Current Issues in and Approaches to Antimicrobial Resistance

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Current Issues in and
Approaches to Antimicrobial
Resistance
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ARI FRENKEL, MD
Infectious Disease Fellow
East Carolina University
Greenville, North Carolina
PAUL COOK, MD
Chief, Division of Infectious Diseases
East Carolina University
Greenville, North Carolina
Dr. Frenkel reports that he has no relevant
financial interests to disclose. Dr. Cook
reports that he has received grants and/
or research support from Gilead Sciences,
Merck, and Pfizer; that he owns shares
of Pfizer stock; and that he serves on the
speakers’ bureaus for Forest Laboratories
and Merck.
I
t is now well known that the use and
overuse of antibiotics has resulted
in increasing resistance by causing
breeding of microorganisms that are
no longer susceptible to available
antimicrobial agents.1 In 2010, health care
providers in the United States prescribed
outpatient setting; this translates into
833 prescriptions per 1,000 persons, and
these numbers do not include the use
of these drugs in hospitalized patients.2
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d.
258 million courses of antibiotics in the
It is estimated that up to 50% of all antibiotics prescribed in the United States in acute care hospitals are
improperly prescribed or needless.3
Annually, more than 2 million individuals are infected
with antibiotic-resistant organisms.4 These patients are
at increased risk for mortality and morbidity as well as
extended hospitalization, and increased health care
costs.5 The Centers for Disease Control and Prevention
(CDC) estimates that in the United States alone, more
than 23,000 people die as a result of antibiotic-resistant
infections each year.4 The cost of antimicrobial resistance has been estimated to exceed $20 billion.6,7 As a
result, the CDC now classifies antimicrobial resistance
as one of the most serious health threats worldwide.4
With advancements in areas such as chemotherapy
for cancer, transplant medicine, dialysis, and immunomodulating treatments for autoimmune diseases, the
need for effective antimicrobial agents has become
even more crucial. Health care providers often are left
with no choice but to treat with drugs that are frequently more expensive, more toxic, and less effective.4 Therefore, it is essential to have mechanisms
in place to reduce the unnecessary use of antibiotics
as well as the duration of use in patients who require
treatment.
INFECTIOUS DISEASE SPECIAL EDITION 2014
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Table 1. Summary of CDC Antimicrobial Resistance Threat Levels
Urgent Threats
Serious Threats
Clostridium
difficile
Acinetobacter
ESBLs
Non-typhoidal
Salmonella
MRSA
Concerning Threats
VRSA
CRE
Campylobacter
VRE
Salmonella
typhi
Streptococcus
pneumoniae
Group A
streptococcus
Gonorrhoeae
Candida
Pseudomonas
aeruginosa
Shigella
Tuberculosis
Group B
streptococcus
A
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CDC, Centers for Disease Control and Prevention; CRE, carbapenem-resistant Enterobacteriaceae; ESBLs, extended-spectrum
β-lactamases; MRSA, methicillin-resistant Staphylococcus aureus; VRE, vancomycin-resistant enterococci; VRSA, vancomycin-resistant
Staphylococcus aureus
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Adapted from reference 4.
s
At present, the CDC places resistant bacterial organisms into 3 categories: urgent, serious, and concerning (Table 1). Each category assigns a “hazard level” of
importance to the threat. An urgent threat refers to a
high consequence of antibiotic resistance, which poses
a significant threat to patients and has the potential to
become a public health concern. A serious threat can also
become an urgent threat, but frequently there are antimicrobial therapeutic options available. A concerning threat
refers to a low risk for resistance, but it is recommended
that bacteria in this category be monitored closely.4
Resistance in Gram-Negative Bacteria
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d.
Resistance of bacteria to antibiotics occurs in a variety
of ways. A common mechanism of resistance is production of β-lactamases, which are enzymes that hydrolyze
the β-lactam ring of penicillins, cephalosporins, and carbapenems, thereby rendering the drugs inactive.8
Although antibiotic resistance can occur in both
gram-positive and gram-negative bacteria (GNB), the
resistance mechanisms are much more complicated in
gram-negative organisms. GNBs such as Pseudomonas
aeruginosa, Klebsiella pneumoniae, and Acinetobacter
baumannii, tend to be highly resistant to antimicrobial
agents. In fact, these bacteria can become resistant to
nearly all antibiotics. The most concerning gram-negative
infections are health care–associated, as these tend to be
the most resistant; this is of particular concern in the ICU,
where some of the highest rates of multidrug-resistant
(MDR) GNBs are found.8
Indeed, patients in the ICU often develop colonization with MDR organisms that then make their way to
the long-term care facilities and even into the community.
This phenomenon can occur when ICU patients circulate
through acute and chronic health care facilities. Multidrug
resistance is defined as resistance by the organism to
more than 1 agent from 3 or more antimicrobial categories. When an organism is resistant to more than 1 agent
in all but 2 categories, it is referred to as extreme drug
resistance. Finally, when an organism is resistant to all
antibiotics, it is referred to as being pan-drug resistant.8,9
The clinically important β-lactamases in gram-negative organisms include AmpC, extended-spectrum
β-lactamases (ESBL), and carbapenemases (Table 2).10
Enterobacter and Citrobacter species commonly possess AmpC-type β-lactamases. These organisms are
typically resistant to first-, second-, and third-generation cephalosporins. The AmpC gene is chromosomal in Enterobacter and Citrobacter and is inducible
by β-lactams. The AmpC gene is poorly expressed or
not expressed in Escherichia coli and Klebsiella species, respectively, but the gene can be acquired from
a plasmid of another organism, thus giving it the same
phenotype as Enterobacter. The carbapenems are
the most reliable drugs for these organisms, although
cefepime, piperacillin/tazobactam, aminoglycosides,
trimethoprim/sulfamethoxazole, and tigecycline may
also be effective.10
ESBL-producing bacteria have the ability to hydrolyze penicillins, cephalosporins, and monobactams. Fortunately, these enzymes have no effect on carbapenems,
which are the drugs of choice for such infections. These
ESBL-producing organisms often carry genes on plasmids that make them resistant to other classes of antibiotics such as aminoglycosides and fluoroquinolones.10
Carbapenemase-producing organisms are increasingly being recognized in Enterobacteriaceae, most
commonly K. pneumoniae, and are designated carbapenemase-resistant Enterobacteriaceae (CRE).11 The carbapenemases are a diverse group of β-lactamases; the
common types are designated serine carbapenemases
(classes A, C, and D) and metallo-β-lactamases (class
B), so-called because of the critical importance of zinc
ion to β-lactamase activity. The latter class includes the
New Delhi metallo-β-lactamase (NDM-1). Because carbapenemase genes are located on plasmids, there is
the potential for rapid transfer of the genetic material to
other organisms, including other species and P. aeruginosa. Also, cotransfer of other resistance genes from the
same plasmid is common, making these organisms resistant to all β-lactams, aminoglycosides, fluoroquinolones,
and tetracyclines.11
Table 2. Summary of Clinically Relevant β-Lactamases in
Gram-Negative Bacteria
Pseudomonas
aeruginosa
Acinetobacter
AmpC β-lactamases

ESBL

Carbapenemases

DNA gyrase/
topoisomerase
mutations

Multidrug efflux
pumps

Porin mutations

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Enterobacteriaceae
Staphylococcus
aureus

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Aminoglycosidemodifying enzymes
Altered penicillinbinding protein

Penicillinase
ESBL, extended-spectrum β-lactamase
Adapted from references 9-12.
common MDR organisms. Treatment of MDR organisms
begins with broad-spectrum antibiotics for the suspected organism.17 Empiric antibiotic therapy should
be based on institution-specific antibiograms. Once an
organism is identified and susceptibilities are available,
antibiotics can be streamlined.17 In certain situations,
the only effective antibiotics are highly toxic drugs such
as colistin.18
In patients with MDR organisms or with CRE, colistin
is frequently used in combination with a carbapenem
such as meropenem. The effectiveness of treatment in
this scenario depends on the site of infection, control
of the source of infection (eg, drainage of an abscess),
and type of resistant organism. Host factors, including
immunosuppression, diabetes, renal function, and age
are major determinants of patient outcomes.17,18
There are investigational agents with activity against
β-lactamases, including carbapenemases. One of the
more promising drugs is avibactam, which has been
used in combination with ceftazidime (Novexel, Forest).
Avibactam has good activity against the class A, C, and
D carbapenemases, but no activity against the class
B metallo-β-lactamases (eg, NDM-1).19 Therefore, it is
important for microbiology laboratories to be able to
identify an organism as one with carbapenemase activity, and also to determine which class of carbapenemase is present.
Treatment of MDR Organisms
Preventing Resistance
Table 3 illustrates major mechanisms of resistance
and the common resistant patterns seen with the more
Preventing the development and spread of resistant
organisms is a difficult and multidisciplinary task that
d.
Ineffective binding of β-lactams to penicillin-binding
protein (PBP) 2a (a mutated form of PBP2) is responsible for the resistance of methicillin-resistant (MRSA).
Ceftaroline, a fifth-generation cephalosporin, is the only
commercially available β-lactam with activity against
MRSA.12 DNA gyrase and topoisomerase mutations lead
to decreased susceptibility to fluoroquinolones. Reduced
susceptibility to fluoroquinolones also may be due to
removal of the drug from the cell via efflux pumps.13,14
Efflux pumps are present in many bacteria and are
responsible for removal of a variety of substances,
including certain antimicrobial agents from the cell.
Upregulation of efflux pumps is a common mechanism
of resistance of both P. aeruginosa and A. baumannii to
carbapenems, particularly meropenem and doripenem,
and to fluoroquinolones. Other forms of resistance seen
with P. aeruginosa include aminoglycoside-modifying
enzymes, and metallo-β-lactamases.13-15
Finally, porins are outer membrane protein channels
that allow certain substances, including some antibiotics, to penetrate the bacterial cell membrane and wall.
Downregulation of the outer membrane proteins results
in resistance of the organism to the drug (eg, imipenemresistant P. aeruginosa). It is not uncommon for phenotypic resistance to certain antibiotics to be due to a
variety of mechanisms, including carbapenemase activity in the presence of decreased expression of porins.15,16
INFECTIOUS DISEASE SPECIAL EDITION 2014
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Table 3. Recommended Treatment of MDR Organisms
Common Organisms
Recommended Treatment
Comments
AmpC β-lactamase
Enterobacter
cloacae and other
Enterobacteriaceae
Pseudomonas
aeruginosa
Any carbapenem or
cefepime (Maxipime IV,
Hospira)
TMP-SMX, quinolone,
tigecycline also may be
effective
ESBL
Klebsiella pneumoniae and other
Enterobacteriaceae
Any carbapenem
TMP-SMX, quinolone,
tigecycline also may be
effective
K. pneumoniae
and other
Enterobacteriaceae
Meropenem or tigecycline
(Tygacil, Pfizer) + polymyxin E (colistin)
Rifampin plus colistin
also may be effective
Alteration of penicillinbinding protein
MRSA
Vancomycin
Daptomycin, linezolid,
TMP-SMX, ceftaroline
are alternatives
Mutation of DNA gyrase and
topoisomerase
Enterococcus faecium
(VRE)
Linezolid (Zyvox, Pfizer)
or daptomycin (Cubicin,
Cubist)
Tigecycline may be an
alternative agent
Decreased permeability plus
increased efflux plus
carbapenemases
P. aeruginosa
Acinetobacter
baumannii
Colistin
Tigecycline may be
effective against
certain strains of
A. baumannii
Aminoglycoside-modifying
enzymes
P. aeruginosa,
A. baumannii
Meropenem (Merrem IV,
AstraZeneca) or imipenem (Primaxin IV, Merck) or
piperacillin/tazobactam
(Zosyn, Pfizer) or cefepime
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Type of Resistance
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Carbapenemase
ESBL, extended-spectrum β-lactamase; MDR, multidrug-resistant; MRSA, methicillin-resistant Staphylococcus aureus;
TMP-SMX, trimethoprim/sulfamethoxazole; VRE, vancomycin-resistant enterococci
Adapted from references 17 and 18.
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W W W. I D S E . N E T
hospitals to report infections, antibiotic use, and resistance.4 The information obtained by these programs
provides insight and useful information on preventing
the spread of resistant infections. It also allows facilities
to aim at particular areas of interest and make needed
improvements.
ASPs, meanwhile, were designed to improve antibiotic use. These programs focus on prescribing the
correct antibiotics at the correct dose and reducing
the duration of antibiotics when longer durations are
no longer beneficial. These programs also reduce the
rates of infections with resistant organisms and with
C. difficile infection.20,21 Additionally, these programs
have proven to reduce treatment failures and improve
patient safety.22,23 Currently, the CDC recommends that
all acute care hospitals set up an ASP.24
For an ASP to function properly, it needs to have
financial support, drug expertise via dedicated pharmacists, the ability to implement recommendations, a
system to monitor the use of antibiotics and resistant
organisms, and the ability to educate others on optimal
antibiotic use. Effective ASPs demand close working
d.
involves both infection control and antimicrobial stewardship (see commentary, page 76). Effective infection
control programs limit the spread of resistant organisms through monitoring and surveillance. Antimicrobial stewardship programs (ASPs) improve the way in
which antibiotics are used by shortening the duration of
antibiotic treatment, limiting the use of broad-spectrum
agents, and monitoring the appropriateness of antibiotic use.
The CDC has implemented the Healthcare-Associated Infections Projects. This program involves a network of state health departments and their academic
medical centers. The program gathers information on
antibiotic resistance and tracks important information
such as the number and frequency of infections, and
those people at risk for the infection. Current programs
include Infection Tracking, Candida Bloodstream Infections, and Antibiotic Use Prevalence Survey. Other programs include Active Bacterial Core Surveillance, and
Healthcare-Associated Infections–Community Interface. Additionally, the CDC’s national Healthcare Safety
network is an electronic reporting system that enables
hospital: implications for antibiotic stewardship. Clin Infect Dis.
2009;49(8):1175-1184.
8. Brusselaers N, Vogelaers D, Blot S. The rising problem of antimicrobial resistance in the intensive care unit. Ann Intensive Care.
2011;1:47.
9. Nicasio AM, Kuti JL, Nicolau DP. The current state of multidrugresistant gram-negative bacilli in North America. Pharmacotherapy.
2008;28(2):235-249.
10. Kanj SS, Kanafani ZA. Current concepts in antimicrobial therapy
against resistant gram-negative organisms: extended-spectrum
beta-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and multidrug-resistant Pseudomonas
aeruginosa. Mayo Clin Proc. 2011;86(3):250-259.
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relationships with infectious diseases, pharmacy, the
microbiology laboratory, quality improvement, information technology, clinicians, and nurses.
ASPs often institute policies that instruct prescribers
on the recommended and appropriate dose, duration,
and indication for antibiotics. Ideally, this information
is made available to all prescribers and is based on
national guidelines. Prior authorization often is required
for antimicrobial agents that have a broad spectrum of
activity, and when there is a particular toxicity or side
effect associated with the antibiotic. ASPs often audit
charts to assure compliance with the regulations that
have been implemented.22,24 Although the primary
focus of antimicrobial stewardship is to assure appropriate use of antibiotics, ASPs also save money. In a
study at the University of Maryland, an ASP saved $17
million over an 8-year period.25
Another means of preventing overuse of antibiotics
and, as a result, the development of antibiotic-resistant
organisms is by appropriate vaccination. Pneumococcal
vaccine has been proven effective as a way to reduce
antibiotic-resistant Streptococcus pneumoniae.26 There
are 2 vaccines: the 23-valent polysaccharide vaccine
(Pneumovax, Merck) and the 13-valent conjugate vaccine (Prevnar 13, Pfizer). It is clear that these vaccines
are underused at present. Vaccination of at-risk populations should help reduce antibiotic use.
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Summary
The effect of antibiotics on the course of medicine
has been enormous. Ironically, antibiotic overuse has
led to increased resistance, and increased morbidity,
mortality, hospital length of stay, and cost. Discovery of
new drugs will be important in the fight against antibiotic resistance. Programs such as infection control and
ASPs are critical to prevent or reduce the growing problem of antibiotic resistance.
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