a GuIde To
suPerbuGs and
anTIbIoTIC resIsTanCe
2
Superbugs and Antibiotic Resistance: A Guide
Table of Contents
Introduction...........................................................................................................3
Bacteria basics...................................................................................................... 4
How are bacteria classified?.................................................................................... 4
The burden of nosocomial bacterial infections................................................. 6
How are bacterial infections treated?.................................................................. 7
What is antibiotic resistance?................................................................................. 9
How do bacteria develop resistance to medicines?......................................... 9
The impact of antibiotic resistance..................................................................... 10
A closer look at Gram-negative bacteria......................................................... 12
Drug-resistant Gram-negative infection.............................................................13
Resistance in Pseudomonas aeruginosa...............................................14
Resistance in Klebsiella pneumoniae.....................................................15
Resistance in Enterobacteriaceae...........................................................15
Resistance in Acinetobacter baumannii................................................15
What does the future hold for treatment of MDR bacteria?......................... 16
Glossary................................................................................................................ 18
Resources............................................................................................................ 22
References........................................................................................................... 23
Superbugs and Antibiotic Resistance: A Guide
3
Introduction
Bacteria can be beneficial or harmful. Beneficial bacteria co-exist with us, living in our gut and on our
skin, without causing disease. However, even “good” bacteria can become harmful when they find
their way to a different part of the body. They may also do harm when they infect someone who has a
compromised immune system, such as a hospitalized patient or someone with an underlying condition
like cancer or diabetes. Harmful bacteria can cause significant illness and even death. Infectious
diseases, including bacterial infections, are the second leading cause of death worldwide.1
Until recently, serious bacterial infections were almost always associated with hospitalization. More than
1.7 million patients in the United States develop a bacterial infection while in the hospital.2 Hospitalacquired – or “nosocomial” – infections cause more deaths than diabetes.2,3 A recent report from
the Agency for Healthcare Research and Quality indicated that while surveillance and diagnosis of
nosocomial infections has improved, rates of infection are not declining.4 In addition, serious infections
contracted outside the hospital have become much more common in recent years.5
Serious bacterial infections – whether they are acquired in or outside of the hospital – are treated
with antibiotics. However, the ability of bacteria to develop resistance to one or more antibiotics is a
growing concern. Methicillin-resistant Staphylococcus aureus, or MRSA, is a particularly worrisome form
of Gram-positive bacteria that was first seen only in hospitalized patients but can now be contracted
outside the hospital setting.5,6 Multi-drug resistance (MDR), which occurs when a bacterium becomes
resistant to three or more classes of antibiotics, is becoming especially common in certain types of
Gram-negative bacteria.7 The threat of MDR Gram-negative bacterial infections is escalating, with more
of these organisms appearing in hospital settings as well as exhibiting resistance to almost all available
treatment options.8-10 Treatment of these so-called “superbugs” remains challenging because the pool
of effective drugs is shrinking and few new Gram-negative antibiotics are in development.8,10
This handbook provides background on bacterial infections and MDR, with additional information
on Gram-negative bacteria. Our intent is to provide context for research and public policy initiatives
designed to understand, prevent, and manage this group of potentially life-threatening infections.
For additional information, please contact Francis McLoughlin at Cubist Pharmaceuticals (781) 860-8777 or [email protected]
Superbugs and Antibiotic Resistance: A Guide
4
Bacteria basics
How are bacteria classified?
Bacteria are primarily classified using a laboratory test known as Gram staining. The Gram stain,
developed by Hans Christian Gram in the late 1800s, identifies two main types of bacteria: Gramnegative and Gram-positive. The original designation was determined by the extent to which the
stain could be washed out of the cell; bacteria that didn’t keep the stain were pink and termed Gramnegative.11 Gram-positive bacteria retain the color of the stain and appear purple.11 The amount of stain
that can be retained is determined by the composition of the outermost part of the bacterium, known
as the cell wall. Even bacteria that cannot be stained by the traditional method are now classified into
these categories.11 Select examples of Gram-negative and Gram-positive bacteria and the diseases they
cause are listed in Tables 1 and 2.
The make-up of the bacterial cell wall not only affects Gram staining but also protects the bacteria from
medicines and a person’s immune system. Although the cell wall composition differs between Gramnegative and Gram-positive bacteria (see Figure 1), both structures form a tight barrier against the
outside environment.11 Few enzymes in the human body are capable of cutting through the cell wall to
destroy the bacterium. The medicine penicillin prevents the formation of a “water-tight” Gram-positive
cell wall, which leads to the destruction of certain bacteria.11 The complex structure of the Gramnegative cell wall protects the bacterium from immune system attack and prevents many antibiotics
from working.
Bacteria also differ in their pathogenicity and virulence, and these differences can be used to
classify them further. Pathogenicity is defined as the ability of the bacteria to cause disease in a
human, whereas virulence is the degree to which the bacterium causes disease.11 Some bacteria that
are normally found in the body, such as Escherichia coli (E. coli) in the colon, can be pathogenic but
are only moderately virulent because they typically only cause disease when they are transferred
to another part of the body.11 Species of bacteria can exist as different strains, with slightly different
genetic makeup. Strains can differ in their pathogenicity and virulence, as well as their response
to treatment. For example, when ingested, certain strains of E. coli can cause deadly food
poisoning outbreaks.
Superbugs and Antibiotic Resistance: A Guide
5
peptidoglycan
layer (cell wall)
pore protein
Figure 1. The bacterial cell wall.12
This figure illustrates the differences in complexity between
outer
membrane
the Gram-positive (A) and Gram-negative (B) cell walls.
Peptidoglycans are molecules composed of sugars and
space
proteins and are a common drug target. The Gram-positive
peptidoglycan
cell wall is composed of peptidoglycans and has two layers.
inner
membrane
The Gram-negative cell wall is more complex, with an outer
membrane
proteins
Gram-negative cell wall also contains pore proteins, which
membrane, a space and a layer of peptidoglycans. The
can pump things back out of the bacterium.
GRAM-POSITIVE
GRAM-NEGATIVE
A
B
Bacterium/Species
Table 1. Examples* of Gram-positive bacteria
Mycobacterium tuberculosis (M. tuberculosis)
Tuberculosis
Staphylococcus aureus (S. aureus)
Skin infections and abscesses,
bloodstream infections, pneumonia,
toxic shock syndrome (TSS)
Clostridium difficile (C. difficile)
Diarrhea
Streptococcus pyogenes (S. pyogenes)
“Strep throat,” scarlet fever, serious
deep tissue infections
Streptococcus pneumoniae (S. pneumoniae)
Pneumonia and meningitis
Enterococcus faecium (E.faceium)
Meningitis in infants
and the diseases they cause.11
*There are many disease-causing bacteria and not
Disease
all are represented within this table.
Superbugs and Antibiotic Resistance: A Guide
6
Bacterium/Species
Disease
Escherichia coli (E. coli)
Food poisoning, urinary tract
infections, various hospitalacquired infections
Treponema pallidum (T. pallidum)
Syphilis
Vibrio cholerae (V. cholerae)
Watery diarrhea (cholera)
Helicobacter pylori (H. pylori)
Chronic gastritis, ulcers
Neisseria meningitidis (N. meningitides)
Meningitis and blood infections
Neisseria gonorrhoeae (N. gonorrhoeae)
Gonorrhea
Pseudomonas aeruginosa (P. aeruginosa)
Pneumonia, septic shock, urinary
tract infections, intra-abdominal
infections, skin infections
The burden of nosocomial bacterial
infections
During a hospital stay, a patient can develop a
nosocomial infection through several means,
including:10
• Person-to-person transmission between
patients or between hospital staff and
patients.
• Implantation of a device, such as a catheter or
tube that can support the growth of bacteria.
• Transfer of a typically harmless bacterium
from the skin or gut to another site of the
body during or after a surgical procedure.
Klebsiella pneumoniae (K. pneumoniae)
Pneumonia, urinary tract infections
• Inhalation of bacteria that can cause disease
in someone who has poor immune system
function.
Acinetobacter baumannii (A. baumannii)
Necrotizing fasciitis, pneumonia,
urinary tract and bloodstream
infections
•L
oss of the protective skin barrier due to
bedsores, burns or surgical incisions.
Enterobacter cloacae (E. cloacae)
Respiratory and urinary tract
infections
Urinary tract infections (UTIs) and lower
respiratory tract infections are among the
most common nosocomial infections.10,13,14
Blood infections (bacteremia) can also occur
when bacteria enter through openings created
for catheters or tag along when devices
are implanted. Along with lower respiratory
infections, these pose the greatest risk to
patients.14 In some instances, blood infections
can develop after the original infection; these
infections are particularly dangerous. It is
estimated that up to 15 percent of bacterial
Table 2. Examples* of Gram-negative bacteria
and the diseases they cause.11
*There are many disease-causing bacteria and
not all are represented within this table.
7
Superbugs and Antibiotic Resistance: A Guide
blood infections originate from a UTI.10 Skin infections can also lead to blood infections. These
infections can be caused by Gram-negative and Gram-positive bacteria and may develop following
exposure via any of the means described above.
Hospital-acquired bacterial infections place a great burden on patients and the healthcare system.
The most recent estimate from the Centers for Disease Control indicates that direct cost of hospitalacquired infections, when adjusted for inflation, exceeds 30 billion dollars each year.15 In addition,
mortality and morbidity rates associated with infection in intensive care units (ICUs) are significant.16
Infections can account for more than 30 percent of the death rate after being hospitalized.17 Even
with treatment, bacterial infections result in longer hospital stays, the need for more medication
and increased risk of morbidity and death.10 For example, patients with hospital-acquired bacterial
infections spend, on average, 15 more days in the hospital and have an additional $156,000 in medical
costs compared to patients who do not develop an infection.18
How are bacterial infections treated?
Medicines that treat bacterial infections can act in multiple ways to help clear the infection, such as by
improving the immune system response, reducing inflammation caused by infection or directly acting
on the bacteria to kill it or stop it from reproducing (antibiotics). Antibiotics are a type of medicine
often derived from compounds produced by other bacteria or molds; they are effective in treating
many bacterial infections.11 Antibiotics are only effective in stopping the growth of bacteria, not other
infectious agents such as viruses and fungi. Antibiotics may be bactericidal, meaning that they not only
inhibit the growth of the bacteria but are also able to kill it.11
Antibiotics can have different mechanisms-of-action that work against the infecting pathogen. The vast
majority of antibiotics fall into the same class and work by preventing the cell wall of the bacteria from
forming (e.g., the beta-lactams, including penicillin) or inhibit the creation of bacterial proteins needed
for survival or reproduction.11 Antibiotics may also prevent bacterial genes from being copied, which
keeps the bacterium from reproducing.11
Figure 2 illustrates the general targets of antibiotics. Table 3 identifies drugs that fall into the two
classes of antibiotics (beta-lactams and non-beta-lactams) that target the cell wall to prevent it from
forming or break it apart.
Superbugs and Antibiotic Resistance: A Guide
8
gene synthesis
quinolones
rifampin
cell membrane polymixins
Figure 2. Targets of antibiotics.12
cell wall synthesis.
vancomycin, penicillins,
cephalosporins
DNA
protein synthesis.
tetracycline, streptomycin
erythromycin, chloramphenicol
Beta-lactams
Penicillin
Vancomycin
Methicillin
Bacitracin
Amoxicillin
Table 3. Antibiotics that work on the cell wall: the
beta-lactams and non-beta-lactams.11
Non-beta lactams
Cephalosporins
Carbapenems
9
box 1.
How.is.resistance.measured?
resistance to specific antibiotics is
determined by measuring “minimum
SuperbugS and antibiotic reSiStance: a guide
antibiotics vary in their ability to treat infections caused by different strains and species of bacteria.
the spectrum of an antibiotic is used to define its potency against different bacterial infections.11
broad-spectrum antibiotics are active against many organisms and, depending on the agent, may be
active against both gram-negative and gram-positive infections.11 narrow-spectrum antibiotics are only
effective against a few types of bacteria.11
inhibitory concentration” (Mic).11
the Mic corresponds to the lowest
More details on medicines used to treat gram-negative infections can be found on page 14 (see table 4).
concentration of drug that can
be used to treat the infection in a
What is antibiotic resistance?
laboratory setting.11 the Mic of an
bacteria can acquire the ability to survive in the presence of drugs that would normally kill them.
bacteria that are no longer susceptible to antibiotics and can survive in the presence of the drug are
called antibiotic-resistant.11 Various strains of the same bacteria may be present in an infected person;
treatment with an antibiotic kills susceptible but not resistant strains. this leads to the “selection”
of resistant strains. in some instances, bacteria can be resistant to multiple drugs; these strains are
considered multi-drug resistant (Mdr).7 Mdr bacteria are often referred to as “superbugs”. existing
medicines may no longer be effective in treating these infections.
antibiotic should fall within a range
that is tolerated by patients.
using this measurement,.susceptible.
bacteria have a Mic that falls within
the normal dosing range of the
antibiotic.11 bacteria can exhibit
different levels of susceptibility to
How do bacteria develop resistance to medicines?
different antibiotics.
bacteria develop antibiotic resistance through genetic changes that can occur when:19
unlike susceptible bacteria, resistant.
bacteria require doses of antibiotic
that have not been shown to be safe
or tolerable for patients.11
• genes move between different bacterial strains or between species.
• Mutations (genetic changes) happen that help confer resistance.
• genes that aid in survival are picked up from the host or environment.
(See box 1: How is resistance measured?)
More specifically, these changes can help the bacterium acquire resistance by:11
• Making it more difficult for the medicines to pass through the cell wall and get inside.
• actively pumping medicines out of the bacterium.
• changing the target of the antibiotic to prevent the drug from binding and having an effect.
• inactivating the antibiotic with bacterial enzymes.
10
Superbugs and Antibiotic Resistance: A Guide
These infections may be resistant to the normal medicines prescribed to treat them. Improper use and
over-prescription of antibiotics to treat humans, along with misuse of antibiotics given to animals and
used in agriculture, promotes development of resistance in these fast-growing, adaptable organisms
because it selects for those that can’t be killed by the antibiotic being used for treatment.19,20
The impact of antibiotic resistance
Antibiotic resistance is a serious global public health concern.20 The first antibiotic-resistant strains
of bacteria were identified more than 60 years ago.20 MDR has been identified in globally-prevalent
infections such as tuberculosis and S. aureus.20 Emerging antibiotic resistance is now being seen in
Gram-negative pathogens including P. aeruginosa. In addition, drug-resistant pathogens that were
previously only seen in hospital settings, such as MRSA, are becoming more common in the community
at large (see Box 2).6
There are few medicines in development to treat resistant forms of bacteria.8,10 Of particular importance
are the so-called ESKAPE bacteria because many of them are resistant to multiple medications:21,22
• Enterococcus, including E. faecium
• Staphylococcus aureus (S. aureus)
• Klebsiella, including K. pneumoniae
• Acinetobacter baumannii (A. baumannii)
• Pseudomonas aeruginosa (P. aeruginosa)
• Enterobacter species, including E. cloacae
The remainder of this guide will discuss resistance in Gram-negative bacteria as well as the growing
burden of MDR Gram-negative infections on the healthcare system.
SuperbugS and antibiotic reSiStance: a guide
11
box 2.
Case.study:.Trends.in.S. Aureus.antibiotic.resistance
S. aureus is known for its ability to rapidly develop resistance
to antibiotics.6 penicillin was introduced as a treatment for S.
aureus infections after World War ii. by the 1960s, more than
which led to the development and use of a second generation
penicillin, methicillin to treat this infection.8 by 2002, 57 percent
of S. aureus infections were resistant to methicillin (i.e MrSa).8
different strains of MrSa, with different types of resistance,
have emerged over the past two decades. these strains may be
resistant to penicillin, methicillin, and another antibiotic used
to treat these infections, vancomycin.6 the trends in MrSa
resistance are illustrated in the graph to the right.6 the first
strain of MrSa, MrSa-1, was identified in the 1960s. Subsequent
resistant strains were found in the 1970s and 1990s.
Historically, MrSa epidemics have been primarily associated
increasing burden of S. aureus resistance
80 percent of S. aureus infections were resistant to penicillin,
with healthcare and hospital-acquired infections, but now
ca-MrSa
Methicillin
introduced
penicillin
introduced
MrSa-iV
MrSa-i
MrSa-ii & -iii
penicillin
resistance
community-acquired MrSa infections in otherwise healthy
individuals are becoming more prevalent.6 community-acquired
MrSa (ca-MrSa) was first observed in the 2000s, as shown in
the graph to the right. recent evidence suggests that epidemics
of MrSa come in waves as more pathogenic and virulent strains
appear, and that community-acquired infections will place a
greater burden on patients and the healthcare system in the
coming years.6
1940
1960
1980
2000
Superbugs and Antibiotic Resistance: A Guide
12
A closer look at Gram-negative bacteria
Gram-negative bacteria are a source of both community and hospital-acquired infections. Overall,
infections caused by Gram-negative bacteria now account for more than 30 percent of common
hospital-acquired infections.23 In addition they are the leading causes of nosocomial pneumonia and
UTIs.14
In a 2009 study, 62 percent of patients hospitalized in an intensive care unit with a respiratory infection
had a Gram-negative infection.16 Patients who had been in the hospital for a longer time period had not
only higher rates of infection, but higher rates of drug-resistant infections with Gram-negative species
such as Pseudomonas and Acinetobacter.16
As described earlier, the structure of the Gram-negative cell wall provides a unique barrier to
antibiotics, which are often not able to cross it. The Gram-negative cell wall also contains proteins
called efflux pumps, or pore proteins, that push medicines back out of the bacterium before they can
have an effect. In addition, some Gram-negative species, such as Pseudomonas, are able to form a
grouping of bacterial cells called a biofilm.24 The biofilm provides a further defense against antibiotics.24
Gram-negative bacteria are also proficient at developing drug resistance.14 In many instances, Gramnegative species can use multiple mechanisms to protect themselves against one antibiotic.7,14 MDR
Gram-negative infections are associated with pneumonia and catheter-related bloodstream infections,
co-infections with other bacteria and fungi, and higher mortality in hospitalized patients.25
Rates of drug-resistant Gram-negative infections are rising and likely will continue rising, placing an
increasing burden on the healthcare system (See Figure 3).8,10,24,26
SuperbugS and antibiotic reSiStance: a guide
13
Key gram-negative culprits in nosocomial infection
include E. coli and four of the six eSKape bacteria:
% incidence
• Klebsiella, including K. pneumoniae
60
• A. baumannii
50
• P. aeruginosa
40
MrSa
30
FQrp
20
10
0
1980
1985
1990
1995
2000
• Enterobacter species, including E. cloacae
Drug-resistant Gram-negative infections
resistance is a growing problem with infections caused
by gram-negative bacteria, particularly those found in
hospital settings.21 treatment of these infections varies
between species. common treatments and mechanisms
of resistance to those treatments are shown in table 4.
Like gram-positive bacteria, gram-negative bacteria can
acquire resistance through multiple means. the type of
resistance determines which class of drug will no longer
be effective. For example:14,24
FIGuRe. 3.. Rising. incidence. of. drugresistant. infections. in. the. united.
States. .incidence of the gram-positive
8
infection MrSa and the gram-negative
infection
fluoroquinolone-resistant
P.
aeruginosa (FQrp) have been steadily
rising since the 1990s.
• changes to the cell wall that prevent antibiotics
from entering or limit their activity against the cell
wall affect penicillins, including methicillin.
• changes to the pumps (pore proteins) found in the
bacterial cell wall can affect most classes of drugs.
• acquisition of genes that produce extendedspectrum beta lactamases (eSbLs), enzymes
that break down antibiotics and prevent them
from working.11 antibiotics sensitive to eSbLs
include penicillins and cephalosporins, along
with some carbapenems.
SuperbugS and antibiotic reSiStance: a guide
14
• production of enzymes that modify aminoglycoside antibiotics, or break down cephalosporin
antibiotics (cephalosporinases) or carbapenem antibiotics (carbapenemases).
• changes to proteins that help make bacterial genetic material can confer resistance to quinolones
or other compounds.
in many instances, gram-negative bacteria have combinations of these resistance mechanisms, making
treatment difficult. they are considered Mdr when they have picked up three or more resistance
mechanisms.7
TABle.4..examples.of.treatments.
and. resistance. mechanisms. of.
Treatment
Resistance.Seen
Mechanisms.of.resistance
Gram-negative.bacteria.14,24,27
box 3.
Pseudomonas aeruginosa:.
The.next.superbug?
recent
surveillance
data
has
indicated that various antibiotic-
Beta lactams
penicillins
cephalosporins
carbapenems
P. aeruginosa
Enterobacter
Klebsiella
Acinetobacter
• cephalosporinases
• extended spectrum-beta
lactamases (eSbLs)
• carbapenemases
Quinolone/
Fluoroquinolones
P. aeruginosa
Acinetobacter
• Mutations in target of
antibiotic
Aminoglycosides
P. aeruginosa
Acinetobacter
• Modification of
aminoglycoside by bacterial
enzymes
resistant forms of P. aeruginosa
are becoming more prevalent
in
u.S.
hospitals.
28
Since
the
last measurements were taken
from 1998-2002, resistance to
antibiotics in this species has
increased nine to 20 percent
Resistance in Pseudomonas aeruginosa
depending on the antibiotic.28
P. aeruginosa can cause disease at multiple sites in the body. it is a common cause of blood infections,
utis, pneumonia, and can also cause intra-abdominal infections.14 resistance to beta-lactams is most
common in P. aeruginosa.24 Mechanisms of resistance can be picked up not only from other bacteria,
but from the environment, making prevention uniquely challenging. Multiple resistance mechanisms
within one bacterium are also common and combinations of antibiotics are typically used as first-line
therapy to circumvent potential resistance.24
resistance to specific antibiotics
can range from one to 31 percent
in P. aeruginosa strains isolated
from hospitals.28,29
Superbugs and Antibiotic Resistance: A Guide
15
Risk factors for a resistant Pseudomonas infection include:24
• Patients in hospital settings, including intensive care units and burn victims.
• Patients with previous exposure to broad-spectrum antibiotics.
• Patients with cystic fibrosis are very susceptible because they are prone to lung infections and are
aggressively treated with a variety of antibiotics.
• Nursing home residents.
Pseudomonas resistance to currently available antibiotics is rising in hospital settings and new
medicines are needed to treat these potentially life-threatening infections (see Box 3: Pseudomonas
aeruginosa: The Next Superbug?).
Resistance in Klebsiella pneumoniae
K. pneumoniae is most often associated with pneumonia and occasionally with UTIs.14 However, it
is also commonly seen as a cause of blood infections.14 K. pneumoniae often shows resistance to
cephalosporins and carbapenems.24,27
Resistance in Enterobacteriaceae
The Enterobacteriaceae species, including E. cloacae, can cause pneumonia, UTIs and blood stream
infections.14 Common types of resistance seen with this group of bacteria include production of ESBLs
and carbapenemases.14,27 Carbapenem-resistant Enterobacteriaceae are particularly difficult to treat.9
Resistance in Acinetobacter baumannii
A. baumannii is a significant cause of pneumonia in intensive care units (ICUs), but rarely causes
UTIs.14,30 These bacteria are particularly resistant to carbapenems and treatment is further complicated
by their ability to form biofilms.14,31 Wounded military personnel returning from combat zones are
particularly at risk for contracting MDR A. baumannii infections.31 In one study performed at a military
hospital, the percentage of MDR A. baumannii isolated rose from four percent to 55 percent over a
seven-year span.32
Superbugs and Antibiotic Resistance: A Guide
16
What does the future hold for the treatment
of MDR bacteria?
As resistance in several Gram-negative species, such as P. aeruginosa, becomes more prevalent,
doctors are turning to older treatments since few other options exist. These older antibiotics, such
as the polymixins, are currently being used to treat carbapenem-resistant Gram-negative bacteria
despite potential toxic side effects for patients.14,21 Not only are new, safer agents needed to treat
these infections, but novel agents that work in different ways than existing medicines are necessary to
prevent cross-resistance to drugs in the same class.8,10 Since 1998, only two novel antibiotics have been
approved in the U.S.33 In addition, a 2009 report from the Infectious Disease Society of America (IDSA)
found that of all compounds in development for the treatment of MDR infections, none had an entirely
Gram-negative spectrum.21
16
Figure
4.
New
antibacterial
agents
approved in the United States, 1983–2007,
per 5-year period33
Number of new antibacterials
14
12
10
8
6
4
2
0
1983-1987
1988-1992
1993-1997
1998-2002
2003-2007
SuperbugS and antibiotic reSiStance: a guide
17
overall, a steady decline has been observed in the approval of new antibacterial agents
in the u.S. (See Figure 4).33 While there is a small pipeline of investigational antibacterial
agents, they are progressing slowly through clinical development, limiting the availability
of new agents to treat emerging Mdr bacterial strains. there are several well-known
factors that contribute to the delay in development of antibacterials, including:
box 4.
New.Antibiotic.Development.
Call.to.Action21
in 2009, idSa published a follow-up report
to its 2004 call-to-action for researchers,
• the high cost of antibiotic development.8,19
policy makers and government institutions,
“bad bugs, no drugs: as antibiotic discovery
• the short treatment length with antibiotics compared to medicines used to treat
chronic conditions, which reduces the return on investment for developers.8,19
• the difficulty of conducting clinical trials to determine the efficacy and safety of
investigational antibacterial compounds.19 Studies are typically required for each
potential indication (i.e. uti, pneumonia) and investigators have difficulty enrolling
large numbers of patients infected with Mdr bacteria.8 also, placebo-controlled
studies, the original gold standard for evaluation of new antibiotics, are not feasible
in patients with Mdr bacterial infections, who would likely die with no treatment.19
For these reasons, the idSa has proposed that new regulatory approaches are
needed to facilitate the development and approval of new antibiotics.34
in an effort to remedy these and other concerns, the Food and drug administration, the
centers for disease control, and the national institutes of Health released a draft “public
Health action plan to combat antimicrobial resistance” in March 2011 that includes
recommendations and roles for the government agencies in surveillance, prevention and
control, research, and product development.35 in addition, the idSa released updated
policy recommendations in February 2011 highlighting the importance of adopting
economic incentives for antibiotic developers, the need for new regulatory approaches
to antibiotic development and the requirement for cooperation between federal
agencies, researchers and drug developers.34
it is critical for resources to be invested by all parties, including academic researchers,
governmental agencies, policy makers, and pharmaceutical companies, to develop novel,
safe and effective treatments for the life-threatening diseases caused by Mdr bacteria
(see box 4: new antibiotic development call-to-action).21
Stagnates…a public Health crisis brews.” in
this newer report, idSa urges:
“now, more than ever, it is essential to create
a robust and sustainable antibacterial research
and development infrastructure – one that can
respond to current antibacterial resistance
now and anticipate evolving resistance. this
challenge requires that industry, academia,
the national institutes of Health, the Food and
drug administration, the centers for disease
control and prevention, the u.S. department
of defense, and the new biomedical advanced
research and development authority at the
department of Health and Human Services
work productively together.”
interagency
engagement
will
help
raise
awareness of the threat of Mdr bacteria;
promote research and development of novel
compounds to treat these potentially deadly
infections; and aid in the development of
surveillance
and
prevention
protect against Mdr outbreaks.
measures
to
Superbugs and Antibiotic Resistance: A Guide
18
Glossary
Acinetobacter baumannii (A. baumannii)
A Gram-negative bacterium that is also one of the ESKAPE bacteria.21,22
Antibiotics
Medicines that kill a bacterium or stop it from reproducing to limit an infection.
Antibiotic-resistant bacteria
Bacteria that are no longer susceptible to antibiotics and survive in the presence of a drug used to treat
the infection.11
Bacteremia
A bacterial blood infection.
Bactericidal
Describes antibiotics that kill a bacterium, rather than simply stop its growth.11
Beta-lactams
A class of antibiotics that act on the cell wall to kill bacteria.11 Specific types of beta-lactam antibiotics
are the penicillins, cephalosporins and carbapenems.11
Biofilm
A grouping of bacterial cells that forms a film on a surface and provides extra protection against
antibiotics.24 P. aeruginosa is a species of bacteria that forms biofilms.24
Broad-spectrum
Describes antibiotics that are active against many organisms. Depending on the agent, may be active
against both Gram-negative and Gram-positive infections.11
19
Superbugs and Antibiotic Resistance: A Guide
Cell wall
The outer barrier of a bacterium. The composition of the cell wall determines whether bacteria are
Gram-positive or Gram-negative.12 Some antibiotics are unable to easily cross the cell wall to gain entry
into the bacterium.
Enterobacteriaceae
A Gram-negative bacteria species that is also one of the ESKAPE bacteria.21,22
ESKAPE bacteria
Six Gram-negative and Gram-positive bacteria that not only cause the majority of nosocomial
infections, but are also becoming increasingly resistant to available antibiotics.22 The ESKAPE
bacteria include: Enterococcus, including E. faecium; Staphylococcus aureus; Klebsiella, including
K. pneumoniae; Acinetobacter baumannii; Pseudomonas aeruginosa; and the Enterobacter species,
including E. cloacae.22
Gram-negative bacteria
Bacteria that have a complex cell wall and do not retain the color of the gram stain.11 Examples of Gramnegative bacteria are Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa).
Gram-positive bacteria
Bacteria that retain the color of the gram stain.11 Examples of Gram-positive bacteria are
Staphylococcus aureus (S. aureus) and Clostridium difficile (C. difficile).
Klebsiella pneumoniae (K. pneumoniae)
A Gram-negative bacterium that is also one of the ESKAPE bacteria.21,22
Minimum inhibitory concentration (MIC)
The lowest concentration of drug needed to inhibit bacterial growth in a laboratory setting.11
Methicillin-resistant Staphylococcus aureus, or MRSA
A Gram-positive bacterium that is often multi-drug resistant.
Superbugs and Antibiotic Resistance: A Guide
20
Multi-drug resistance (MDR)
Resistance of a bacterium to multiple antibiotics. Typically defined as resistance to three or more
antibiotic classes.7
Narrow-spectrum
Antibiotics that are only effective against a few types of bacteria.11
Nosocomial infection
A hospital-acquired infection.13
Pathogenicity
The ability of a bacterium to cause disease in a human.11
Pseudomonas aeruginosa (P. aeruginosa)
A Gram-negative bacterium that is also one of the ESKAPE bacteria.21,22
Resistant bacteria
Bacteria that have a high MIC and require doses of antibiotic that have not been demonstrated to be
safe or tolerable for patients.11
Selection
When treatment kills susceptible strains of bacteria, but not resistant strains, leaving the resistant
strains to survive and replicate.20
Spectrum
A term used to define the potency of an antibiotic against different bacterial infections. Antibiotics may
have broad or narrow spectrums.11
Strains
A group of bacteria within a species that have a slightly different genetic makeup. Strains can differ in
susceptibility and resistance to antibiotics.
21
Superbugs and Antibiotic Resistance: A Guide
Susceptible bacteria
Bacteria with a MIC that falls within the range where drug levels are achieved with normal dosing of
an antibiotic.11
Superbugs
Bacteria that have a high MIC and require doses of antibiotic that have not been demonstrated to be
safe or tolerable for patients; these bacteria are resistant to multiple antibiotics and may no longer
treatable with available medicines. Also see resistant bacteria and multi-drug resistant bacteria.
Virulence
The degree to which a bacterium causes disease.11
Superbugs and Antibiotic Resistance: A Guide
22
Resources
American Society for Microbiology (ASM)
http://www.asm.org/
Centers for Disease Control and Prevention (CDC): Antibiotic/Antimicrobial Resistance website
http://www.cdc.gov/drugresistance/index.html
Food and Drug Administration (FDA): Antibiotic Resistance website
http://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/
AntibioticsandAntibioticResistance/default.htm
Infectious Disease Society of America (IDSA)
http://www.idsociety.org/default.aspx
Institute of Medicine (IOM)
http://www.iom.edu/
National Institutes of Health (NIH)
http://www.nih.gov/
National Institute of Allergy and Infectious Diseases (NIAID): Antimicrobial Resistance
http://www.niaid.nih.gov/topics/antimicrobialresistance/Pages/default.aspx
Society for Healthcare Epidemiology of America (SHEA)
http://www.shea-online.org/
World Health Organization
http://www.who.int/en/
Superbugs and Antibiotic Resistance: A Guide
23
References
1. World Health Organization. The global burden of disease: 2004 Update. 2004. http://www.who.int/
healthinfo/global_burden_disease/2004_report_update/en/index.html. Accessed April 13, 2011.
2. Klevens RM, Edwards JR, Richards Jr CL, et al. Estimating health care-associated infections and
deaths in U.S. hospitals, 2002. Public Health Rep. 2007;122:160-166.
3. Kochanek KD, Murphy SL, Anderson RN, Scott, C. Deaths: Final data for 2002. Natl Vital Stat Rep.
2004;53(5):1-116.
4. Agency for Healthcare Quality and Research (AHQR). 2009 National Healthcare Quality Report:
Patient safety. Updated March 2010. http://www.ahrq.gov/qual/nhqr09/Chap3.htm. Accessed April
13, 2011.
5. Centers for Disease Control. People at Risk of Acquiring MRSA Infections. Updated August 9, 2010.
http://www.cdc.gov/mrsa/riskfactors/index.html. Accessed April 26, 2011.
6. Chambers HF, DeLeo FR. Waves of resistance: Staphylococcus aureus in the antibiotic era. Nat Rev
Microbiol. 2009;7:629-641.
7. Hirsch EB and Tam VH. Impact of multidrug-resistant Pseudomonas aeruginosa infection on patient
outcomes. Expert Rev Pharmacoeconomics Outcomes Res. 2010;10(4):441-451.
8. Infectious Disease Society of America (IDSA). Bad Bugs, No Drugs: As antibiotic discovery
stagnates…A public health crisis brews. 2004. http://www.idsociety.org/10x20.htm. Accessed
April 13, 2011.
9. Nordmann P, Cuzon G, Naas T. The real threat of Klebsiella pneumoniae carbapenemase-producing
bacteria. Lancet Infect Dis. 2009;9(4):228-236.
10. Decision Resources. Gram-Negative Infections. 2009. Waltham, MA.
11. Ryan K, Ray CG, Ahmad N, Drew WL, Plorde J. Sherris Medical Microbiology. 5th edition. The McGraw
Hill Companies, Inc. 2010.
12. Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York:Garland
Science; 2002.
13. World Health Organization. Prevention of hospital-acquired infections: A practical guide, 2nd edition.
2002. http://www.who.int/csr/resources/publications/drugresist/WHO_CDS_CSR_EPH_2002_12/
en/. Accessed April 13,2011.
24
Superbugs and Antibiotic Resistance: A Guide
14. Peleg AY, Hooper DC. Hospital-acquired infections due to Gram-negative bacteria. N Engl J Med.
2010;362:1804-1813.
15. Scott RD. The direct medical costs of healthcare-associated infections in U.S. hospitals and the
benefits of prevention. Updated March 2009. www.cdc.gov/ncidod/dhqp/pdf/Scott_CostPaper.pdf.
Accessed April 26, 2011.
16. Vincent J-L, Rello J, Marshall J, et al. International study of the prevalence and outcomes of infection
in intensive care units. J Am Med Assoc. 2009;302(21):2323-2329.
17. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G,Carcillo J, Pinsky MR. Epidemiology of severe
sepsis in the United States: Analysis of incidence, outcome and associated costs of care. Crit Care
Med. 2001;29(7):1303-1310.
18. Pennsylvania Health Care Cost Containment Council (PHCCC). Hospital-acquired infections in
Pennsylvania: Data reporting period: 2006 & 2007. 2009. http://www.phc4.org/reports/hai/07/
default.htm. Accessed April 13, 2011.
19. Choffnes ER, Relman DA, Mack A, Rapporteurs, Forum on Microbial Threats and the Institute of
Medicine. Antibiotic resistance: Implications for global health and novel intervention strategies:
Workshop summary. 2010. http://www.nap.edu/catalog.php?record_id=12925. Accessed
April 13, 2011.
20. World Health Organization (WHO). Antimicrobial resistance: A global threat. Essential Drugs
Monitor. 2000;28-29:1-36.
21. Boucher HW, Talbot GH, Bradley JS, et al. Bad bugs, no drugs: No ESKAPE! An update from the
Infectious Diseases Society of America. Clin Infect Dis. 2009;48:1-12.
22. Rice LB. Federal funding for the study of antimicrobial resistance in nosocomial pathogens: No
ESKAPE. J Infect Dis. 2008:197;1079-1081.
23. Hidron AI, Edwards JR, Patel J, et al. Antimicrobial-resistant pathogens associated with healthcareassociated infections: Annual summary of data reported to the National Healthcare Safety Network
at the Centers for Disease Control and Prevention, 2006-2007. Infect Control Hosp Epidemiol.
2008;29(11)996-1011.
24. K
unz AN, Brook I. Emerging resistant Gram-negative aerobic bacilli in hospital-acquired infections.
Chemotherapy. 2010;56:492-500.
25. Raymond DP, Pelletier SJ, Crabtree TD, et al. Impact of antibiotic-resistant Gram-negative bacilli
infections on outcome in hospitalized patients. Crit Care Med. 2003;31(4):1035-1041.
25
Superbugs and Antibiotic Resistance: A Guide
26. Brown NP, Pillar CM, Sahm DF, Peterson J, Yektashenas B. Trends towards increased resistance
among clinically important Gram-negative pathogens in the US; Results from 10 years of TRUST
surveillance (1999-2009). Poster presented at: 50th Interscience Conference on Antimicrobial
Agents and Chemotherapy; September 2010; Boston MA. Abstract C2-696.
27. Kanj SS, Kanafani ZA. Current concepts in antimicrobial therapy against resistant Gram-negative
organisms: Extended-spectrum b-lactamase-producing Enterobacteriaceae, carbapenemresistant Enterobacteriaceae, and multidrug-resistant Pseudomonas aeruginosa. Mayo Clin Proc.
2011;86(3):250-259.
28. National Nosocomial Infections Surveillance (NNIS) System. National Nosocomial Infections
Surveillance (NNIS) System report, data summary from January 1992 through June 2004, issued
October 2004. Am J Infect Control. 2004;32:470-485.
29. Z
hanel GG, Decorby M, Adam H, et al. Antimicrobial resistance in 18,538 pathogens from Canadian
hospitals: CANWARD study 2007-2009. Poster presented at: 50th Interscience Conference on
Antimicrobial Agents and Chemotherapy; September 2010; Boston MA. Abstract C2-698.
30. Gaynes R, Edwards JR, and the National Nosocomial Infections Surveillance System. Overview of
nosocomial infections caused by Gram-negative bacilli. Clin Infect Dis. 2005;41(6):848-854.
31. Dallo SF, Weitao T. Insights into acinobacter war-wound infections, biofilms and control. Adv Skin
Wound Care. 2010;23(4):169-174.
32. Keen EF 3rd, Murray CK, Robinson BJ, Hospenthal DR, Co EM, Aldous WK. Changes in the
incidences of multidrug-resistant and extensively drug-resistant organisms isolated in a military
medical center. Infect Control Hosp Epidemiol. 2010;31(7):728-732.
33. Spellberg B, Powers JH, Brass EP, Miller LG, Edwards JR. Trends in antimicrobial drug development:
Implications for the future. Clin Infect Dis. 2004;38:1279-1286.
34. Infectious Disease Society of America (IDSA). Combating antimicrobial resistance: Policy
recommendations to save lives. Clin Infect Dis. 2011;52(Suppl 5):S397-S428.
35. Interagency Task Force on Antimicrobial Resistance, co-chaired by the Centers for Disease Control
and Prevention, the Food and Drug Administration and the National Institutes of Health. A public
health action plan to combat antimicrobial resistance. Updated March 2011. http://wwwn.cdc.gov/
publiccomments/comments/a-public-health-action-plan-to-combat-antimicrobial-resistance-draft.
aspx. Accessed April 13, 2011.