Antibiotic Resistance Thesis Statement

Four different strategies of adaptive laboratory evolution

To compare the effect of the ALE methodology on final pheno- and genotypes we evolved E. coli to three different antibiotics using four different ALE strategies. The antibiotics chosen for this experiment represent three major groups of antibiotics. Two of the drugs, amikacin (AMK) and tetracycline (TET), target the ribosome with the former being bactericidal and the latter being bacteriostatic. The third drug, piperacillin (PIP), is a bactericidal drug targeting cell-wall biosynthesis. The four different selection regimes can be divided into two categories: (1) A gradient approach in which the population that tolerates the highest drug concentration is passed to a fresh drug gradient every 22 h; and (2) an increment approach in which the evolving population is passed every 22 h to a new drug concentration increased by fixed increments (Figure ​1).

Figure 1

Experimental design of the study: adaptation of E. coli K12 to three antibiotics following four adaptation protocols with different selection strengths. The four selection systems are named “gradient,” “100% increment,”...

A 20-fold dilution of the gradient evolved populations was chosen based on a model by Wahl et al. (2002), to allow a high variation in the transferred population and to base fixation of mutations on the optimal adaptation rather then on limiting bottlenecks. According to Wahl et al. (2002) a 10-fold dilution of the population would be optimal but previous experiments in the laboratory showed a small increase in the inhibitory drug concentration for AMK and TET when a 10-fold dilution was used. To avoid an inoculum effect, which is a significant increase in the inhibitory concentration caused by a larger amount of organisms in the inoculum (Brook, 1989), we chose a 20-fold dilution (Supplementary Figure 2).

After 14 days of adaptive evolution in the gradient setup, the populations exposed to AMK tolerated on average 512 mg/l of the drug, corresponding to a 170-fold increase compared to the media adapted wild type (P = 2.89654E−27, student's t-test) (Figure ​2A). The PIP evolved lineages grew in drug concentrations of 192 mg/l on day 14 of the ALE experiment, equal to a 80-fold increase compared to the media adapted wild type (P = 0.00109527, student's t-test). However, large oscillations in resistance were observed for the PIP evolved lineages during the course of the experiment (Figure ​2B). This variation could be explained by an inoculum effect, which is more frequently observed for beta-lactam antibiotics (Eng et al., 1984, 1985; Brook, 1989). Lineages evolved to TET did not reach the same drug tolerance compared to AMK or PIP evolved lineages, but still grew in 15 mg/l TET, exceeding the media adapted wild type inhibitory concentration (IC) by 15 times (P = 2.04072E−06, student's t-test) (Figure ​2C). These values are in accordance with previous findings where the IC90 values (the drug concentration at which growth of 90% of the population is inhibited) of isolated colonies were determined after 14 days of adaptive evolution in a gradient system using the same strain and drugs (Munck et al., 2014). Only PIP evolved lineages appear more resistant in the present study, which is attributed to the inoculum effect caused by the larger passaging volume.

Figure 2

Overview of the adaptation potential over time for each drug: (A) amikacin, (B) piperacillin, and (C) tetracycline. The lineages adapted under the gradient method follow the maximal selection pressure wherefore it can be observed that lineages from the...

In the increment approach three different rates of environmental change were tested (Figure ​1), for which the selective pressure (e.g., antibiotic concentration) was increased by 100, 50, or 25% every day. Similar to the gradient approach the 100% increment setup applies a high selection pressure with the risk of exceeding the adaptive potential of the bacterium leading to extinction of the lineages (Figure ​1).

Similar resistance levels can be accompanied by different fitness costs

We were interested in observing how the different rates of environmental change affected the final genotypes and phenotypes. By design, lineages would be adapted to different antibiotic concentrations at the end of the experiment, depending on the specific ALE approach. Accordingly, we decided to compare the lineages when they had reached the clinical breakpoint (defined by EUCAST, 2016). Gradient evolved lineages were analyzed at the time point when they had reached or exceeded the clinical breakpoint for 2 consecutive days. Increment evolved lineages were analyzed at the time point when the lineage had reached the clinical breakpoint. As most of the 100% increment lineages failed to reach the clinical breakpoint we excluded these lineages from the analysis.

One colony was obtained from each lineage at the time point where the population had reached the clinical breakpoint and the antibiotic tolerance was determined. The IC85 values were normalized to the average IC85 of the media adapted strains (Figure ​3A).

Figure 3

Phenotypic changes in drug resistance and growth rate after the adaptive laboratory evolution experiment. (A) The fold-increase of the IC85 compared to the wild type (WT) is displayed for each drug. The evolved resistance levels are not significantly...

For AMK and TET adapted strains the resistance level of the gradient evolved strains was above the clinical breakpoint (Figure ​3A). In contrast, only one of the strains adapted to PIP was above the clinical breakpoint. High fluctuations in resistance level were observed in the PIP adapted lineages (Figure ​2B) suggesting that an inoculum effect rather than real adaptation contributed to the population tolerance. The inoculum used in this study corresponded to about 108 CFU/ml and did not indicate inoculum effect in previous experiments (Supplementary Figure 2). Yet, it is exceeding the reported CFU/ml concentration causing inoculum effect for PIP (Bryson and Brogden, 2012).

The resistance levels of the 25% increment evolved strains displayed a normal distribution around the clinical breakpoint for TET and PIP and were above the clinical breakpoint for AMK, whereas the 50% increment strains displayed a slightly lower tolerance (Figure ​3A). However, when comparing gradient and increment adapted strains, only TET evolved strains showed a significant (P < 0.05 Kruskal-Wallis one-way analysis of variance) difference in their resistance levels (Figure ​3A).

Many resistance-conferring mutations are known to confer a fitness cost, which can often be detected by a reduced growth rate (Linkevicius et al., 2013). Since the selection regime seems to influence the fitness of the resulting lineages (Lindsey et al., 2013), we measured the growth rate of the same isolated colonies that were used for the IC85 determination and an additional six isolated colonies for each lineage, resulting in 28 clones for the gradient approaches and 56 clones for the increment experiments (Figure ​3B). Adaptation to AMK generally seemed to be connected with a reduced growth rate compared to the other drugs.

For all three drugs the 25% increment strains grew significantly (Kruskal-Wallis one-way analysis of variance P < 0.05) faster than the gradient adapted strains (Figure ​3B). The growth advantage of the increment lineages could be due to a larger number of generations that they underwent compared to the gradient evolved lineages providing better opportunity for fitter mutants to outcompete resistant mutants with larger fitness costs and to accumulate compensatory mutations that can balance the fitness costs of resistance conferring mutations. However, the time that a population was evolved for and the doubling time are not significantly correlated (R = −0.019, Pearson's product-moment correlation coefficient, P = 0.71). Accordingly, it is likely that the shorter doubling time of the increment lineages is due to a lower selection pressure toward drug resistance, resulting in an increased selection for high growth rate. This finding is in line with previous studies reporting that E. coli lineages evolved to rifampicin under sudden drug increase have a significantly reduced growth rate compared to lineages evolved to more gradual drug increases (Lindsey et al., 2013) and that E. coli lineages adapted to 22 different antibiotics under mild selection have an elevated growth rate compared to lineages evolved under strong selection regimes (Oz et al., 2014). Yet, no correlation was found between the resistance level and the growth rate suggesting that a mutation that confers high-level resistance is not necessarily linked to a high fitness cost and vice versa (Supplementary Figure 4).

Genotypes of lineages adapted under different selection pressures overlap

The strains used for IC85 determination and growth rate measurements were sequenced in order to uncover the underlying genetic changes. We identified a total of 173 mutations across 92 sequenced strains (Supplementary Table 5). Large insertions and deletions made up 26.5% of the total number of mutations (Supplementary Figure 5A). These larger genetic rearrangements are frequently overlooked but can play important roles in the genetic adaptation process. Two of the eight parallel strains adapted in a 25% increment to AMK have three identical SNPs in common, suggesting potential cross-contamination between the lineages. Therefore, only one of the strains was used for the following analysis.

On average we identified about two mutations in each strain across the different experiments (Supplementary Figure 5B). Even though the 25% increment lineages were evolved for more generations until they reached the clinical breakpoint there was no significant difference in the number of mutations between experimental setups (P > 0.5, Students t-test) and the number of mutations in the sequenced isolates did not correlate significantly with the number of generations (R = 0.19, Pearson's correlation, P = 0.097).

Whether a mutation confers resistance, compensates fitness costs of other mutations or hitchhikes with a resistance mutation is difficult to determine without re-introducing specific mutations alone and in combinations into the non-evolved wild type. However, if a gene is mutated in more than one independent strain it is likely that the mutation was selected for (Lieberman et al., 2011; Yang et al., 2011; Sandberg et al., 2014). We filtered our dataset according to this criterion and found that 88.8% of genes mutated in the gradient evolved strains were also mutated in the increment strains (Figure ​5). Except mutations in the ATP synthase gamma chain (atpG) and the cytochrome bo(3) ubiquinol oxidase subunit 2 (cyoA), all mutated genes of the gradient strains in the filtered dataset have also been found to be mutated in the 25% increment strains (Figure ​5). The clones carrying one of the two mutations have an average doubling time that is four times higher than the wild type and twice as high as the average of all strains adapted to AMK. Therefore, it is likely that these mutations come with a high fitness cost, and accordingly were not fixed in the 25% increment lineages.

Figure 5

Genetic adaptations to the antibiotics amikacin (AMK), piperacillin (PIP), and tetracycline (TET). The color represents the number of strains in percent that harbor a mutation, identified in at least two independent lineages. Almost all mutations identified...

Interestingly, the increment-adapted strains carried not only most of the mutations found in the gradient adapted strains, but also many mutations that were solely identified in the increment strains (Figure ​5). Such mutated genes are for example nuoB, nuoC, and nuoH, subunits of the NADH-quinone oxidreductases that shuttle electrons from NADH to quinones in the respiratory chain that have been identified to confer resistance toward AMK in previous studies (Kohanski et al., 2007; Schurek et al., 2008; Girgis et al., 2009; Wong et al., 2014). In addition, these mutations were linked to the collateral-sensitivity phenotypes of aminoglycosides toward many other classes of antibiotics (Lázár et al., 2014), suggesting that mutations in these genes are relevant for the collateral sensitivity phenotype toward TET, that was not observed in the gradient lineages when they reached the clinical breakpoint, but only in strains isolated from the end point of the gradient evolved lineages.

Mutations in the genes fusA, sbmA as well as in two different two component systems, cpxRA and arcAB appeared to be the dominating mutations in all strains adapted to AMK (Figure ​5). All mutations have been previously linked to AMK resistance (Laviña et al., 1986; Busse et al., 1992; Johanson and Hughes, 1994; Salomón and Farías, 1995; Macvanin and Hughes, 2005; Kohanski et al., 2008, 2010; Pena-Miller et al., 2013; Lázár et al., 2014; Munck et al., 2014). Mutations in the elongation factor G encoding gene fusA have been shown to result in collateral sensitivity toward beta-lactam antibiotics, as observed in this study for PIP (Macvanin and Hughes, 2005).

acrR was found to be the predominantly mutated gene in the PIP evolved lineages regardless of the experimental setup (Figure ​5). Mutations in acrR as well as in marR and rob, also identified to be mutated in the increment strains adapted to PIP, lead to the multiple antibiotic resistance (mar) phenotype, which was described to confer resistance toward a variety of drugs including beta-lactam antibiotics and tetracyclines. This finding explains the cross-resistance observed for TET and PIP evolved lineages in this experiment (George and Levy, 1983; Cohen et al., 1989; Ariza et al., 1995; Maneewannakul and Levy, 1996; Oethinger et al., 1998). The lack of mutations in marR and rob in the gradient adapted strains might account for the difference in cross-resistance toward TET compared to the 25% increment adapted strains. However, it can be speculated that these mutations would also occur in a gradient system if the inoculum effect can be avoided, since they were observed previously in an experiment following the gradient approach (Munck et al., 2014). Another frequently observed mutation in PIP adapted strains affects the drug target, the peptidoglycan synthase ftsI (penicillin-binding protein 3) (Figure ​5) (Matic et al., 2003; Blázquez et al., 2006). Interestingly, mutations in cpxA were solely found in 25 and 50% increment strains adapted to PIP (Figure ​5). Mutations in this gene can confer up to 2-fold increases in resistance to beta-lactam antibiotics (Srinivasan et al., 2012; Bernal, 2014). Since a 2-fold increase in drug resistance is moderately low, it can explain why the mutation was only found in 25 and 50% increment lineages that were exposed to low antibiotic concentrations and why it was not identified in the gradient or 100% increment lineages.

The lineages adapted to TET showed, similar to PIP, mutations in genes belonging to the mar phenotype (Figure ​5). In addition to mutations belonging to the mar phenotype, two other mutated genes, dksA and waaP, were identified which were previously only indirectly linked to antibiotic susceptibility (Yethon et al., 1998; Yethon and Whitfield, 2001; Hansen et al., 2008; Tamae et al., 2008; Liu et al., 2010). Interestingly, the only gene duplications observed in this experiment were all found in three different lineages in the 50% increment strains adapted to TET. Two genes, yicS and yibT, with uncharacterized gene products, were duplicated as well as phoU, whose deletion mutant was more susceptible toward antibiotics suggesting a potential role in antibiotic tolerance (Li and Zhang, 2007).

The significant difference in resistance between gradient and increment evolved lineages might be explained by the abundance of mutations in marR. Almost all strains adapted under the gradient approach carry a mutation in marR, whereas this genetic change was only observed in a few lineages evolved in the increment regime (Figure ​5). Lineages harboring mutated marR were overall 15% more resistant to TET than all TET adapted lineages on average. However, they also had an increased doubling time by ~27% compared to the average. ΔmarR mutants were previously linked to an impaired fitness (Marcusson et al., 2009), suggesting that mutations in marR are more likely to dominate a population under strong selection.

The clones adapted under the gradient approach seem to have fewer mutations in the filtered data set in comparison to the increment lineages. However, they often carry mutations that were only detected once in the whole experiment (Supplementary Table 5), therefore the gradient adapted lineages display a higher diversity in unique mutations. In order to quantify the similarity and dissimilarity between genotypes in the different experimental setups, we did a pairwise comparison between all strains using the unfiltered data set. The overlap of mutated genes between the pairs was calculated in percent of the total number of mutated genes found in the two strains. We chose to analyze the similarity on the gene level and not on SNP or gene family level, since it was suggested as appropriate measure to detect parallel or convergent evolution (Achaz et al., 2014). The genetic similarity within the gradient evolved replicates was on average around 30–50% (Figure ​6). The strains adapted under the 25 and 50% increments were about 45 and 30% similar to each other when adapted to AMK and PIP and only around 20 and 10% alike when evolved to TET (Figure ​6). Interestingly, the genetic similarity of strains evolved using different selection regimens was comparable to the similarity within replicates from the same selection regimen (Figure ​6). The similarity of the gradient and the 25% increment strains was maximal about 3% below and 12% above the group internal similarity of either the gradient or the increment 25 strains (Figure ​6). This result underlines that the genetic similarity between the different selection regimens is similar to the genetic similarity observed between parallel lineages that were evolved under identical conditions.

Figure 6

Similarity of lineages evolved to different selection strengths. The similarity between different strains was calculated in pairwise comparisons by analyzing the percentage of genes that were mutated in both strains compared to the total number of mutations...

The Overuse of Antibiotics

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Thesis: With the advent of antibiotics in 1929 Fleming said, "The time may come when penicillin can be bought by anyone in the shops.Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant."With the overuse of antibiotics today we have seen this very idea come to be.Over usage is caused most prevalently by a lack of education on the part of the patient.Thus stated, the way to overcome such a circumstance is to educate, not only the patient but also the physician.

Generally in life, an overabundance of anything is thought of as a blessing.For instance, most people would say that there is no point where someone has too much money, or too much time; however, having and using too many antibiotics can be a problem.With the advent of antibiotics in 1929 Fleming warned that, "The time may come when penicillin can be bought by anyone in the shops.Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant."[1]Following with Fleming's words antibiotics need to be prescribed in a judicious fashion, not of one with a careless action, "one third of the 150 million outpatient prescriptions are unnecessary."[2]With the overuse of antibiotics today we have seen this very idea come to be.Over usage is caused most prevalently by a lack of education on the part of the patient.Thus stated, the way to overcome such a circumstance is to educate, not only the physician but also the patient.
Alexander Fleming started the history of antibiotics in the 1920's with his discovery of penicillin.When penicillin was first discovered and used widely, it was touted as a wonder drug, and consequently was used as one.Though not necessarily harmful to the patient penicillin was used for much more infections than it was able to combat.Today the same practice is observed in the medical profession, however at this point it is due more to the detriment of an uneducated public.Studies have been carried out that show the huge over usage of antibiotics.In the seventies Soyka et al, concluded, "60% of physicians surveyed gave antibiotics for the treatment of the common cold."[3], and by common knowledge the common cold is a virus, something that cannot be treated by an antibiotic.Nyquist

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et al and Gonzales et al, in the nineties report, "In the United States more than one fifth of all antibiotic prescriptions for children and adults are written for upper respiratory tract infections or bronchitis, conditions that are almost always viral."[4],[5] Schwartz et al, report, "10-50% of outpatient antibiotic prescriptions are unnecessary."[6]A report featured in a recent, September 12, 2001, edition of Journal of American Medical Association (JAMA) Linder and Stafford report, "the only common cause of sore throat warranting antibiotics is only cultured five to seventeen percent in adults complaining of a sore throat."[7]Thus illustrating the fact that over the years after antibiotics were discovered the use has drastically gone up and the awareness and or education about the use of antibiotics has remained little to nothing.
Many causes can be blamed for the overuse of antibiotics.Mostly the blame can be put on the consumer or patient and their overall lack of education.This is more than just a higher level of learning this would an education that is specific to the needs of prescribing and the overall use of antibiotics.This cause, though the most prevalent, is not the only cause.Diagnostic uncertainty, patient expectations, and malpractice litigation are other causes that ideally have played into the overuse of antibiotics.

While most blame can be put onto the patient the physician is also at fault in some cases.With the demanding scheduling in a doctor's office, the physician is usually on a time intensive table.He or she must rush in and out of patient rooms seeing many different types of symptoms.Thus with a hurried schedule physicians would rather err on the side of prescribing too much rather than too little, or even at all.[8]In the same breath it is said that it is easier and takes less time to prescribe an antibiotic than it does to tell the patient why you are not prescribing one.The use of testing devices to gain knowledge about an illness is the only way in which the correct, if any, antibiotic is needed.Physicians tend to skip these defining tests to save time and money in the office.It is also reported that physicians tend to not perceive the amount of patient satisfaction in giving antibiotics, meaning that some patients don't really want the antibiotics.[9]

Insurance companies could also have the blame pointed in their direction.The multiple changes and pressures that insurance companies cause doctors to undergo can be shown to increase the amount of antibiotics that are given.For instance, an insurance company would gladly pay for a prescription rather than a follow up visit.Meaning that the physician feels pressured into giving antibiotics because the authority that brings him/her patients is holding this proposition over there head.Thus, the physicians are more likely to prescribe to appease the insurance company.With the often changes of a primary provider, perhaps as often as six to twelve months, the doctor feels that the patient isn't really trusting him/her, because they are new to seeing the physician, therefore the doctor feels that he/she must do everything possible to make the patient feel comfortable and more importantly to gain the trust of the patient.Thus, the doctor is more likely to over prescribe because he/she wants to convey to the patient that he/she is competent in treating illnesses.[9]

The main blame for the over usage of antibiotics is due the lack of education of the public.The general public doesn't have a grasp for the difference between that of a virus and a microbial infection.With this simple bit of knowledge, much of the overuse would be eliminated, because after all, antibiotics cannot treat a virus.Patient's expectations play into what the mindset of the patient is when he/she steps into the doctor's office.For instance, say a patient is experiencing symptoms similar to his or her spouse was feeling a week ago, and the spouse had been treated with an antibiotic and now is feeling better.Now the patient goes to the doctor with one item on his/her agenda, to get that same antibiotic.The doctor sees the patient and decides that it is a virus, but before the doctor has time to tell the patient this, the patient goes into the spiel and his/her spouse felt the same and that the doctor prescribed an antibiotic and they felt better.So now the doctor is in a predicament and most likely chooses to just prescribe.This of course, being a hypothetical example, is most likely played out in a doctor's office on a daily basis.After getting and taking this antibiotic the person then feels better after a week or so, because that is the normal life span of a virus.This problem is quite evident in a family setting, because both antibiotics and viruses are shared.Prior experience plays into the equation most prevalently when it is the previous experience of that patient.Patients of a lower income level are also more likely to demand antibiotics for illnesses.[10]Patients that come from disadvantaged situations are more likely to want a quick fix, they do not want to know about why they are sick, and all that they care about is that they want to get better and back to work.

In a world that is so time and money oriented it is easy to see how patients want to get in and out of the doctors office, after all time is money.This not only goes for the work force, but also for the children.Educators and daycare personnel most often require that student or toddler must have had antibiotics to be able to continue to be at school or the daycare.[9]Therefore if the physician does not prescribe an antibiotic than a parent will have to stay at home with the child until he/she is better.This causes problems for the parents because of working schedules and cash flow.With the direction that the world is going these days this problem will only increase.Larger corporations usually means less family oriented and therefore fewer sick leaves are allowed, especially in the case of children.

In the past the over prescribing of antibiotics for upper respiratory illnesses (URI) has created a supply and demand system.[11]Early in the history of antibiotics some properties of the antibiotics and the microbes that they were being used on were still being discovered.Since that time many new discoveries and breakthroughs have been made and now we know much more than when antibiotics were first discovered, or invented.Only history and the lack of knowledge can be blamed for this, however the reoccurrence of this now is due to lack of education.

The need for the reduction or stoppage of antibiotic overuse is made apparent by the recent increase of antibiotic resistant strains of bacteria and the cost of fighting these "super bugs".This has also become an issue in the recent past with the advent of the bio-terrorism using anthrax in postal mailings.In four recent newspaper articles and one online news headline experts are warning that with the used of Cipro to treat anthrax we are causing a much larger problem in risking the loss of a crucial class of antibiotics.[12],[13],[14],[15],[16] Even with the continuous advent of new and more powerful drugs by breakthrough medical technologies the bacteria are still finding ways to become resistant.In a September 7 news report on Stenger concluded that "the United States must spend between $30 billion and $50 billion a year"[17] to fight these super bugs.With figures of that magnitude, it is hard not to see that there is a problem.Where would money like that come from, certainly not from selling the antiquated antibiotics.

With a grandiose problem ahead of mankind one would expect a grandiose solution to remedy the problem.However a much simpler and down to earth ideal is one that should prevail.Education is perhaps the strongest tool to influence a group of people, for bad or good.Giving knowledge in an easy and foolproof way of interpretation and is among the simplest way of showing someone the right way in which to carry out a task.So why not then use the simple tool of education to enlighten others as to solution of the problem at hand.

Educating the general public is an idea that the Center for Disease Control and Prevention (CDC) has set out to do.In July of 2000, the CDC added seven states, to make a total of twelve, "to the campaign to reduce the number of unnecessary antibiotic prescriptions."The CDC's campaign is one in which billboards, TV and radio spots, bus stops, and newspapers will be used as the vector to reach the general public.The messages will most likely be ones of simple nature, so that the general public, for example ones that have no biological background, will be able to read and comprehend.[2]This is a first step in the education process.By putting this information out into the hands of the public it will create it's own sense of awareness.Colorado is one such state in which the CDC is starting their campaign.Coloradoans are very keen on the idea; one mother says, "They [doctors] push antibiotics way too much."[18]Colorado will be allotted two million dollars of federal funds for this ad campaign.This form of education is a general one, one in which the public will be able to gain a general knowledge of the subject.This is advantageous to get the ball rolling, so to speak.With this groundwork laid, many patients own curiosity will get the better of them and then the physicians will be primed to supplement the learning process.

Giving patients information through education during the visit is a crucial way of education.This is the time in which the patients can put their newfound knowledge to work.The knowledge is applicable and relevant at the time, which aids in the learning process.If educational material is introduced at this time in the patient-physician relationship it is more likely to be viewed as authoritative, reports say.[8]Verbal instruction is not necessarily the easiest way for everyone to learn therefore pamphlets and patient education sheets should be prepared and given out at that time as well, so that the patient will be given the opportunity to learn more about their situation.The doctor would most likely make pamphlets and patient education sheets or an organization well versed in the subject.These supplemental education tools could be written with greater detail because the patient for one will be with the doctor when he or she receives the sheet and also the groundwork of CDC's ad campaign mentioned above will have been laid.Having this form of education tailored to each patient would be an ideal but highly improbable way of going about it; however having narrower spectrum educational sheets would be sufficient.Possibly with these information sheets some long-term and short-term affects of reducing antibiotic overuse should be stated.Some long-term affects being mainly the decrease in the numbers of antibiotic resistant bacterial strains.Short-term effects include changing the amount of office visits and the type of therapy used, ei. diet, herbs, lifestyle changes, etc.[8]

Education at the level of elementary children would also be merited.Talking with children at young ages, though not in a ground-shaking manner, could introduce the idea and difference between viruses and bacterial infections.This along with handing out information at places such as community organizations, childcare centers, and pharmacies would be beneficial.Again the whole idea behind this education is to repeat and reinforce, therefore the more that the public sees and is made aware of the problem of antibiotic overuse the more likely it is to stick with them.

The physician must also gain education.Possibly what the patient needs and/or wants is not always to have pills to take care of their problem.Physicians should be enlightened as to the newer and more foolproof testing methods to insure the amount and correct antibiotic is administered.More time should be taken with a patient, as alluded to before.By taking the time in the office to explain and educate the patient as to the illness that they are facing, and clearly laying out treatment options is more advantageous to the patient and to the well being of the antibiotics.

Along with education national guidelines for judicious antibiotic use would need to be drawn up and then more importantly followed.Having these guidelines set on a national level could cause predicaments and physicians would be less likely to use those guidelines.[19]Most commonly these guidelines are not followed because of there is a lack of clinical applicability seen by the practicing physician.A solution is to set very general guidelines at the national level and then allow for a more local refinement of these general guidelines, therefore the physicians would be more likely to follow guidelines that they had set out.[20]Overall the bureaucracy of these guidelines should not be so tight as to limit the decision making process of the physician.

Upon the advent of antibiotics Alexander Fleming warned that these antibiotics, if misused could lead to grave problems, this warning was not heeded and now the warning has come to pass.With more and more bacterial strains gaining antibiotic resistance something must be done.In a society based around time and money it puts undesirable strains on doctors and physicians to be rushed into prescribing medicine.This in turn causes a gross over usage of antibiotics.Constant overuse of antibiotics has been shown to lead to antibiotic resistant strains of bacterial.Lack of education is the leading causation in this problem.Therefore, by educating the public as to reasoning behind prescribing is the way to reduce the overuse of antibiotics.

[1] Fleming, Alexander; Penicillin; Nobel Lecture, December 11, 1945

[2] Staff writers; CDC expands campaign against overuse of antibiotics; 2000, June 01, posted @ 5:57 p.m.EDT;

[3] Soyka LF, Robinson DS, Lachant N, Monaco J; The misuse of antibiotics for treatment of upper respiratory tract infections in children; Pediatrics; 1975; 55: pp 552-556

[4] Gonzales R, Steiner JF, Sande MA; Antibiotic prescribing for adults with colds, upper respiratory tract infections, and bronchitis by ambulatory care physicians; JAMA; 1997; 278; pp 901-4

[5] Nyquist AC, Gonzales R, Steiner JF, Sande MA; Antibiotic prescribing for children with colds, upper respiratory tract infections, and bronchitis; JAMA; 1998; 279; pp 875-7

[6] Schwartz B, Barden L, Dowell S, Lackey C; Why doctors over prescribe antibiotics; Presented at the International Conference on Emerging Infectious Diseases, Atlanta, 1998; 66

[7] Linder, J.A.; Stafford, R.S.; Antibiotic Treatment of Adults With Sore Throat by Community Primary Care Physicians, A National Survey, 1989-1999; JAMA: Journal of the American Medical Association; 2001, September 12; Vol 286, No. 10; pp1181-1186

[8] Belongia, E.A., Schwartz, B; Strategies for Promoting Judicious use of Antibiotics by Doctors and Patients, BMJ: British Medical Journal, 09/05/98, Vol. 317 Issue 7159, pp668-671

[9] Pichichero, M. E.; Understanding Antibiotic Overuse for Respiratory Tract Infections in Children; Pediatrics, 1999, December, Vol. 104, Issue 6, pp1384-8

[10] Chan CS; What do patients expect from consultations for upper respiratory tract infections?; Family Practice; 1996; 43; pp229-35

[11] MacFarlane J, Holmes W, MacFarlane R, Britten N; Influence of patient's expectations on antibiotic management of acute lower respiratory tract illness in general practice: questionnaire study; BMJ (British Medical Journal); 1997; 315; pp1211-4

[12] Zuger, A.; Experts Say Cipro Overuse Could Lead to Problems; 2001, October 19, New York Times on the Web

[13] Russell, S; ANTIBIOTIC: Overuse of Cipro can breed lethal bacteria; 2001 October 17; San Fransico Chronicle;

[14] Ostrom, C; Antibiotics dangerously overused, group warns; 2001, October, 17; Seattle Times;

[15] Vergano, D; New growing threat: Resistance to Cipro antibiotic; 2001, October 24; USA TODAY;

[16]Willis, M; Aggressive Use of Antibiotics; 2001, October 29;

[17] Stenger, R.; Report: Fighting the Mutant Super Bugs Costs Billions; 2001, September 7,

[18] Sherry, A; Colorado will test ads to cut use of antibiotics; Denver Post; 2001, August 01;,1002,53%257E84257,00.html

[19] Christakis DA, Rivara FP; Pediatrician's awareness of and attitudes about four clinical practice guidelines; Pediatrics; 1998; 101; pp825-830

[20] Faryna A, Wergowske GL, Goldenburg K; Impact of therapeutic guidelines on antibiotic use by residents in primary care clinics; Journal of General Internal Medicine; 1987;2; pp102-107

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