Antibiotic Resistance
Yacob Habboush; Nilmarie Guzman.
Author Information and Affiliations
Last Update: June 20, 2023.
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Continuing Education Activity
Antibiotics are powerful drugs that are used to combat once fatal diseases. As with any
powerful medication, antibiotics carry a wide range of adverse effects. The appropriate use
of such agents has a high beneficiary effect that outweighs the risks. However,
once antibiotics are unnecessarily used, patients experience no benefits while their
susceptibility to the side effects is still present. Moreover, antibiotics disrupt the
composition of the infectious agent, leading to bacterial adaptation or mutations, and in
turn, to new strains that are resistant to the current antibiotic regimen. The inappropriate
use of antibiotics in one patient might develop a resistant strain that spreads to other
patients that do not use antibiotics, which makes this issue a pressing public health
problem. In 2015, 30% of the outpatient antibiotics prescribed were unnecessary, with
acute respiratory infections holding the highest unnecessary use of antibiotics at 50%. This
activity reviews the considerations for the use of antibiotics and discusses the role of the
interprofessional team in educating patients and providers on when they are necessary and
when they should be avoided.
Objectives:
Explain the purpose of antibiotics.
Describe the issues of concern with the unnecessary prescription of antibiotics.
Review the clinical significance of being judicious in prescribing antibiotics.
Summarize the current antibiotic stewardship guidelines set forth by the Infectious
Diseases Society of America (IDSA) and the role of the interprofessional team in
following these guidelines.
Introduction
Recognition of issues related to the use of antibiotics has been present since their early
clinical introduction in the 1940s. Since then, the use of antimicrobials and often
inappropriate use of these have been increasing. Antibiotic resistance in the United States
kills approximately 23,000 patients a year and incurs over $20 billion in additional medical
expenses. Antibiotic stewardship was established to combat this trend and was recognized in
1996 to draw attention to the rising incidents in mortality and morbidity associated with
inappropriate use of antibiotics. Antimicrobial agents are at least partially responsible for
the development of serious infections, such as Staphylococcus aureus, vancomycin-resistant
enterococci, extended-spectrum B-lactamase producing Enterobacteriaceae, and other
infectious agents. The focus of the stewardship programs is to improve clinical outcomes,
decrease antibiotic resistance, and decrease healthcare costs. In 2007, stewardship
programs were nationally recognized and reinforced by the publication of the stewardship
guidelines from the Infectious Disease Society of America (IDSA) in association with the
Society of Healthcare Epidemiology of America (SHEA). These guidelines were helpful in
developing an institutional program to enhance antimicrobial stewardship.[1][2][3]
Antibiotics are powerful drugs that are used to combat once fatal diseases. As with any
powerful medication, antibiotics carry a wide range of adverse effects. The appropriate use
of such agents has a high beneficiary effect that outweighs the risks. However,
once antibiotics are unnecessarily used, patients experience no benefits while their
susceptibility to the side effects is still present. Moreover, antibiotics disrupt
the composition of the infectious agent, leading to bacterial adaptation or mutations, and in
turn, to new strains that are resistant to the current antibiotic regimen. The inappropriate
use of antibiotics in one patient might develop a resistant strain that spreads to other
patients that do not use antibiotics, which makes this issue a pressing public health
problem. In 2015, 30% of the outpatient antibiotics prescribed were unnecessary, with
acute respiratory infections holding the highest unnecessary use of antibiotics at 50%.
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Function
Antibiotic resistance occurs when bacteria evolve to evade the effect of antibiotics through
multiple different mechanisms. Dissemination of antibiotic resistance genes is an ecological
and public health concern. Certain bacteria are able to neutralize an antibiotic by altering its
component to render it ineffective. Others might be able to export the antibiotics out of the
bacteria, and some can modify their outer structure and receptors so that antibiotics cannot
attach to them. These mechanisms might lead to some bacteria surviving the use of the
specific antibiotic and developing a resistance that can be passed to other bacteria as they
multiply. Bacteria also can become resistant through mutation of their genetic material.
The mechanism of antibiotic resistance is commonly categorized into the following four
groups:
1. Intrinsic Resistance: Bacteria might survive an antibiotic due to intrinsic resistance
through evolution by changing their structure or components. For example, an
antibiotic that affects the wall-building mechanism of the bacteria, such as penicillin,
cannot affect bacteria that do not have a cell wall.
2. Acquired Resistance: Bacteria can obtain the ability to resist the activity of a
particular antimicrobial agent to which it was previously susceptible. Bacteria can
acquire resistance through a new genetic mutation that helps the bacterium survive
or by getting DNA from a bacterium that already is resistant. An example is
Mycobacterium tuberculosis resistance to rifamycin.
3. Genetic Change: Bacterium DNA might change and alter the production of protein,
leading to different bacterial components and receptors which render the bacteria
unrecognized by the antibiotic. Bacteria sharing the environment might harbor
intrinsic genetic determinants of resistance that would alter the genomics of the
bacteria. An example is Escherichia coli (E. coli) and Haemophilus influenza resistance
to trimethoprim.
4. DNA Transfer: Bacteria can share genetic components with other bacteria and
transfer the resistant DNA through a horizontal gene transfer. Usually, bacteria
acquire external genetic material through three main stages:
Transformation (through naked DNA incorporation)
Transduction (through the process of phagocytosis)
Conjugation (through direct contact).
An example is Staphylococcus aureus resistance to methicillin (MRSA).
Several organisms are resistant to multiple antibiotics. For example, isolated E. coli and
Enterococcus that are inhibited by cefoxitin, ciprofloxacin, or erythromycin are usually
resistant to at least one antibiotic and sometimes multiple antibiotic types
including macrolides, tetracyclines, beta-lactams, quinolones, sulfonamides, tetracyclines,
and rifamycin.
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Issues of Concern
In the past, medicine was able to stay ahead of antimicrobial resistance through research
and the development of new agents to overcome the different types of resistance patterns;
however, with the recent development of vancomycin-resistant enterococci and the new
subtypes of methicillin-resistant Staphylococcus aureus, antibiotic resistance is more
prevalent and only can be minimized through stewardship. To combat the rising use
of antibiotics, medical and public health professionals have to collaborate to reduce the
inappropriate use of antibiotics. Physicians will have to balance the risks of not treating or
inadequately treating against the risk of antibiotic use regarding adverse effects, drug
interactions, cost, and antibiotic resistance. From a clinical perspective, many providers may
not be highly concerned about their antibiotic prescribing habits since many patients expect
to get an antibiotic when they visit a physician for an issue they perceive as bacterial. A
didactic educational discussion with the patient is necessary to change the overprescribing
phenomenon. Patients should be educated on the viral etiology of different infectious
disease syndromes in which antibiotics are unnecessary. The prescription of antibiotics in
these circumstances is futile. It exposes the patients to undesirable side effects or drug-drug
interactions and increases healthcare costs, in addition to contributing to the development
of antimicrobial resistance. For instance, a patient with infectious mononucleosis is treated
with oral amoxicillin and develops a rash.[4][5]
Antibiotic stewardship aims to provide a guide for the appropriate use of antibiotics. One of
the general principles is to manage patients empirically and then tailor antibiotic therapy
based on microbiology results. There are multiple strategies a stewardship program can
focus on such as educational, antimicrobial formulary restrictions, prospective audit and
feedback, computer-assisted notifications, molecular testing technology, application of
management guidelines, and interprofessional strategies. The core components of an
antibiotic stewardship program are leadership commitment, accountability, antibiotic
expertise, actions to tailor antibiotic use, tracking of antibiotic use, reporting antibiotic use,
and educating clinicians on appropriate antibiotic use.
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Clinical Significance
It is important to recognize that the concept of antimicrobial resistance in clinical practice is
a relative phenomenon with high complexity. Engaging patients is crucial for successful
antimicrobial stewardship to reduce rates of antibiotic resistance. Educating patients on
what they can do to keep themselves safe is part of the discussion on improving antibiotic
use. This includes raising awareness about the adverse effects of antibiotics as well as
the potential consequences of unnecessary antibiotic use. Also, finding different diagnostic
tools to help in guiding the antibiotic treatment is highly beneficial, such as the Overlap2
Method, a new initiative to determine the synergic effect of antibiotics on different
antimicrobials. Clinical approach to antimicrobial stewardship might differ from outpatient
to inpatient settings; however, all share the goal of improving antibiotic use as a core
component of fighting antibiotic resistance.[6][7]
Measuring the clinical significance of antimicrobial stewardship is complicated and can be
assessed by clinical and economic outcomes. A recent study compared the use of
continuous antibiotics versus intermittent antibiotics to manage bronchiectasis (by
assessing the reduction in the frequency and duration of exacerbations) to the risks of
managing antibiotic resistance and minimizing side effects demonstrated a lack of high-
evidence studies assessing the impact of stewardship programs. Hence, more prospective
clinical trials are needed to evaluate the impact of antimicrobial stewardship on clinical
outcomes. Outcome measures to utilize are decreased in the length of stay, lower
readmission rates, and shorten the period to place the patient on proper effective therapy.
On the other hand, economic outcomes provide stronger results showing the benefits of
such stewardship programs. Economic outcomes do not only refer to the antimicrobial
expenditure, but also include the costs of the drug, microbiology, length of stay, and
infectious disease specialists. More significant savings can result from improved clinical
outcomes due to decreased length of stay and reduction in complications related to
antibiotic use, such as with Clostridium difficile associated disease.
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Other Issues
Antibiotic Stewardship guidelines by the Infectious Diseases Society of America
(IDSA) mainly focus on the following:[8]
Incorporate direct interaction and feedback to the prescriber to reduce inappropriate
antimicrobial use
Restrict formulary antimicrobial use by requiring specialized authorizations
Develop institution-specific clinical pathways based on local microbiology and
resistance patterns
Streamlining and de-escalate therapy to eliminate redundant combination therapy
Ensure dose optimization based site of infection, pharmacokinetic, and
pharmacodynamic characteristics
Develop clinical pathways advising providers about appropriate parenteral to oral
conversions
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Enhancing Healthcare Team Outcomes
In 2017, the Joint Commission announced new stewardship standards requiring every
hospital in the United States to have a stewardship program. However, many hospitals have
yet to adopt these programs, and many institutions fear that smaller hospitals may not have
the ability to develop effective stewardship programs. There are a few possible solutions to
overcome these barriers such as joining a larger healthcare system to utilize their resources,
pooling resources from other hospitals, and facilitating the use of their state's health
department resources. Stewardship is a function of a health system that is usually managed
by the government to oversee and regulate healthcare. Antimicrobial stewardship programs
require a systematic measurement and coordinated interventions between clinicians,
infection control personnel, pharmacists, and informational technology designed to promote
the optimal use of antibiotic agents, including their choice, dosing, route, and duration of
administration.[9][10]
