Bacteriology at UW-Madison
The Microbial World
Lectures in Microbiology by Kenneth Todar PhD University of Wisconsin-Madison Department of Bacteriology
Bacterial Resistance to Antibiotics
© 2009 Kenneth Todar PhD
In the past 60 years, antibiotics have been critical in the fight
against infectious disease caused by bacteria and other microbes.
Antimicrobial chemotherapy has been a leading cause for the dramatic
rise of average life expectancy in
the Twentieth Century. However, disease-causing microbes that have
become resistant to antibiotic drug
therapy are an increasing public health problem. Wound infections,
gonorrhea, tuberculosis, pneumonia, septicemia and childhood ear
just a few of the
diseases that have become hard to treat with antibiotics. One part of
problem is that bacteria and other
microbes that cause infections are remarkably resilient and have
developed several ways to resist antibiotics and other antimicrobial
drugs. Another part of the problem is due to increasing
use, and misuse, of existing antibiotics in human and veterinary
medicine and in agriculture.
In 1998, in the
United States, 80 million prescriptions of antibiotics for human use
were filled. This equals 12,500 tons in one year. Animal and
agricultural uses of antibiotics are added to human use. Agricultural
practices account for over 60% of antibiotic usage in the U.S., so this
adds an additional 18,000 tons per year to the antibiotic burden in
Nowadays, about 70 percent of the bacteria that cause infections in
hospitals are resistant to at least one of the drugs most commonly used
treatment. Some organisms are resistant to all approved antibiotics and
can only be treated
with experimental and potentially toxic drugs. An alarming increase in
of bacteria that cause community acquired infections has also been
especially in the staphylococci and pneumococci (Streptococcus
which are prevalent causes of disease and mortality. In a recent study,
25% of bacterial pneumonia cases were
shown to be resistant to penicillin, and an additional 25% of cases
resistant to more than one antibiotic.
Microbial development of resistance, as well as economic incentives,
resulted in research and development in the search for new
antibiotics in order to maintain a pool of effective drugs at all
times. While the development of resistant strains is inevitable, the
slack ways that we administer and use antibiotics has greatly
exacerbated the process.
Unless antibiotic resistance problems are detected as they emerge, and
actions are taken immediately to contain them, society could be faced
with previously treatable diseases that have become again untreatable,
as in the days before antibiotics were developed.
History of antibiotics and emergence of
The first antibiotic, penicillin, was discovered in 1929 by Sir
Alexander Fleming, who observed inhibition of staphylococci on an agar
plate contaminated by a Penicillium mold. Fleming was
searching for potential antibacterial compounds.
He noticed that a patch of the mold Penicillium notatum had
grown on a plate containing the bacterium Staphylococcus and
that around the mold there was a zone where no Staphylococcus
could grow. After more research, he was able to show that culture broth
of the mold prevented growth of the Staphylococcus
even when diluted up
to 800 times. He named the active substance penicillin but was unable
to isolate it.
In the center of the plate is a
colony of Penicillium notatum, a mold that produces penicillin.
After appearance of the mold colony, the plate was overlaid with a
bacterial culture of Micrococcus
luteus which forms a yellow "lawn" of
growth. A zone of inhibition of bacterial growth surrounds the fungal
colony where penicillin has diffused into the medium.
later, in 1939, Ernst Chain and
Howard Florey developed a way to isolate penicillin and used it to
treat bacterial infections during the Second World War. The new drug
came into clinical usage in 1946 and made a huge impact on public
health. For these discoveries Fleming, Chain and Florey were awarded
the Nobel prize in 1945. Their discovery
and development revolutionized modern medicine and paved the way for
the development of many more natural antibiotics.
In 1946, penicillin became
available for treatment of bacterial infections, especially those
by staphylococci and streptococci. Initially, the antibiotic was
effective against all sorts of infections caused by these two
Gram-positive bacteria. Penicillin had unbelievable ability to kill
these bacterial pathogens without harming the host that harbored them.
It is important to note that a significant fraction of all human
infections are caused by these two bacteria (i.e., strep
throat, pneumonia, scarlet fever, septicemia, skin infections, wound
While Fleming was
working on penicillin, Gerhard Domagk, a German doctor, announced the
discovery of a synthetic molecule with antibacterial properties. He
named the compound Prontosil, and it became the first of a long series
synthetic antibiotics called sulfonamides or sulfa drugs. Prontosil was
introduced to clinical use in the 1930s and was used to combat urinary
tract infections, pneumonia and other conditions. While sulfa drugs in
many cases are not as effective as natural antibiotics, they are now in
widespread use for the treatment of many conditions. Gerhard Domagk was
awarded the Nobel prize in 1939 for his discovery of Prontosil.
In the late 1940s and early 1950s, new antibiotics were introduced,
including streptomycin, chloramphenicol and tetracycline, and the age
of antibiotic chemotherapy came into full being. These antibiotics were
effective against the full array of bacterial pathogens including
Gram-positive and Gram-negative bacteria, intracellular parasites, and
the tuberculosis bacillus. Synthetic antimicrobial agents such as the
"sulfa drugs" (sulfonamides) and anti-tuberculosis
drugs, such as para aminosalicylic acid (PAS) and isoniazid (INH),
into wider usage.
The first signs of antibiotic resistance
There has probably been a gene pool in nature for resistance to
antibiotic as long as there has been for antibiotic production,
for most microbes that are antibiotic producers are resistant to their
own antibiotic. In retrospect, it is not surprising that resistance to
penicillin in some strains of staphylococci was
recognized almost immediately after introduction of the drug in 1946.
after their introduction in the late 1940s, resistance to
streptomycin, chloramphenicol and tetracycline was noted. By 1953,
during a Shigella outbreak in Japan, a strain of the dysentery
bacillus (Shigella dysenteriae)
was isolated which was
multiple drug resistant, exhibiting resistance to chloramphenicol,
tetracycline, streptomycin and the sulfonamides. Over the years, and
continuing into the present almost every known bacterial pathogen has
developed resistance to one or more antibiotics in clinical use.
Evidence also began to accumulate that bacteria could pass
genes for drug
resistance between strains and even between species. For example,
antibiotic-resistance genes of staphylococci are carried on
plasmids that can be exchanged with Bacillus,
providing the means for acquiring additional genes and gene
Some are carried on transposons, segments of DNA that can exist either
the chromosome or in plasmids. In any case, it is clear that
genes for antibiotic resistance can be exchanged between strains and
species of bacteria by means of the processes of horizontal gene
Multiple drug resistant organisms
Multiple drug resistant organisms are resistant to treatment with
several, often unrelated, antimicrobial agents as described above in Shigella. Some of the most
important types of multiple drug resistant
that have been encountered include:
MRSA - methicillin/oxacillin-resistant Staphylococcus aureus
VRE - vancomycin-resistant enterococci
ESBLs - extended-spectrum beta-lactamases (which are resistant to
cephalosporins and monobactams)
PRSP - penicillin-resistant
MRSA and VRE are the most commonly encountered multiple drug resistant
organisms in patients residing in non-hospital healthcare facilities,
such as nursing homes and other long-term care facilities. PRSP are
more common in patients seeking care in outpatient settings such as
physicians' offices and clinics, especially in pediatric settings.
ESBLs are most often encountered in the hospital (intensive care)
setting, but MRSA and VRE also have a significant nosocomial ecology.
Methicillin-Resistant Staph Aureus.
MRSA refers to
aureus", which are strains of the bacterium that are resistant
to the action of
methicillin, and related beta-lactam antibiotics (e.g. penicillin and
have evolved resistance not only to beta-lactam
antibiotics, but to several classes of antibiotics. Some MRSA are
resistant to all but one or two antibiotics, notably
vancomycin-resistant. But there have been several reports of VRSA
(Vancomycin-Resistant Staph Aureus) that are troublesome in the ongoing
battle against staph infections.
MRSA are often sub-categorized as Hospital-Associated MRSA (HA-MRSA) or
(CA-MRSA), depending upon the
circumstances of acquiring disease. Based on current data, these
are distinct strains of the bacterial species.
HA-MRSA occurs most frequently among patients who undergo invasive
medical procedures or who have weakened immune systems and are being
treated in hospitals and healthcare facilities such as nursing homes
and dialysis centers. MRSA in healthcare settings commonly causes
serious and potentially life threatening infections, such as
bloodstream infections, surgical site infections or pneumonia.
In the case of HA- MRSA, patients who already have an MRSA infection or
who carry the bacteria on their bodies but do not have symptoms
(colonized) are the most common sources of transmission. The main mode
of transmission to other patients is through human hands, especially
healthcare workers' hands. Hands may become contaminated with MRSA
bacteria by contact with infected or colonized patients. If appropriate
hand hygiene such as washing with soap and water or using an
alcohol-based hand sanitizer is not performed, the bacteria can be
spread when the healthcare worker touches other patients.
MRSA infections that occur in otherwise healthy people who have not
been recently (within the past year) hospitalized or had a medical
procedure (such as dialysis, surgery, catheters) are categorized as
community-associated (CA-MRSA) infections. These infections are usually
skin infections, such as abscesses, boils, and other pus-filled
About 75 percent of CA-MRSA infections are localized to skin and soft
tissue and usually can be treated effectively. However, CA-MRSA strains
display enhanced virulence, spread more rapidly and cause more severe
traditional HA-MRSA infections, and can affect vital organs leading to
widespread infection (sepsis), toxic shock syndrome and pneumonia. It
is not known why some healthy people develop CA-MRSA skin infections
that are treatable whereas others infected with the same strain develop
severe, fatal infections.
Studies have shown that rates of CA-MRSA infection are growing fast.
One study of children in south Texas found that cases of CA-MRSA had a
14-fold increase between 1999 and 2001.
CA-MRSA skin infections have been identified among certain populations
that share close quarters or experience more skin-to-skin contact.
Examples are team athletes, military recruits, and prisoners. However,
more and more CA-MRSA infections are being seen in the general
community as well, especially in certain geographic regions.
Also, CA-MRSA are infecting much younger people. In a study of
Minnesotans published in The Journal of the American Medical
Association, the average age of people with MRSA in a hospital or
healthcare facility was 68. But the average age of a person with
CA-MRSA was only 23.
More people in the U.S. now die from MRSA infection than from AIDS.
aureus was responsible for an estimated 94,000 life-threatening
infections and 18,650 deaths in 2005, as reported by CDC in the Oct.
17, 2007 issue of The Journal of the American Medical Association. The
national estimate is more than double the invasive MRSA prevalence
reported five years earlier. That same year, roughly 16,000 people in
the U.S. died from AIDS, according to CDC. While most invasive
MRSA infections could be traced to a hospital stay or some other health
care exposure, about 15% of invasive infections occurred in people with
no known health care risk. Two-thirds of the 85% of MRSA infections
that could be traced to hospital stays or other health care exposures
occurred among people who were no longer hospitalized. People over age
65 were four times more likely than the general population to get an
MRSA infection. Incidence rates among blacks were twice that of the
general population, and rates were lowest among children over the age
of 4 and teens.
(ESBL) - producing Gram-negative
bacteria Extended-spectrum beta-lactamases (ESBLs) are
lactamases that have recently been
found in the Enterobacteriaceae.
ESBLs are capable of
hydrolyzing penicillins, many narrow spectrum
cephalosporins, many extended-spectrum cephalosporins,
oxyimino-cephalosporins (cefotaxime, ceftazidime), and monobactams
(aztreonam). Beta-lactamase inhibitors (e.g. clavulanic acid) generally
inhibit ESBL producing strains. ESBL producing isolates are most
commonly Klebsiella ssp,
predominantly Klebsiella pneumoniae,
and E. coli, but they have
been found throughout the Enterobacteriaeae.
Because ESBL enzymes are plasmid mediated, the genes encoding these
enzymes are easily transferable among
different bacteria. Most of these plasmids not only contain DNA
encoding ESBL enzymes but also carry genes conferring resistance to
several non-ß-Lactam antibiotics. Consequently, most
ESBL isolates are resistant to many classes of antibiotics. The most
frequent coresistances found in ESBL-producing organisms are
aminoglycosides, fluoroquinolones, tetracyclines, chloramphenicol, and
sulfamethoxazole-trimethoprim. Treatment of these multiple
organisms is a therapeutic challenge.
ESBL producing strains have been isolated from abscesses, blood,
catheter tips, lung, peritoneal fluid, sputum, and throat cultures.
apparently have a world-wide distribution. Rates of isolation vary
greatly worldwide and within geographic areas and are
rapidly changing over time. In the United States, between 1990 to 1993,
survey of the intensive care units of 400 hospitals recorded an
increase from 3.6% to 14.4% in ESBL producing strains of Klebsiella. In
1994, the CDC reported that 8% of Klebsiella
spp from a few large
centers produced ESBLs. In Europe, as of 1995, ESBLs occurred in
of Klebsiella ssp from
patients in ICUs, although they were found in patients up to
30%-40% frequency in
Known risk factors for colonization and/or infection with organisms
harboring ESBLs include admission to an intensive care unit, recent
surgery, instrumentation, prolonged hospital stay and antibiotic
exposure, especially to extended-spectrum beta-lactam antibiotics.
Use of extended-spectrum antibiotics exerts a selective pressure for
emergence of ESBL producing strains. The resistance plasmids can then
transferred to other bacteria, not necessarily of the same species,
conferring resistance to them.
The lower GI tract of colonized patients is the main
reservoir of these organisms. Gastrointestinal carriage can
persist for months. In some cities in the United States, nursing
homes may be an important reservoir of ESBL producing strains. Nursing
home patients are more likely to be treated empirically with
antibiotics, and thus on admission to a hospital to be more likely to
possess an ESBL producing strain. Patient to patient transmission of
ESBL producing organisms occurs via
the hands of hospital staff. It is known that ESBL
producing strains can survive in the hospital environment.
Nosocomial infections in patients occur through the
administration of extended spectrum beta-lactam antibiotics or via
transmission from other patients via health care workers, who become
colonized with resistant strains via exposure to
patients or other health care workers. Spread of ESBL producing strains
can be minimized by good infection
control practices, especially by good hand washing
Bacterial mechanisms of antibiotic resistance
mechanisms have evolved in bacteria which confer them with antibiotic
resistance. These mechanisms can either chemically modify the
antibiotic, render it inactive through physical removal
from the cell, or modify target site so that it is not recognized by
most common mode is enzymatic inactivation of the antibiotic. An
existing cellular enzyme is modified to react with the antibiotic in
such a way that it no longer affects the microorganism. An alternative
utilized by many bacteria is the alteration of the antibiotic
target site. These and other mechanisms are shown in the the
figure and accompanying table below.
Mechanisms of antibiotic resistance in bacteria
uptake into cell
efflux from the cell
or reduces binding of antibiotic to cell target
cleavage or modification to inactivate antibiotic molecule
bypass of inhibited reaction
of antibiotic target (titration)
The acquisition and spread of antibiotic
resistance in bacteria
The development of
inevitable following the introduction of a new antibiotic. Initial
rates of resistance to new drugs are normally on the order of
1%. However, modern uses of antibiotics have caused a huge increase in
the number of resistant bacteria. In fact, within 8-12 years after
wide-spread use, strains resistant to multiple drugs
become widespread. Multiple drug resistant strains of some
bacteria have reached the proportion that virtually no antibiotics are
available for treatment.
Antibiotic resistance in bacteria may be an inherent trait of the
organism (e.g. a particular type of cell wall structure) that renders
it naturally resistant, or it may be acquired by means
of mutation in its own DNA or acquisition of resistance-conferring DNA
from another source.
Inherent (natural) resistance. Bacteria may be inherently
resistant to an antibiotic. For example, an organism lacks a transport
system for an antibiotic; or an organism lacks the target of the
antibiotic molecule; or, as in the case of Gram-negative bacteria, the
cell wall is covered with an outer membrane that establishes a
permeability barrier against the antibiotic.
Acquired resistance. Several mechanisms are developed by
order to acquire resistance to antibiotics. All require either the
of existing genetic material or the acquisition of new genetic
material from another source.
Vertical gene transfer
The spontaneous mutation frequency for antibiotic resistance is on the
order of about of about 10-8-
This means that one in every every 108- 109
in an infection will develop resistance through the process of
mutation. In E. coli, it has been estimated that
streptomycin resistance is acquired at a rate of approximately 10-9
when exposed to high concentrations of streptomycin. Although mutation
is a very
rare event, the very fast
growth rate of bacteria and the absolute number of cells
attained means that
it doesn't take long before resistance is developed in a population.
Once the resistance genes have developed, they are transferred
directly to all the bacteria's progeny during DNA replication. This is
known as vertical gene
transfer or vertical evolution.
The process is strictly a matter of Darwinian evolution
driven by principles of natural selection: a spontaneous mutation in
the bacterial chromosome imparts resistance to a member of the
bacterial population. In the selective environment of the antibiotic,
the wild type (non mutants) are
killed and the resistant mutant is allowed to grow and flourish
spontaneous mutation is responsible for the acquisition of antibiotic
resistance. Lateral or horizontal
gene transfer (HGT) is a process
whereby genetic material contained in small packets of DNA can be
transferred between individual bacteria of the same species or even
between different species.
There are at least three
mechanisms of HGT, equivalent to the three processes of genetic
exchange in bacteria. These are transduction, transformation or
occurs when there is direct cell-cell contact between two
bacteria (which need not be closely related) and transfer of small
pieces of DNA called plasmids takes place. This is thought to be the
main mechanism of HGT.
a process where parts of DNA are taken up by the
bacteria from the external environment. This DNA is normally present in
the external environment due to the death and lysis of another
occurs when bacteria-specific viruses (bacteriophages) transfer DNA
between two closely related bacteria.
horizontal gene transfer (HGT) in bacteria
The combined effects of fast growth rates to large densities of cells,
genetic processes of mutation and selection, and the ability to
account for the extraordinary rates of adaptation and evolution that
be observed in the bacteria. For these reasons bacterial adaptation
(resistance) to the antibiotic environment seems to take place very
rapidly in evolutionary time. Bacteria evolve fast!
Tests for sensitivity and resistance
to antibiotics. (Left) The size of the zones of inhibition of microbial
growth surrounding the antibiotic disks on the plate are an indication
of microbial susceptibility to the antibiotic. (Right) By
the use of these disks it is also possible to detect the occurrence of
individual mutants within
the culture that have developed antibiotic resistance. This image shows
close-up of the novobiocin disk (marked by an arrow on the whole plate)
which individual mutant cells in the bacterial population that were
to the antibiotic and have given rise to small colonies within the zone
medical and agricultural practices that lead to antibiotic resistance
In the face of a microbe's inherent ability to develop antibiotic
resistance, many societal. medical and agricultural practices
contribute to this process, foremost of which are discussed below.
Antibiotics in food and water
are not the only source of antibiotics in the environment. In the
antibiotics can be found in beef cattle, pigs and poultry. The same
antibiotics then find their way into municipal water systems when the
runoff from housing facilities and feedlots contaminates streams and
groundwater. So it's a double hit: we get antibiotics in our food and
drinking water, and we meanwhile promote bacterial resistance.
feeding of antibiotics to animals is banned in the European Union and
many other industrialized countries. Maybe they know something we don't.
Indiscriminate use of antibiotics in agriculture and veterinary
The non-therapeutic use of antibiotics in livestock production makes up
at least 60 percent of the total antimicrobial production in the United
States. Irresponsible use of antibiotics in farm animals can lead
to the development of resistance in bacteria associated with the animal
or with people who eat the animal. Such
resistance can then be passed on to human
pathogens by mechanisms of HGT.
Of major concern is the use of antibiotics as feed additives given to
farm animals to promote animal growth and to prevent infections (rather
than cure infections). The use of an antibiotic in this way contributes
emergence of antibiotic-resistant pathogens and reduces the
effectiveness of the antibiotic to combat
Antibiotic resistance in genetically
Antibiotic-resistance genes are used as "markers" in genetically
modified crops. The genes are inserted into the plant in early stages
of development to in order to detect specific genes of interest . e.g.
herbicide-resistant genes or insecticidal toxin
genes. The antibiotic-resistance genes have no further role
to play, but they are not removed from the final product. This practice
has met with criticism because of the potential that the
antibiotic-resistance genes could be acquired by microbes in the
some cases these marker genes confer resistance to front-line
antibiotics such as the beta-lactams and aminoglycosides.
Inappropriate use of antibiotics in the medical environment
One problem is the casual use of antibiotics in medical situations
where they are of no value. This is the fault of both health care
workers and patients. Prescribers sometimes thoughtlessly prescribe
'informed' demanding patients with antibiotics. This leads to use of
in circumstances where they are of not needed, e.g. viral upper
respiratory infections such as cold
except when there is
serious threat of secondary bacterial infection. Another problem
is patient failure
to adhere to regimens for prescribed antibiotics.
Patients and doctors need to realize their responsibility when they
begin an antibiotic regimen to combat an infectious disease. There are
several measures that should be considered.
• Patients should not take antibiotics for which there is no medical
value (corollary: doctors should not prescribe antibiotics for
which there is no medical value).
• Patients should adhere to appropriate prescribing guidelines and take
antibiotics until they have finished.
• Patients should be give combinations of antibiotics, when necessary,
to minimize the development of resistance to a single antibiotic (as in
the case of TB).
• Patients need to be given another antibiotic or combination of
antibiotics if the first is not working.
The following are recommendations to combat the development of
antibiotic resistance in bacteria and other microorganisms.
Search for new antibiotics. To combat the
occurrence of resistant bacteria, biotechnology and pharmaceutical
constantly research, develop and test new antimicrobials in order to
maintain a pool of effective drugs on the market.
Stop the use of antibiotics as growth-promoting substances in farm
animals. Of major concern is the use of antibiotics as feed additives
farm animals to promote animal growth and to prevent infections rather
than cure infections. The use of such antibiotics contributes to the
emergence of antibiotic-resistant bacteria that threaten human health
and decreases the effectiveness of the same antibiotics used to combat
Use the right antibiotic in an infectious situation as determined by
antibiotic sensitivity testing, when possible.
Stop unnecessary antibiotic prescriptions. Unnecessary antibiotic
prescriptions have been identified as causes for an enhanced
rate of resistance development. Unnecessary prescriptions of
when antibiotics are prescribed for viral infections (antibiotics have
no effect on viruses). This gives the opportunity for indigenous
bacteria (normal flora)
to acquire resistance that can be passed on to pathogens.
Finish antibiotic prescriptions. Unfinished antibiotic prescriptions
may leave some bacteria alive or
may expose them to sub-inhibitory concentrations of antibiotics for a
prolonged period of time. Mycobacterium tuberculosis is a slow
growing bacteria which infects the lung and causes tuberculosis. This
disease kills more adults than any other infectious disease. Due to the
slow growing nature of the infection,
treatment programs last for months or even years. This has led to many
cases on unfinished prescriptions and 5% of strains now observed are
completely resistant to all known treatments and hence incurable.
such as the UK have regulations concerning the use of
antibiotics in animal feed.
Several other possible solutions have been proposed or implemented to
combat antibiotic resistance.
In the pharmaceutical industry, past and current strategies to combat
resistance have not been effective. Pharmaceutical companies are
less costly strategies to develop antibiotics.
A decrease in the number of prescriptions for
antibiotics, especially in small children, is occurring.
Large scale public health
education efforts are underway to stress the importance of
finishing prescriptions. Indeed, in many places, failure to finish
tuberculosis prescriptions can result in jail time.
The discovery of antibiotics was a leap in modern medicine. They have
been able to stop the growth or
kill many different kinds of microorganisms. However, bacteria have
proven to be much more innovative and adaptive than we
imagined and have developed resistance to antibiotics at an ever
increasing pace. Bad practices and mismanagement have only
exacerbated the situation. We could soon return to a state of medical
health that was as dire as that which occurred prior to antibiotic use.
However, with more research, education of the public, and well thought
out regulations, the problems
can be solved. Several
strategies are currently used to find new antibacterial compounds and
new strategies are in development and trial.
Not only is there a problem in finding new antibiotics to fight old
diseases (because resistant strains of bacteria have emerged), there is
a parallel problem to find new antibiotics to fight new diseases. In
the past three decades, many "new" bacterial diseases have been
discovered (E. coli O157:H7 gastric ulcers, Lyme disease, toxic
shock syndrome, "skin-eating" streptococci). Already broad patterns of
exist in these pathogens, and it seems likely that we will soon
need new antibiotics to replace the handful that are effective now
against these bacteria, especially as resistance begins to emerge among
them in the selective environment antibiotic chemotherapy.
It is said that the discovery and use of antibiotics and immunization
procedures against infectious disease are two developments in the field
of microbiology that have contributed about twenty years to the average
life span of humans in developed countries where these practices are
employed. While the greater part of this span in time is probably due
to vaccination, most of us are either
still alive or have family members or friends who are still alive
an antibiotic conquered an infection that otherwise would have killed
If we want to retain this medical luxury in our society we must be
and proactive We must fully understand how and why antimicrobial
work, and why they don't work, and realize that we must maintain a
ahead of microbial pathogens that can only be contained by antibiotic
Written and Edited by Kenneth Todar. All rights
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