US
Pharm. 2006;5(Student suppl):14-17.
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
Several 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.
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 (e.g., 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 Antibiotic
s, which provides a
series of questions to address before an antibiotic is selected, can help
pharmacists counsel patients.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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