen- at least one antibiotic-associated ADE [12]. Fifty-
ces, including antibiotic-specific ADEs, emergence six (20%) nonclinically indicated antibiotic
of resistance, and selection of pathogenic bacteria, regimens were associated with an ADE. Aminogly-
for example, Clostridium difficile. A recent study cosides, parenteral vancomycin, and trimethoprim-
found that US adults aged at least 20 years had sulfamethoxazole were associated with the highest
145 490 emergency department (ED) visits attrib- rates of ADEs at 21.2 episodes per 10 000 person-
uted to antibiotic ADEs each year from 2011 to days. Antibiotics most frequently associated with
2015 [7]. Similarly, a Centers for Disease Control CDI were third-generation cephalosporins, cefe-
and Prevention (CDC)-authored study found that pime, and fluoroquinolones.
70 000 ED visits were made annually for antibiotic Antibiotics are associated with a variety of tox-
ADEs among children aged of 19 years or less from icities, including specific-drug related adverse
2011 to 2015, which accounts for 46.2% of ED visits events, and the development of multidrug-resistant
for ADEs that results from systemic medication [8]. infections and CDI. One potential solution to miti-
Both studies concluded that antibiotics are a com- gate the negative consequences associated with anti-
mon cause of ED visits for ADEs and represent an biotic use is the implementation of ASPs. ASPs are
important opportunity for ASPs in optimizing recommended by the CDC, European Centre for
patient safety. A single-center study quantified the Disease Prevention and Control and the WHO in
incidence of ADEs associated with broad-spectrum response to the misuse of antibiotics [13,14]. The
&
antibiotics in a hospital setting [9 ]. The most fre- primary goal of ASPs is to optimize the appropriate
quently prescribed antibiotics were piperacillin/ usage of antibiotics to improve clinical outcomes
tazobactam, meropenem, and vancomycin. Of 689 while minimizing unintentional consequences of

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 Role of antimicrobial stewardshi p in adverse events Bauer et al.

use, including emergence of resistance, toxicity, significantly improve patient safety by leading a
selection of pathogenic bacteria (e.g., C. difficile) collaborative effort to reduce antibiotic-associated
[15]. ADEs, including drug-specific events and the devel-
The effectiveness of ASPs in the reduction of opment of multidrug-resistant infections and CDI.
pathogenic bacteria has been well documented. These important patient safety initiatives will allow
Specifically, AMS initiatives have been shown to ASPs to continue to generate support among hospi-
be highly effective in decreasing CDI rates [16– tal administrators, clinicians, policy makers, and
18]. Data from the United Kingdom revealed signif- patients. In the past, ASPs have focused on cost
icant reductions in CDI associated with decreases in savings as primary justification. However, with an
targeted antibiotic use [16]. Additional studies have increased focus in healthcare on quality, safety, and
demonstrated the ability of ASPs to decrease the outcomes data as key components of reimburse-
incidence of multidrug-resistant infections. Cook ment, there is an opportunity to refocus the value
et al. [19] showed that restricting ciprofloxacin use of ASPs from only cost savings to quality metrics
improved the susceptibility of Pseudomonas aerugi- such as preventing antibiotic-associated ADEs and
nosa to the Group 2 carbapenems, such as imipenem development of MDR organism infections and CDI.
or meropenem. A reduction by 90% in the use of
ciprofloxacin between 2000 and 2010 led to a con-
current reduction (25% to 10–15%) in the propor- STRATEGIES FOR ANTIMICROBIAL
tion of carbapenem-resistant P. aeruginosa. Further, STEWARDSHIP PROGRAMS IN THE
Baur et al. [20] reviewed 32 studies published from 1 PREVENTION OF ADVERSE EVENTS
January 1960 to 31 May 2016 to evaluate how ASPs The prevention of antibiotic-related ADEs requires a
affected the incidence of infection and colonization multidisciplinary, coordinated response and effort.
with multidrug-resistant (MDR) bacteria and C. dif- ASPs should collaborate with other disciplines,
ficile among inpatients. The authors noted that in including patient safety, hospital senior leadership,
hospitals with ASPs, Gram-negative bacteria inci- frontline staff, and medical, pharmacy and nursing
dence fell by more than half (51%; P < 0.0001), staff leadership to identify and prioritize safety
extended-spectrum beta-lactamase-producing Gram- issues and develop risk-reduction strategies.
negative bacteria incidence fell by 48% (P ¼ 0.0428), Table 1 outlines the responsibilities of ASPs in the
Methicillinresistant Staphylococcus aureus decreased prevention of antibiotic-associated ADEs. It is
by 37% (P ¼ 0.0065) and the incidence of C. difficile important for ASPs to consult with and advise clini-
fell by nearly one third (32%; P ¼ 0.003). cal teams on opportunities and strategies to reduce
Despite the well documented benefits of AMS, adverse events. They should encourage system med-
there remains additional opportunities for ASPs to ication error reporting through an established and

Table 1. Responsibilities of antimicrobial stewardship programs in the prevention of adverse events

Responsibility Activities

Leadership Oversee the planning, creation, and review of antibiotic safety plan
Lead processes to collect information on adverse events
Proactively develop and lead implementation of adverse event prevention strategies
Participate in the planning, design, and implementation of antibiotic-related technology
Provide education and communication across the organization
Provide an annual report
Antibiotic safety expertise Serve as a resource on antibiotic safety
Oversee investigation of antibiotic-related adverse events
Actively participate in Antibiotic Subcommittee and/or Pharmacy and Therapeutics Committee
Review and analyze antibiotic-related adverse events and use appropriate data analysis techniques to
determine solutions
Practice change Collaborate with other departments to identify and prioritize antibiotic-related safety surveillance and develop
strategies to prevent adverse events
Participate and lead department and hospital committees related with to antibiotic safety
Encourage medication error reporting
Provide education on best antibiotic-use practices
Employ continuous quality-improvement techniques
Research and education Design and implement education strategies and programs
Disseminate information on best practices related to antibiotic use
Contribute to the literature on antibiotic safety

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Antimicrobial agents

accepted system that utilizes adequate detection hypersensitivity reaction. The authors concluded
methods and through other appropriate avenues that the AMS intervention using b-lactam test dose
such as Pharmacy and Therapeutics Committee, procedures were safe and an important tool. The
Medication Safety Committee, and Antibiotic Sub- clinical and economic outcomes of penicillin skin
committee. testing as an AMS initiative in a community health
An ASP physician and/or pharmacist should system was also evaluated [27]. The investigators
meet with the medication safety pharmacist at a performed a quasi-experimental study that com-
regular frequency (i.e., monthly) to review antibi- pared an intervention group of patients who com-
otic-associated ADEs. During the review, the ASP pleted penicillin skin testing with a matched control
and medication safety pharmacist should evaluate group of patients who were penicillin allergic. Sev-
ADEs and determine appropriate interventions to enty of the 98 patients (71%) who tested negative
prevent future events. In addition, antibiotic- had changes directly made to their antibiotic regi-
related ADEs should be reviewed and discussed at mens. Beta-lactam days of therapy for the penicillin
AMS meetings ensuring all members have an skin testing group were 666/1094 compared with
understanding of events and are able to contribute the control group at 386/984. These studies demon-
to solutions. Further, ASPs should present a sum- strate the significant impact of ASPs on delabeling
mary of ADEs and solutions as a standing agenda penicillin allergies to provide optimal therapy and
item at Antibiotic Subcommittee and Pharmacy potentially reducing ADEs.
and Therapeutics Committee. The presentation In an effort to decrease multidrug-resistant
of the events at these committees allows for docu- organism infections and CDI, ASPs should collabo-
mentation of solution requirements by necessary rate with other healthcare providers in ensuring that
individuals. Further, education to clinicians on antibiotics are only prescribed when an infection is
best practices to prevent ADEs should be provided present with the recommended agent, dose, moni-
throughout the institution. Education of the toring, and duration. This can be accomplished
patient so they understand how to take and are through a variety of ASP-directed interventions,
knowledgeable about their antibiotic, know how to including preauthorization, prospective audit and
monitor for ADEs, and identify signs that warrant feedback, education, and facility-specific clinical
follow-up is important for ensuring optimal out- practice guidelines. Preauthorization has been asso-
comes. Finally, ASPs should implement continuous ciated with a significant reduction in the use of
quality improvement principles to assess and restricted agents [28–30]. Outcome studies with
report on the status of efforts to improve antibiotic preauthorization have shown decreased antibiotic
safety. use and decreased antibiotic resistance, particularly
An additional ASP initiative to reduce ADEs is among Gram-negative pathogens. Importantly, pre-
the evaluation and appropriate delabeling of beta- authorization studies have demonstrated no adverse
lactam allergies. Beta-lactam antibiotic allergies, events for patients. Prospective audit and feedback
reported by up to 15% of hospitalized patients, have also been shown to improve antibiotic use,
significantly impact antibiotic prescribing [21,22]. reduce antibiotic resistance, and reduce CDI rates
Alternatives to b-lactam antibiotics may be less without a negative impact on patient outcomes [31–
effective and can result in adverse events for 33]. Education is a common tool for ASPs. Strategies
patients, including CDI [23,24]. Most patients include educational meetings with didactic lectures
with a documented penicillin allergy can be and distribution of educational pamphlets and
safely treated with penicillins and other b-lactams. materials. ASP-directed education should focus on
Importantly, penicillin allergy evaluation is recom- the appropriate use of antimicrobials based on insti-
mended by current antibiotic stewardship guide- tutional organism and susceptibility data, disease-
lines [25]. focused guidelines, and additional initiatives.
There are several examples of ASPs assessing the Improvements in antibiotic use are associated with
safety of, and subsequent allergy documentation implementation of facility-specific initiatives that
associated with an AMS intervention. A retrospec- have included statistically significant increases in
tive cohort study was conducted in a large health- likelihood of adequate guidelines initial therapy, use
care system consisting of two academic and three of narrower-spectrum antibiotic regimens, earlier
community acute care hospitals to evaluate b-lac- switch from intravenous to oral therapy, and shorter
tam antibiotic test dose outcomes, including ADEs duration of treatment without adverse effects on
&
[26 ]. Overall, the authors identified 1046 test-doses other clinical outcomes. These ASP-directed initia-
with 78 patients [7.5%; 95% confidence interval tives are important in decreasing multidrug-
(CI), 5.9–9.2%] had signs or symptoms of an ADE resistant organism infections and subsequent devel-
and 40 (3.8%; 95% CI, 2.8–5.2%) had a confirmed opment of CDI.

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 Role of antimicrobial stewardshi p in adverse events Bauer et al.

ENDORSEMENT FROM CLINICAL AND HAIs in the EU. At the World Health Assembly
PROFESSIONAL ORGANIZATIONS organized by the World Health Assembly in May
Nonpayment policies for ADEs by national orga- 2019, patient safety was at the forefront of the
nizations, such as the Centers for Medicaid and agenda. Although there has been an emphasis on
Services (CMS) and the Joint Commission on patient safety in the EU, just like the United States,
Accreditation of Healthcare Organizations are we recommend these organizations now provide
increasing in prominence and are viewed as an metrics and standards to guide hospitals and hold
incentive to reduce the incidence of these events. them accountable in decreasing antibiotic-related
In October 2008, the CMS discontinued additional ADEs and toxicities, directly impacting patient safety.
payments for certain hospital-acquired infections
(HAIs) that were deemed preventable [hospital-
acquired conditions (present on admission indica- CONCLUSION
tor)] [34]. The effect of this policy on rates of HAIs
The role of ASPs in the prevention of ADEs is an
was evaluated in 2012. The results revealed that
important initiative in promoting patient safety. It
there were no significant changes in quarterly rates
is imperative for ASPs to demonstrate their efforts in
of central catheter-associated bloodstream infec-
alternative ways besides solely reporting antibiotic
tions in the postimplementation vs. preimplemen- cost reductions. ASPs’ impact on the prevention and
tation period, (incidence-rate ratio, IRR, 1.00;
reduction of ADEs is a way to emphasize the neces-
P ¼ 0.97), catheter-associated urinary tract infec-
sity and importance of the program. ASP members
tions (IRR, 1.03; P ¼ 0.08), or ventilator-associated
should meet with the patient safety officer and
pneumonia (IRR, 0.99; P ¼ 0.52) after the policy
additional hospital leadership to discuss antibi-
implementation. These results demonstrate that
otic-related ADEs and offer solutions. In addition,
although the CMS nonpayment policy may provide
metrics related to antibiotic-related ADEs, including
organizational awareness in preventing HAIs, a
number of events prevented should be regularly
greater focus should be on the design of such non- reported and discussed with the patient safety offi-
payment policies to ensure that they improve out-
cer and hospital leadership. Lastly, with the increase
comes. This policy was expanded in 2015 as part of
in multidrug-resistant bacteria, ASPs can have the
the hospital-acquired condition Reduction Program
direct impact on decreasing the incidence of infec-
under the Affordable Care Act with penalties
tions and colonization with these bacteria in addi-
employed to hospitals as an incentive to prevent
tion to C. difficile. The ‘Do no harm’ decree exhorted
costly adverse events and to link payment to pro-
of all healthcare providers needs to be the principle
grams that drive better health outcomes [35]. Under
we all stand behind to make a sustainable impact on
this initiative, Medicare will penalize over 750 hos- patient care.
pitals in 2018 for their lagging performance on
measures designed to prevent HAIs.
Acknowledgements
We recommend that policies that have been
None.
implemented by the CMS in preventing HAIs need
to be extended to antibiotics to decrease preventable
Financial support and sponsorship
consequences with a focus on patient outcomes.
Moreover, specific to AMS, the Joint Commission None.
recently published core standards for ASPs, serving
as a national, standardized performance measure- Conflicts of interest
ment system; however, there were no metrics At the time of writing, R. K. was employed by Merck &
provided in regard to adverse events related to anti- Co., Inc, MRL, Kenilworth, NJ, USA. R.K. is now
biotics [36]. employed by Expert Stewardship, Inc.; Newport Beach,
Patient safety and HAIs have been on the Euro- CA, USA.
pean Union (EU) and WHO agenda and there is
increased consensus that this area should receive
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