I. Abstract
A. Statistics
1. The problem: Developing resistance
2. Current % resistant strains
II. Introduction and Background
1. Cell Wall Inhibitors2. Protein Synthesis Inhibitors
B. How do bacteria become resistant?
1. Spontaneous mutation2. Conjugation
3. Transduction
III. Body
A. The causes of drug-resistance
1. Over-prescription2. Use in food industry
3. Cost-cutting?
B. Solutions
1. Judicious prescription / More strict legal regulation2. Banning use on farm
3. Increase pharmaceutical research
4. Hunt for new drugs in new places
5. Genomics
6. Other solutions
IV. Conclusion
When penicillin was first administered in 1943, it proved to be extraordinary at wiping out nasty cases of syphilis, tuberculosis, gonorrhea, and meningitis infection. With the threat of these deadly infections in ‘check,’ pharmaceutical industries then cut back on their research to discover even more effective antibiotics. This new-found medical confidence inspired patients to merrily run to the clinic to get penicillin prescriptions for everything from nausea and diarrhea to running nose and sneezing, and doctors to happily prescribe the ‘miracle drug.’
However, microorganisms are now evolving and developing unprecedented
resistance to penicillin and other once potent drugs, like vancomyocin.
Currently, vancomyocin is the most potent drug on the market, and ¼
of all enterococci are resistant to it ("A New Gap…," 1997).
In the April 28, 1994 issue of the New England Journal of Medicine, researchers
identified a bacteria that was resistant to all antibiotics (Lewis, 1997).
The number of resistant strains of bacteria are rapidly growing, and a panic
is beginning to spread in the medical field, as it has been caught ‘off-guard’
by the most recent developments. It takes decades to develop new antibiotics,
and the pharmaceutical industries have spent the last few decades focusing
on other concerns. Even though our arsenal of antibiotics is diminishing,
it is clear that there will be no new ‘miracle drugs’ for quite
some time. Since we will soon run out of effective antibiotics, we must
do what we can to preserve the potency of our current resources.
This paper will provide a background on how antibiotics work and also on the mechanism by which bacteria acquire resistance. Also part of this text will be a discussion of the possible causes of the current antibiotic dilemma. Examples will highlight for the reader the arguments of experts on all sides of the issue. A number of theoretical solutions to the problem will also be presented. The conclusion of the discussion will focus on which solutions should be used and what we, as bystanders, can do to help prolong the lifespan of the current antibiotics.
The primary function of antibiotics is to help kill pathogens that threaten
the health of the individual. They do this by getting inside of the disease-causing
organism and disrupting its vital processes. There are several ways to disrupt
the processes, two major mechanisms will be discussed: One way is to interfere
with cell wall synthesis. Beta-lactams are the class of antibiotics that
perform this function. Among the Beta-lactams are penicillin and cephalosporin
("How do antibiotics work?" 1997). Another antibiotic mechanism
is to interrupt protein synthesis. Tetracyclines and erythromyocin function
in this way ("How do antibiotics work?" 1997). They belong to
a class of antibiotics named aminoglycerides.
Under normal conditions in bacteria, there is an equilibrium between the
building (transpeptidation) and tearing down (autolysis) of cell walls.
The building of cell walls in bacteria is catalyzed by the enzyme transpeptidase.
During antibiotic attack on cell wall synthesis, Beta-lactams bind to this
enzyme preventing its full function and causing a weak cell wall to be constructed.
The antibiotics also interfere with the feedback of autolysis. They stimulate
the bacteria to produce an excess of autolysins, which then break down the
weakened cell wall. Once the cell wall is permeated, water can enter and
cause the bacteria cell to burst ("How do antibiotics work?" 1997).
Interruption of protein synthesis is done primarily by binding to the light ribosomal subunit during protein synthesis. The messenger RNA then carry the complex to the transfer RNA for the addition of the heavy subunit. However, the heavy subunit cannot be added because the antibiotic is blocking is binding site. So, the synthesis of the protein terminates in an incomplete stage bacteria can be permeated and killed.
How do bacteria become resistant?
Bacteria have three basic ways to combat antibiotic attack, all involve
some change in their DNA. The most common way that bacteria develop resistance
is by spontaneous mutation. Although, most mutations result in the death
of the cell, one surviving mutant will a new generation within 20 minutes.
Then, that entire generation of mutant progeny can produce many more generations
with the drug-resistant mutation within hours. So, the rapid reproduction
time of bacteria makes spontaneous generation a valid threat for drug-resistance.
The bacteria that causes tuberculosis works in this way. Staphylococcus
aureus is also capable of self-mutation in response to an antibiotic
(Lewis, 1997).
A second method, which is considered to be the most dangerous mechanism
of acquiring drug-resistance, is conjugation. In this case, the bacteria
are actually acquiring the resistance through a reproductive process. The
process occurs between two bacteria. It involves the activity of bacterial
plasmids. Plasmids are circular molecules of extra chromosomal DNA that
carry the genetic information of bacteria. They are frequently involved
in passing on mutations for antibiotic resistance. In the process, the "donor"
bacterium attaches to the "recipient" bacterium. The plasmid of
the donor replicates, and then a copy of the donor’s genetic material
is passed on to the recipient cell. If the donor possesses a gene for drug-resistance,
it may be passed on to the recipient in this way.
Researchers have had the greatest difficulty controlling this mechanism. The reason it has been tough to control is because plasmids can jump from one bacterium to another. In the process, they may drop pieces of their DNA including genes for resistance. This mechanism proved to be most deadly in 1968 when 12,500 Guatemalans died from infection by a drug-resistant strain of Shigella diarrhea (Lewis, 1997).
Transduction is a third method by which bacteria acquire resistance. Transduction involves a transfer of genetic information during an attack by a bacteriophage (a virus that attacks bacteria). The phage binds to a site on the bacterial cell membrane. It, then injects, and replicates, its DNA inside the bacterium. Then, the virus will either multiply until it bursts the bacterial cell, or incorporate the genes it carries into the DNA of bacterium. If this information contains a gene for antibiotic resistance, the host cell progeny will then pick up the resistance and pass it on to all future generations. During transduction, bacteriophages can also pick up pieces of the host cell’s DNA. So, a phage without a resistant gene could also obtain it from the host cell. It’s in this way that Neisseria gonorrhoeae obtains its drug-resistance (Lewis, 1997).
There is much debate as to who and what are responsible for the development
of the resistant strains. The finger has been pointed in three directions
by researchers, doctors, and patients: Researchers and patients, alike,
place the blame on the doctors who have made access to antibiotics so easy.
These doctors, in response, argue that they have prescribed these antibiotics
in such high amounts due to the enormous pressure placed on them by the
patients. Other individuals feel that farmers in the food industry should
bear some responsibility for the current predicament. Still, some doctors
blame the managed care and cost-cutting tactics for the crisis.
Many researchers believe that antibiotics, like penicillin, have been over-prescribed
for years. Doctors, themselves, admit that they have been somewhat careless
in the distribution of antibiotics: In the May 17, 1997 issue of Science
News, a group of surveyed doctors said that they believed that they could
reduce the number of prescriptions by 20-50% without harming patients. These
responses fit with the estimates of researchers that one-third of the fifty
million prescriptions given each year are unnecessary (Smaglik).
These findings also have ethical and moral implications. Doctors are fully aware of the dangers of antibiotic overuse, yet they continue to over-prescribe medications. Health care providers have a legal, ethical, and moral obligation to "do the most good with the least harm." The behavior of over-prescription causes one to ask whether they are doing their duty?
A case study was run on patients with runny noses and sinus headaches to determine the true effectiveness of antibiotic treatment for these conditions. Doctors did a double-blind random study where they gave half of the patients an antibiotic for their conditions, the other half a placebo. The study showed that after one week, 83% of the patients given the antibiotic reported feeling better, and 78% of the patients given the placebo reported an improved condition. The results show only a 5% difference with the use of an antibiotic (Smaglik, 1997).
Other experts blame the development of resistance on the food industry.
In 1992, 13,300 people died of bacterial-resistant infections ("A New
Gap…," 1997), 9,000 of these were food-borne (Lewis, 1997). It
is common practice nowadays for farmers to feed their livestock antibiotics
and hormones in an effort to grow the largest and healthiest animals for
the food market. In fact, 50% of all antibiotics used are given to farm
animals (King, 1997).
However, some scientists believe that this practice has been more detrimental
than beneficial; they believe that repeated consumption of meat from these
livestock leads to the development of antibiotic resistance in the consumer.
There are two explanations for this: One is because when antibiotics are
given to livestock, the vulnerable bacteria are killed, but the resistant
survive to produce generations and generations of drug-resistant bacteria.
Then when the meat is eaten, the bacteria are passed to the consumer, who
can become infected. Because the bacteria are so "hardened" (drug-resistant)
it is nearly impossible to treat these infections.
An alternative mechanism involves the consumer ingesting a quantity of antibiotic
each time he/she eats the meat. If the person regularly eats this meat,
the bacteria already present his/her body will have constant exposure to
the consumed antibiotic. Again, the drug-resistant bacteria will be allowed
to survive and multiply. Later on, when a doctor prescribes a drug for this
individual, its effectiveness may be greatly decreased due to the continual
ingestion of, and exposure to, antibiotics present in meat (King, 1997).
In the January 18, 1997 issue of New Scientist, researchers reported a link between farm animals given drugs and antibiotic resistance. Individuals who ingested the meat of these animals were found to be more susceptible to resistant strains of Salmonella and Enterococcus faecalis (Bonner, 1997).
A group of unsatisfied doctors has recently directed the blame toward the managed care organizations. These doctors claim that the organizations’ attempts to cut medical costs are responsible for the antibiotic crisis (Thompson, 1996). Their claim is based on the fact that the organizations are pushing doctors to use one drug at a time, rather than a combination of drugs, to use cheaper drugs, and different methods of application. The doctors argue that this compromises their treatment of patients. They say that many times combinations of drugs are more effective than one single drug, and that they see larger improvements with oral application than intravenous. They insist that the outcome of the managed care is to use weaker drugs and less effective methods of delivery (Thompson, 1996). These arguments add fuel to the fire for individuals against managed care.
Solutions to the Problem
There have been several suggestions for solutions to the problem. Two involve
legal interventions, two involve pharmaceutical research, one deals with
genomics, one discusses phage therapy. Some recent gains have been made
in research and formation of these solutions.
The first suggestion, a very favored option, is to legally regulate the
prescription of antibiotics. This would force doctors to justify their prescriptions.
It would also encourage them to be more prudent in their choice to use or
not use antibiotics (Dowell and Schwartz, 1997).
A second solution, which is receiving quite a bit of media attention, is
to ban the use of antibiotics in the growth of livestock. Some countries,
like Germany and Denmark, have already taken steps toward activating this
solution. The European Commission is recommending that avoparcin, an antibiotic
which keeps livestock healthy and subsequently promotes growth, be banned.
The Commission believes that resistance in the farmyard could lead to bacterial
resistance in hospitals. A particular concern is that the Staphlococcus
aureus bacteria is becoming resistant to vancomyocin. An outbreak of
Staph infections could be catastrophic to ill hospital patients (Coghlan,
1997).
A third answer, which is already in progress, is to increase pharmaceutical
research for new drugs. At the onset of the crisis, researchers shifted
their focus back to developing new antibiotics. Experts are really pushing
for faster-acting, more potent antibiotics. This would help alleviate the
problem of patients not completing the prescription because more potent
antibiotics would require less doses.
Currently, there are two drugs waiting for approval: Synercid and Sparfloxacin.
Synercid functions to inhibit protein synthesis. In a ‘test run’
of the antibiotic, 70-95% patients showed improvement. Sparfloxacin is considered
to be in the antibiotic class of fluoroquinoline. It’s similar, but
stronger. Sparfloxacin has been used for pneumonia, sinusitis, and bacterial
bronchitis. Although neither drug has been approved by the FDA, both have
been used in emergency situations where all other drugs have failed ("Finding
Solutions to Bacterial Resistance," 1997).
In addition, researchers feel that if any new antibiotics are to be discovered,
they will have to come from a different source than the previous ones. For
this reason, they have proposed a fourth solution to begin combing new habitats
and organisms for antibiotic properties. For example, a chemical in the
stomach of sharks has been found to demonstrate some medical properties.
Other organisms of interest include bees, grasshoppers, and algae. Researchers
are also looking into various plant types for medicine power (Nemecek, 1997).
A fifth suggestion to the drug-resistance problem is genomics. Genomics involves manipulating the genetic codes of disease-causing microbes. In order for antibiotics to work, pathogenic organisms must have a cellular label that they can recognize. The genetic code is what determines the location and dynamics of the label. Therefore, in genomics, scientists change the sequencing of the microbe’s genetic code to determine new targets for antibiotic attack. In doing this, they may be able to renew the potency of certain antibiotics. Research on genomics is currently being performed with the HIV virus (Nemecek, 1997).
In addition to these five solutions, a couple other suggestions have
been made. Some scientists are proposing that if certain antibiotics are
‘taken out of circulation,’ than the bacteria will evolve to be
vulnerable to those antibiotics. There has been some research with E.
coli to show that this has not worked, even with drugs that haven’t
been used for almost thirty years.
Another, less favored, solution involves the use of phage therapy. Phages
are viruses that infect bacteria. In earlier times, some researchers believed
that phage therapy would be the cure all. It’s believed that the phages
would be more effective because in one dose they could multiply to 1 million
copies in a day. Researchers of phage therapy also say that there are more
pure ways to grow phages compared to antibiotics. They also add that the
body can rapidly eliminate phages (Travis, 1996).
Which solutions should we push for?
As stated above, some of these solutions are already in progress. For example, the World Health Organization is already in the process of establishing definite criteria for the prescription of antibiotics ("Bacterial Resistance to Antibiotics," 1997). More important than restricting the prescription of drugs, is educating the patients. The government should take large steps to inform the public of the dangers of antibiotic overuse and the methods by which drug-resistance can be prevented.
However, this is not a comprehensive solution to the problem. Something
must be done to control the use of antibiotics on the farm. The United States
has not done too much to reconcile this situation. Since the recent E.coli
outbreaks, the issue has been given more coverage, but more attention needs
to be given ("Bacterial Resistance to Antibiotics," 1997). We
should push for stricter legal regulation of the use of hormones and drugs
in livestock growth.
What can we do to help ourselves?
One thing that consumers can do to protect themselves against E.coli infection is to make sure meat is properly cooked. Studies have shown that 72 % of E. coli can be killed just by thorough cooking (Lewis, 1997).
Another contribution we can make is to prevent the spread of infection. This includes hygiene techniques, such as washing hands before eating, after the use of the bathroom, before preparing food. It also includes common courtesies such as covering sneezes and coughs. It may seem futile, but the more hosts a pathogen has, the more opportunities it has to mutate.
There are several other things that we can do to help the situation as bystanders. The primary action we can take is to become educated. It is important for patients to know that they are contributing to the problem when they demand prescriptions for even the slightest illness. It is also critical that patients realize that they must take all of their medication as prescribed. Taken less than what is prescribed leaves resistant strains in the body to reproduce.
We should consider it our moral and ethical obligation to take action
and help preserve antibiotic arsenal. It’s wasteful that we have put
ourselves in the situation of having to spend millions of dollars to develop
new antibiotics. Conscientiousness and conservation is not the complete
solution, but it certainly gives us something to think about the next time
we go to the doctor for a "cure" for the common cold.
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