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US
Pharm.
2006;1:HS-24-HS-28.
For more than 50 years,
pharmacists have dispensed antibiotics to treat infections caused by bacteria
and other microorganisms. After their discovery in 1928, antibiotics rapidly
grew in number and potency, causing doctors and scientists to almost entirely
disregard the challenge of treating bacterial diseases.1 However,
much has changed since then, as bacterial resistance now undermines the
efficacy of antimicrobial agents.
The misuse and overuse of
antibiotics have resulted in a continuous evolution of bacteria resistant to
the drugs that were previously able to control them. Bacterial resistance was
demonstrated when penicillin was first administered during clinical trials.
Initial cultures of Penicillium were contaminated with Escherichia
coli, which produced an enzyme that degraded penicillin. In the second
clinical trial in 1943, one of 15 patients died from a streptococcal infection
after E. coli had become resistant to the antibiotic.2 Soon
after, a description of penicillinase-producing strains of Staphylococcus
aureus was published in 1944, and scientists learned that bacteria could
become resistant to penicillin.3
Other bacteria have shown
antibiotic resistance. For example, clinicians have tried to control the
spread of methicillin-resistant S. aureus (MRSA) bacteria since it was first
identified in the 1960s. In the mid-1970s, Haemophilus influenzae and
Neisseria gonorrhoeae became resistant to penicillin. Even vancomycin,
often the antibiotic of last resort, is in jeopardy; in 2002, a
vancomycin-resistant S. aureus (VRSA) isolate was recovered from a
hospital patient in Michigan. The resistant determinant may have been acquired
through the exchange of genetic material from a vancomycin-resistant
enterococcus.
Researchers now know that
antibiotic-resistant genes existed long before humans began developing and
using antibiotics.2 Bacteria that create antibiotics are protected
by genes that make them resistant to the antibiotics they produce. Some
bacteria that do not produce antibiotics also have resistant genes. As a
result, many researchers are predicting a return to the pre–antibiotic era in
which only supportive treatment would be available to manage infections. While
the evolution of bacteria towards resistance to antimicrobial drugs represents
the general evolution of bacteria that is unstoppable, much can be done to
delay the subsequent spread of antibiotic resistance.4
How Widespread Is Bacterial
Resistance?
There has been an
alarming rise in resistant (often multidrug resistant) hospital- and
community-acquired bacteria during the past two decades both in the United
States and worldwide.5 Currently, every country in the world is
plagued with drug-resistant diseases such as gonorrhea and lethal
staphylococcal infections.4 According to the Public Health Action
Plan published in 2000, drug-resistant pathogens are a growing menace to all
people, regardless of age, gender, or socioeconomic background.6
Resistance increases and
occurs more rapidly with bacteriostatic agents (e.g., tetracyclines,
sulfonamides, macrolides) than with bactericidal drugs (e.g., aminoglycosides,
beta-lactams).7 Antimicrobial resistance is also more likely to
emerge when widespread usage is combined with suboptimal dosage.8
A number of clinically
important microbes have developed resistance to available antimicrobials, such
as Streptococcus pneumoniae (pneumonia, ear infections, and
meningitis), S. aureus and Pseudomonas aeruginosa (skin, bone,
lung, and bloodstream infections), E. coli (urinary tract infections),
Salmonella (foodborne infections), and Enterococcus and
Klebsiella spp. (infections transmitted in health care settings).
Up to 30% of S. pneumoniae
strains found in some parts of the U.S. are no longer susceptible to
penicillin, and multidrug resistance is common. Approximately 11% of these
strains are resistant to third-generation cephalosporins, and resistance to
fluoroquinolones has occurred. In addition, nearly all strains of S. aureus
in the U.S. are resistant to penicillin, many are resistant to newer
methicillin-related drugs, and some have a decreased susceptibility to
vancomycin. Many other pathogens, such as HIV, the bacteria that cause
tuberculosis and gonorrhea, the fungi that cause yeast infections, and the
parasites that cause malaria are becoming resistant to standard therapies.
The Mechanism of Resistance
Research efforts
previously directed toward discovering new antibiotics are now largely focused
on learning the mechanics of bacterial resistance. Bacteria have developed two
types of strategies for circumventing the action of antibiotics: (1) by
mutation where an alteration in a gene produces a change in later generations
or (2) by incorporating exogenous genetic material as described previously in
the first reported VRSA case in Michigan.9 The end result is a
decreased or complete lack of susceptibility of the organisms to antibiotics
that were previously effective. While some bacteria have intrinsic resistance
mechanisms that predate the introduction of antibiotics, others have developed
resistance due to many contributing factors, such as overuse, suboptimal
dosing, incorrect choice of antibiotic, incorrect duration of treatment, or
inappropriate route of administration.
Understanding the mechanisms
and effects of mutation can be quite complicated. For example, fluoroquinolone
resistance, in part, "arises from spontaneous mutations in the genes encoding
the enzyme subunits. With GyrA and ParC units of the resistant bacteria, amino
acid changes are generally localized to a region of the enzyme in the amino
terminus that contains the active site, a tyrosine that is covalently linked
to the broken DNA strand during enzyme action. For the GyrB and ParE subunits
of resistant bacteria, amino acid changes, when present, are usually localized
to the midportion of the subunit in a domain involved in interactions with
their complementary subunits."10 In simpler terms, bacteria
can become resistant to fluoroquinolones by making one or a few mutations to a
gene that encodes a DNA gyrase subunit, an enzyme involved in returning newly
replicated DNA to its supercoiled form. As a result, the antibiotic no longer
binds to the mutant enzyme.2
The mechanism of amino-lactam
resistance of S. pneumoniae involves genetic mutations that alter
penicillin-binding protein structure and results in decreased affinity for all
beta-lactam antibiotics.11 This mechanism of resistance is acquired
through a process known as natural transformation, in which a
particular genome encoding the alteration is picked up from other pneumococci
and incorporated into their own DNA. Bacteria, single-celled organisms, often
donate antibiotic-resistant genes to other species of bacteria in the human
body. There are three common forms of horizontal gene transfer: transduction,
conjugation, and transformation. Horizontal gene transfer is distinguished
from vertical transfer, which occurs between a parent and its offspring.
Horizontal gene transfers are fairly common in nature and may have contributed
to the genetic diversity now evident in bacteria.12
The ability of pneumococcal
strains to acquire resistance from a wide variety of organisms is particularly
disturbing, given the prevalence of enterococci bacteria that carry a
transferable gene for vancomycin resistance. Resistance to vancomycin occurs
when several genes encode several proteins that comprise a pathway for
changing the peptidoglycan cross-linking peptides into a form that no longer
binds vancomycin but can still be cross-linked by bacterial enzymes.2
MRSA and vancomycin-resistant enterococci (VRE) cause nosocomial infections
and are associated with increased rates of illness and death. Both organisms
are now endemic in many institutions, particularly in intensive care units.
13
Bacterial Strategies
Bacteria use
several strategies to combat antibiotics. First, they can produce specific
proteins that chemically modify the antibiotic to prevent the drug from
interfering with the activity that it was designed to inhibit. Second,
bacteria can insert a protein or efflux pump into its cytoplasmic membrane.
This pump can eject the antibiotic as soon as the antibiotic moves into the
cytoplasm. As a result, the concentration of the antibiotic in the vicinity of
the bacterial ribosomes is too low to effectively inhibit the synthesis of
bacterial proteins. A third strategy is to chemically modify or mutate the
target of the antibiotic so that no binding occurs. For example, some bacteria
become resistant to penicillin by mutating the enzymes that penicillin
inhibits, which are essential for forming the rigid cell wall.2
The Economic Impact of
Bacterial Resistance
The economic impact
of antimicrobial resistance is substantial. The estimated annual cost of
hospitalizations due to S. aureus infections is $122 million; for
nosocomial infections, the figure approaches $5 billion.14
Enterococci are the most common cause of nosocomial infections, and vancomycin
is often the only effective agent. Of approximately 19,000 deaths directly
caused by nosocomial infections in 1992, 28% were resistant to the preferred
antibiotic treatment in intensive care units, making nosocomial infections the
11th-leading cause of death in the U.S.14 In addition, more than
90% of strains of S. aureus in U.S. hospitals are resistant to
penicillin and beta-lactam antibiotics, and the incidence of VRE increased
20-fold between January 1989 and March 1993.14
Is There a Solution?
Clinicians today
should consider new approaches for treating patients while minimizing
excessive antibiotic use. It has been estimated that at least one half of
antibiotic use in the developed world--and perhaps more in the developing
world--is inappropriate.15 To help combat this problem, two
important points should be considered. First, when treating seriously ill
patients, potentially resistant pathogens must be covered even if it is
necessary to use a broader range of antibiotics. Second, antibiotics should
not be used in clinical situations in which the patient will not benefit from
receiving the drug, such as with viral upper respiratory infections.
Current research has proven
that a patient's likelihood of carrying a resistant organism is doubled if he
or she has taken any antibiotic for any reason with the previous two months.
16 This study demonstrated a dose-response relationship to increasing
exposure of trimethoprim, as well as increasing amoxicillin resistance with
any exposure to beta-lactam antibiotics.16
How to Counsel Patients
Patients should be
informed that most infections do not require antibiotics; in fact, antibiotics
may actually harm a patient by affecting the beneficial bacteria in his or her
body and may be detrimental to society by encouraging bacterial resistance.
17 Patients should be aware that antibiotics destroy beneficial bacteria
as well as pathogens. When infections are treated with an antimicrobial agent,
all bacteria in the host are affected, including the normal residents. This
can result in the selection of resistant commensals, particularly in children
who are frequently given oral antibiotics. These conditions favor the transfer
of genes from the surviving organisms to human pathogens.4
Moreover, non–disease-causing bacteria are essential parts of the body's
natural armor against infectious bacteria.18 It may appear that
compliance with an antibiotic regimen is more likely when pharmacists explain
the root causes of resistance to patients.
The Handbook of Antibiotics
, which provides a series of questions to address before an antibiotic is
selected, can help pharmacists counsel patients (table 1).19 The
Centers for Disease Control and Prevention (CDC) has sponsored several
conferences to promote appropriate antibiotic use in the community.
Information on the most recent conference is available on the CDC Web site and
can be used to enhance patient compliance.20 The FDA has addressed
the issue of bacterial resistance through a number of initiatives, including a
Public Health Action Plan to Combat Antimicrobial Resistance and a "Get Smart:
Know When Antibiotics Work" campaign.21 More information on
these initiatives is available on the FDA Web site.
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