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Understanding Antimicrobial Resistance

Lauren Floris, PharmD; David Cluck, PharmD, BCPS, BCIDP, AAHIVP; Abby Singleton, PharmD, BCPS

US Pharmacist. 2020;45(3):HS-10--HS-16.

Abstract and Introduction

Abstract

Bacteria are remarkably adaptable organisms with an innate ability to circumvent damage if exposed to a toxic environment.
Antimicrobial-resistant bacteria are present worldwide, and many common infections are becoming more difficult to treat.
Continued resistance is rapidly eliminating treatment options for patients, and the cost burden to treat a multidrug-resistant
infection is climbing. Owing to the substantial costs associated with drug development, the introduction of novel antibiotics has
lagged behind the increase in bacterial resistance. To address this crisis, pharmacists can take an active role in antimicrobial
stewardship and foster understanding of how bacteria evade even the strongest available antimicrobial agents.

Introduction

Bacteria are remarkably adaptable organisms with an innate ability to circumvent damage if exposed to a toxic environment.
Since the development of the first antibiotic less than a century ago, there has been an exponential growth in antimicrobial
resistance that is disproportionate to the rate at which antibiotics are introduced.[1] The emergence of resistance and the
inversely stagnant development of novel antibiotics related to the substantial costs associated with drug development have
worsened the impact of infectious diseases on mortality and healthcare costs. Continued resistance is rapidly eliminating
treatment options for patients, and the cost burden to treat a multidrug-resistant infection is climbing, reaching more than $2.2
billion annually in the United States.[2] Antibiotic resistance has been found in most bacteria, but several bacteria are particularly
problematic and are becoming common among hospital-acquired infections: Enterococcus faecium, Staphylococcus aureus,
Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae (ESKAPE pathogens).[3–
5] The CDC recently published an updated list of the most threatening resistant organisms in the U.S. based on hospitalizations
and mortality data from 2017 ().[6]

Table 1. Most Threatening Resistant Organisms in the U.S., 2019

Watch List Concerning Threats Serious Threats Urgent Threats

Azole-resistant Erythromycin-resistant GAS MRSA Carbapenem-resistant
Aspergillus fumigatus Clarithromycin-resistant GBS Multidrug-resistant Acinetobacter
Drug-resistant Pseudomonas aeruginosa CRE
Mycoplasma genitalium VRE Candida auris
Drug-resistant ESBL-producing Clostridioides difficile
Bordetella pertussis Enterobacteriaceae Drug-resistant
Drug-resistant Neisseria gonorrhoeae
Streptococcus pneumoniae
Drug-resistant tuberculosis
Drug-resistant
Campylobacter
Drug-resistant Salmonella

CRE: carbapenem-resistant Enterobacteriaceae; ESBL: extended-spectrum beta-lactamase; GAS: group A Streptococcus;

GBS: group B Streptococcus; MDR: multidrug-resistant; MRSA: methicillin-resistant Staphylococcus aureus; VRE: vancomycin-
resistant enterococci. Source: Reference 6.

The CDC estimates that more than 47 million antibiotic courses are prescribed each year in the U.S. for infections that do not
need antibiotic treatment.[7] The misuse and overuse of antibiotics have put the world at risk, and the growing threat prompted
the World Health Organization to issue a global action plan for antimicrobial resistance in 2015.[8] In the same year, the U.S.
formulated a national action plan for combating antibiotic-resistant bacteria.[6] These initiatives launched the implementation of
antimicrobial stewardship (AMS) programs and research to prevent further resistance. Unfortunately, bacteria adapt quickly, and
the development of antimicrobial agents is truly a race against time. With each new agent designed to overcome a resistance
mechanism, pathogens inevitably establish new strategies to withstand the next antibiotic. Few agents have been introduced
since 2010 (), and even fewer have activity against ESKAPE pathogens.[9] As of June 2019, only 42 antibiotics were in clinical
development, and just three in five agents entering phase III trials are approved.[9] Preventing further resistance requires not

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only persistent AMS to reserve existing agents, but also a fundamental understanding of antibiotic mechanisms of action and
the strategies bacteria employ to resist these agents.

Table 2. Antibiotics Approved Since 2010

Approval
Antimicrobial Agent Year Indication(s) Coverage
Ceftaroline (Teflaro) 2010 SSTI, CAP MRSA
Fidaxomicin (Dificid) 2011 Diarrhea associated with C difficile
Clostridioides difficile
Bedaquiline (Sirturo) 2012 Pulmonary tuberculosis Mycobacterium tuberculosis
Dalbavancin (Dalvance) 2014 SSTI MRSA
Tedizolid (Sivextro) 2014 SSTI MRSA, VRE
Oritavancin (Orbactiv) 2014 SSTI MRSA, VRE
Ceftolozane-tazobactam 2014 HAP/VAP, cIAI, cUTI ESBL organisms, Pseudomonas
(Zerbaxa)
Delafloxacin (Baxdela) 2017 SSTI, CAP MRSA
Meropenem-vaborbactam 2017 cUTI CRE
(Vabomere)
Plazomicin (Zemdri) 2018 cUTI CRE, aminoglycoside-resistant
Enterobacteriaceae
Cefiderocol (Fetroja) 2019 cUTI CRE, Acinetobacter, Pseudomonas
Omadacycline (Nuzyra) 2019 SSTI, CAP MRSA, VRE, Pseudomonas,
Klebsiella
Imipenem-cilastatin-relebactam 2019 cUTI, cIAI CRE, Pseudomonas
(Recarbrio)

CAP: community-acquired pneumonia; cIAI: complicated intraabdominal infection; CRE: carbapenem-resistant Enterobacteria-
ceae; cUTI: complicated urinary tract infection; ESBL: extended-spectrum beta-lactamase; HAP: hospital-acquired pneumonia;
MRSA: methicillin-resistant Staphylococcus aureus; SSTI: skin and soft-tissue infection; VAP: ventilator-associated pneumonia;
VRE: vancomycin-resistant Enterococcus. Source: Reference 9.

Epidemiology

Antimicrobial-resistant bacteria are present in every country in the world, and many common infections are becoming more
difficult to treat.[10] For example, urinary tract infections (UTIs) caused by resistant Escherichia coli have reduced the efficacy of
fluoroquinolones globally. Gonorrhea treatment failure with third-generation cephalosporins has been reported in at least 10
countries. More than 2.8 million antibiotic-resistant infections occur each year in the U.S., leading to more than 35,000 deaths.[6]
There is also a direct relationship between the prevalence of resistant pathogens and rates of sepsis-related outcomes. In a
recent study that examined this correlation in hospitalized patients in the U.S. from 2011 to 2014, the highest rates of sepsis
were associated with fluoroquinolone-resistant E coli, third-generation cephalosporins and carbapenem-resistant Klebsiella
species, and vancomycin-resistant Enterococcus (VRE).[11]

Resistance Mechanisms

There are two types of bacterial resistance: intrinsic and acquired. In intrinsic resistance, the antibiotic never possessed activity
against the pathogen ().[3–5]Acquired resistance is achieved through the transfer of genetic material that confers resistance.
Some bacterial genes are carried on plasmids—small, circular, double-stranded DNA molecules that are distinct from
chromosomal DNA.[12]Plasmids are transferred from one bacterium to another through conjugation, and this exchange can
occur between bacteria of different species. The strategies that bacteria use to develop acquired resistance are encoded on
plasmids and may be classified into four mechanisms: 1) decreased permeability of the cell wall to antibiotics; 2) modification of
enzymes to inactivate antibiotics; 3) drug target site changes; and 4) efflux pumps that remove antibiotics from the cell.[4] Drug
inactivation through enzymes is the predominant mechanism used by bacteria, and the expression of genes that encode these
enzymes may be induced by particular medications (facultative) or constantly expressed (constitutive).

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Table 3. Examples of Pathogens With Intrinsic Resistance

Organism(s) Antimicrobial Agent(s)

Gram-positive pathogens Aztreonam, colistin
Gram-negative pathogens Glycopeptides, oxazolidinones, daptomycin
Pseudomonas Tetracyclines, many beta-lactams, ertapenem, TMP-SMX
Enterococci Cephalosporins, fluoroquinolones, macrolides, TMP-SMX, clindamycin, ertapenem
Acinetobacter Ertapenem, ampicillin, amoxicillin
Staphylococci Fluoroquinolones, macrolides
Anaerobes Aminoglycosides, fluoroquinolones, many beta-lactams, macrolides
Serratia Amoxicillin-clavulanate, ampicillin
Klebsiella, Proteus Ampicillin

TMP-SMX: trimethoprim-sulfamethoxazole.
Source: References 3, 4.

Multidrug-resistant Enterococcus

Enterococci, which are predominantly benign gut bacteria, may be the best-known family of microbes equipped with intrinsic and
acquired antibiotic resistance. Of particular concern are E faecium and Enterococcus faecalis. These organisms can have
multiple acquired resistance mechanisms, thereby resulting in multidrug resistance.[13] High levels of resistance may exist to
beta-lactams (through beta-lactamase enzymes and altered binding proteins), vancomycin (via changes in peptidoglycan
synthesis; known as VRE), and aminoglycosides (through enzymatic degradation).[14,15] Ampicillin remains the drug of choice
for susceptible Enterococcus infections, but few options remain to treat systemic multidrug-resistant Enterococcus infections;
these include linezolid, daptomycin, and tigecycline.[3,14]

Methicillin-resistant Staphylococcus Aureus (MRSA) and MecA

MRSA first appeared in the early 1960s, shortly after the introduction of methicillin.[16] As with most gram-positive organisms,
the cell wall serves as the main target for antimicrobial agents and consequently fosters acquired antimicrobial resistance. For S
aureus to be considered MRSA, the bacterium must possess the mecA gene, which encodes for a structural change in
penicillin-binding protein 2a (PBP2a).[17] This change prevents beta-lactam antibiotics from binding to the cell wall. Laboratory
testing for S aureus susceptibility to methicillin is not commonly performed, owing to the instability of methicillin plates; rather,
MRSA is determined by a similar beta-lactam: oxacillin. The Clinical Laboratory Standards Institute defines methicillin resistance
as an oxacillin mean inhibitory concentration of at least 4 mcg/mL, and isolates resistant to oxacillin are resistant to all beta-
lactams, with few exceptions (e.g., ceftaroline).[18]

Extended-spectrum Beta-lactamase (ESBL)–Producing Organisms

Many gram-negative species of bacteria have been found to possess acquired resistance to beta-lactam antibiotics through the
production of beta-lactamase. This enzyme deactivates the agent's antimicrobial properties by hydrolyzing its beta-lactam ring.
[19] The first beta-lactamase to be isolated was a penicillinase identified in E coli in 1940, before penicillin entered medical use.
New agents were developed over the years to resist the effects of this enzyme, including broad-spectrum cephalosporins.
Predictably, the introduction of these antibiotics led to resistance against broader-spectrum agents, giving rise to the ESBL
enzyme. Currently, more than 150 ESBLs are found in many different Enterobacteriaceae species and in P aeruginosa.[20]

Carbapenems have remained the drug of choice for ESBL-producing pathogens. This beta-lactam antibiotic subgroup includes
meropenem, ertapenem, doripenem, and imipenem-cilastatin. All of these agents—with the exception of ertapenem, which does
not have activity against Acinetobacter or Pseudomonas—have demonstrated efficacy against ESBLs.[3] Similar to the selective
development of ESBL enzymes following the introduction of broad-spectrum cephalosporins, there has been an emergence of
carbapenem-resistant pathogens capable of hydrolyzing carbapenems through the activity of a carbapenemase enzyme.

Carbapenemase Enzyme

Carbapenems are the broadest-spectrum antibiotics available and are favorable choices for many resistant gram-negative
nosocomial infections.[21] As effective as these agents are, there has been an increase in carbapenem-resistant organisms as a
result of carbapenem overuse, leaving patients with limited to no treatment options. Carbapenem-resistant Enterobacteriaceae
(CRE) and Acinetobacter are associated with a combined hospitalization of 21,600 patients and 1,800 deaths each year in the
U.S.[6] Other possible carbapenemase-producing organisms include K pneumoniae, P aeruginosa, and E coli.[21]

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In order to preserve these antibiotics, carbapenem-sparing agents with activity against ESBL-producing pathogens should be
used whenever possible. Such agents include piperacillin-tazobactam, cefepime, and ceftolozane-tazobactam.[22] However,
carbapenems are preferred for certain infection sites, including the bloodstream and lungs. In the MERINO trial, 30-day mortality
was higher in patients with ESBL E coli or K pneumoniae–associated bacteremia that was treated with piperacillin-tazobactam
versus a carbapenem.[23]

Much effort has gone into developing new antibiotics to combat these bacteria. A new cephalosporin, cefiderocol, which was
approved in 2019 to treat UTIs, has activity against CRE. Recent beta-lactam combinations (meropenem-vaborbactam and
ceftazidime-avibactam) have shown good in vitro activity against CRE and are becoming available on many hospital formularies
to treat UTIs, intraabdominal infections, and respiratory tract infections.[24] The polymyxins (colistin and polymyxin B), an older
antibiotic class, have fallen out of favor because of their renal and neurologic toxicities; however, they are effective against
carbapenem-resistant pathogens and may be useful for salvage therapy.[25] Both polymyxin agents are highly similar and have
a narrow therapeutic window, requiring careful dosing and close monitoring of renal function, although polymyxin B is associated
with less nephrotoxicity than colistin.

P Aeruginosa

Pseudomonas is an opportunistic gram-negative pathogen responsible for a large number of nosocomial infections.
Antimicrobial agents used to treat Pseudomonas include beta-lactams, fluoroquinolones, and aminoglycosides, but this genus
can display multiple mechanisms of resistance. Intrinsically, Pseudomonas has a relatively low membrane permeability (up to
100 times lower than that of E coli).[26] The acquired-resistance mechanisms potentially expressed by Pseudomonas include
any of the four previously described strategies. Fluoroquinolones exhibit antimicrobial activity by targeting bacterial enzymes
involved in DNA replication.[9,10] Fluoroquinolone-resistant strains of Pseudomonas avoid this effect by mutating the genes
encoding for those enzymes. Aminoglycoside-resistant Pseudomonas is capable of producing aminoglycoside-modifying
enzymes. Beta-lactam resistance in Pseudomonas is due to modifications in penicillin-binding proteins, overexpression of efflux
pumps, and enzymatic drug inactivation.[26]

Increased exposure of Pseudomonas to an antipseudomonal beta-lactam antibiotic has been shown to increase the risk of
developing resistance.[27] In a retrospective cohort study of 7,118 patients, each additional day of antipseudomonal beta-lactam
therapy was associated with a 4% increased risk of new resistance at 60-day follow-up. To avoid continuing resistance, diligent
efforts should be made to limit beta-lactam exposure to the shortest effective duration.

Enterobacteriaceae and AmpC

More than 100 species of Enterobacteriaceae exist, but a few pathogens in this family (Serratia marcescens, Morganella
morganii, Proteus vulgaris, Citrobacter species, and Enterobacter species) possess an inducible beta-lactamase enzyme known
as ampC.[28] The ampC enzyme, which is normally not expressed, does not appear to confer resistance against many
antibiotics upon first glance at a culture and sensitivity report, but this may be deceiving. Many penicillins and first- to third-
generation cephalosporins do not show resistance, but these agents activate ampC and will induce resistance. The presence of
ampC is not detectable by most laboratories, but if resistance to cefoxitin is displayed on culture and sensitivity reports, this can
serve as a surrogate marker for ampC, in which case penicillins and narrow-spectrum cephalosporins should be avoided.[29]

The Pharmacist's Role

Pharmacists serve as medication experts on healthcare teams, and given the rapid expansion of the pharmacist's professional
role, they are optimally positioned to assess treatment necessity and appropriate antibiotic selection. Their knowledge of
antibiotic mechanisms of action and strategies used by resistant bacteria enables pharmacists to make evidence-based
decisions about drug therapy even without formal training in infectious diseases. The Society of Infectious Diseases
Pharmacists recognizes that every pharmacist can contribute to AMS.[30]

Objective data have been published that illustrate the impact pharmacists have on the use of antimicrobials. A literature review
that investigated the clinical and economic impact of pharmacist-led interventions related to antimicrobial use showed a
decrease in antibiotic costs up to 95%, as well as reductions in readmission, mortality, and infection rates.[31] Selection of the
most appropriate agent positively affects patient outcomes and ensures the preservation of available antimicrobial resources.

Conclusion

The pathogens and mechanisms described in this article are limited to those that are involved in the global crisis of antimicrobial
resistance. Bacteria are ancient organisms equipped with the abilities necessary for survival in their environment, including the
host who is taking antibiotics. The gap between increasing resistance and drug development is growing wider, which
necessitates heightened AMS and a comprehensive understanding of how bacteria evade even the strongest available
antibiotics. The time expended in attempts to develop new antibiotics capable of withstanding the latest resistance mechanism
has proven futile. Pharmacist involvement in drug selection and AMS can improve patient outcomes and prevent further

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progression of bacterial resistance. Developing new medications is not the solution to this crisis, but preserving the available
agents is critical.

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US Pharmacist. 2020;45(3):HS-10--HS-16. © 2020 Jobson Publishing

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