By: James Peacock

Welcome back to our series on Antibiotic Resistance. This is the third, and final, part of the series, where we look at the responses and potential solutions put forth by the medical community in an effort to solve the issue of antibiotic resistance. Part one can be found here, while part two can be found here.

Just as a quick refresher, in part one we looked at how antibiotics came about, and how they developed over time. The antibiotic era first really got its start in the early 20th Century, although antibiotics have been unknowingly used for centuries. The first major antibiotic discovery was made in 1928 when Scottish scientist Alexander Fleming discovered that Penicillium had antibiotic properties. The first antibiotic, penicillin, would be mass produced beginning in 1945, and instantly revolutionized the way that illnesses were treated. Scientists would go on to discover nine different classes of antibiotics at a relatively quick pace, but the number of new discoveries would take a sharp downturn after 1962. Antibiotics themselves work in a variety of ways but mainly focus on disrupting the natural processes of bacteria, leading to the death of the pathogen or the prevention of its reproduction. Over time, scientists realized that the lack of new discoveries would not be the only issue with antibiotics, as it appeared that bacteria were slowly becoming resistant to antibiotics used by medical professionals. Bacterial development of antibiotic resistance through the process of natural selection and mutation was also covered.

Part two covered why bacteria are developing resistance to our antibiotics and one specific gene that signaled that the antibiotic resistance problem has become a global health crisis. The development of antibiotic resistance is directly related to the exposure of bacteria to antibiotics. The use, and in some cases overuse, of antibiotics in the treatment of illnesses, the prevention of illnesses and contamination of animals, and the prevention of contamination during the growing of produce all lead to bacteria being exposed in more and more quantities to antibiotics, which results in the development of antibiotic resistance. This resistance has gradually worn away the effectiveness of antibiotics. Colistin was eventually declared as the antibiotic of last resort, as no bacteria had developed resistance to it. Beginning in 2015 though, the growing prevalence of MCR-1, a plasmid gene that provides resistance to colistin, caused some panic and elevated antibiotic resistance to a crisis that needed immediate solutions. The gene was first seen in China, but rapidly made its way to both Europe and the United States. With health officials tracking the spread of antibiotic resistance closer than ever before, several different solutions have been proposed in an effort to deal with this growing issue.

International Cooperation

The growing risk and development of antibiotic resistant bacteria has led countries to not only begin tracking incidence and researching solutions but has also fostered international cooperation endeavors in an effort to bring about solutions at a quicker pace. One of the most important of these partnerships is between the European Union and the United States. This Transatlantic Taskforce on Antimicrobial Resistance (TATFAR) has, since 2009, led the cooperation efforts between these two entities. They have made a series of recommendations and proposals to foster continued cooperation, as well as bring about solutions to the antibiotics crisis. Every so often, the Taskforce will publish works that detail their recommendations. The last major progress report came in 2014, when they offered recommendations in three key areas related to halting the spread of antibiotic resistance. These areas dealt with the appropriate use of antimicrobial drugs in medicine, prevention of drug-resistant infections, and strategies to improve the pipeline of new antibacterial drugs for use in human medicine.

More recent publications, released in 2016, focused on developing an economic incentive for pharmaceutical companies to pursue new antibiotics. Because the cost of developing antibiotics is already high and is only getting worse, many companies shy away from new research. TATFAR has said that a combination of push incentives, pull incentives, and/or de-linkage models may help promote antibiotic development. Push incentives usually come in the form of tax credits and government subsidies, while pull methods might include milestone payments or patent buyouts. De-linkage models involve paying companies via established revenues instead of high volume sales. This would help reduce the chance that companies aim for a higher volume of sale in an effort to improve their return on investment. TATFAR recommends some or all of these measures, as the rate that resistance is spreading is outpacing the rate that new antibiotics are being made.

TATFAR is not the only international cooperative effort, nor is it the oldest. In 1948, The United Nations-developed World Health Organization was established to help track and organize aid for health issues that exist on a global scale. Whether it is providing medicines and aid to developing countries, or offering advice to policymakers in various countries, the WHO has been on the forefront of the global health scene for more than 50 years. In February 2017, though, the WHO focused their efforts on antibiotic resistance and released a list of bacteria that they say new antibiotics are “urgently needed” for. The list of 12 bacteria is divided into three tiers and is depicted below. Some of these bacteria, such as Shigella, Salmonellae, Campylobacter, and Enterococcus to name a few, are common causes of food poisoning.

 

Priority Tier Bacteria
Priority 1: Critical Acinetobacter baumannii
Pseudomonas aeruginosa
Enterobacteriaceae
Priority 2: High Enterococcus faecium
Staphylococcus aureus
Helicobacter
Campylobacter spp.
Salmonellae
Neisseria gonorrhoeae
Priority 3: Medium Streptococcus pneumoniae
Haemophilus influenza
Shigella spp.

New Antibiotics

With both national and international efforts to solve the antibiotic resistance crisis, there have been quite a few ideas on how the medical community can both fight existing resistance and help prevent further resistance from evolving. These solutions tend to focus on three main areas: Developing new antibiotics, modifying the ones that already exist, and reducing the dependence on antibiotic use.

While the development of the antibiotic age led to a rapid increase in the number of antibiotics, the antibiotic discovery boom would prove to be short-lived, as new classes of antibiotics became harder and harder to develop. The drop off of discoveries began around 1962, and continues to the present day. In one of the most recent antibiotic discoveries, scientists at Northeastern University developed a totally new antibiotic, named teixobactin. Teixobactin works by inhibiting a bacteria’s ability to produce a cell wall. This leaves the bacteria unstable, and it will eventually die. While the antibiotic will not work on all bacterium, it has been shown to be effective against bacteria that cause tuberculosis and anthrax. Continued study will uncover which bacteria teixobactin are effective against.

Interestingly, teixobactin is hardly the star of its own show. What stands out the most about the discovery of teixobactin is the new method, dubbed the iChip, used to discover it. What has mostly caused the downturn in antibiotic development is the fact that scientists cannot seem to grow many bacteria in a laboratory setting. With only a fraction of bacteria growing with current culturing methods, as much as 99% of bacteria in environmental settings have remained uncultured, severely hampering scientist’s abilities to develop new antibiotics. The iChip uses a porous plate that houses some agar membranes. By passing the plate through a mixture of environmental cells, an average of one cell per hole is captured. That cell is then incubated, which allows for the culturing of bacteria that were previously not able to be cultured. This method is about 9 times more effective than petri dishes in terms of bacterial recovery. This method will allow for more of the uncultured bacteria to be cultured, and may lead to another era of rapid antibiotic discovery.

Teixobactin is not the only antibiotic currently in development. In the past few years, antibiotics including Tigecycline, Doripenem, Telavancin, Ceftaroline, Tedizolid, Dalbavancin, Oritavancin, Ceftolozane/Tazobactam, and Ceftazidime/Avibactam have all been approved by the FDA. Some have even made their way to clinical usage. Unfortunately, especially in the case of Tigecycline, resistance is already emerging due to these antibiotics coming from already existing antibiotic classes. There are also, as of December 2014, more than 30 new antibiotics currently being developed. However, as many as 4 out of 5 antibiotics will never make it through the development process. Antibiotics that are successfully approved will still need to go through clinical trials, which means that the newest antibiotics are still 3 to 5 years away from widespread use.

Modification of Current Antibiotics

While the development of new antibiotics and antibiotic discovering methods offers hope for the future, in many cases new antibiotics will not be available for many years, if they even complete the development process. Another way to help antibiotics fight antibiotic resistance was recently highlighted by discoveries concerning the antibiotic vancomycin. Vancomycin works by disrupting a bacteria’s ability to build a cell wall, and it has taken 60 years for bacteria to develop resistance. Now that resistance is starting to appear, though, scientists have begun to look at ways to increase the effectiveness of vancomycin. They were successful, and in a study published in the past few weeks, a more powerful vancomycin was announced. These findings dealt with the addition of three new mechanisms to the antibiotic. These modifications allow the antibiotic to be effective against previously resistant bacteria, as was shown in the study. The newly modified vancomycin was able to eliminate Enterococci bacteria, both the original form and the vancomycin-resistant form. Enterococci bacteria can cause foodborne illness, which can develop into potentially life-threatening bacteremia or endocarditis. The WHO, back in February, classified Enterococcus bacteria as one of the bacteria in urgent need of new antibiotics. The modified vancomycin has about a 1000 fold increase in activity, which could lead to the prevention of further antibiotic resistance for many years.

Reducing Antibiotic Dependency

The development and modification of antibiotics will help fight the increasing resistance of bacteria to our treatment options. However, that does not address the root of the problem, which is the fact that bacteria are repeatedly and in many cases unnecessarily exposed to antibiotics. This exposure, as we talked about in part 2 of our series, mainly comes from the over prescription of antibiotics, as well as their overuse in the food production industries. There have been several ways proposed to help stem the tide of antibiotic overuse.

One of these methods, according to a study that is ongoing, may be to reduce the usage of antibiotics in the growing and protecting of various produce products by using probiotics. Not all bacteria cause illness, in fact, many are considered “friendly”. Bacteria grow naturally in the intestines of most animals, even humans. Recent estimates have actually placed the number of bacterial cells in the human body at around 38 trillion, compared to only 30 trillion human cells. Friendly bacteria are also one of the best sources that we derive antibiotics from. With that in mind, recent discoveries of lactic acid bacteria in Australia have led researchers to hypothesize that certain bacteria may help keep harmful bacteria from growing on produce. A recent study showed that these lactic acid bacteria might strongly inhibit the growth of both Salmonella and Listeria bacteria, both of which have caused foodborne illness outbreaks through produce. As more research is done, the use of probiotics to promote the growth of these bacteria may become more common in an effort to stop Salmonella and Listeria bacteria. Further research may also reveal other friendly bacteria that inhibit the growth of more harmful bacteria that can cause foodborne illness outbreaks.

The use of probiotics is not only limited to the production of food items. Research is also being done into the bacteria found in the gut’s ability to act as a line of defense for foodborne pathogens like Listeria monocytogenes. A recent study in mice showed that antibiotic use in would make the mouse more susceptible to a Listeria infection. These mice were also made more susceptible to Listeria after being treated with common chemotherapy drugs. These chemotherapy drugs are known to decimate the immune system of patients, putting them at a higher risk of not only developing an infection, including a foodborne illness infection, but also developing severe complications from that infection. Researchers then identified four distinct species of bacteria commonly found in the intestines that were, when used together, able to limit the growth of Listeria colonies inside the mice. By inhibiting growth, the Listeria was unable to cause a serious infection because they were prevented from spreading into other tissues. These findings suggest that in immunocompromised patients, such as cancer patients, and in others who have a higher risk of developing a serious Listeria infection, such as pregnant women, probiotic treatments will be able to help prevent the growth of Listeria. By preventing growth, serious Listeria infections can be prevented, meaning that fewer antibiotics will need to be prescribed. Further research could potentially reveal similar results for other foodborne pathogens, like Salmonella, E. coli, and Campylobacter.

The other front in reducing antibiotic overuse in society is to control the prescription of antibiotics. As we discussed earlier, some modified antibiotics are proving to have a 1000 fold increase in activity. This would allow fewer amounts of antibiotic to be prescribed without sacrificing any effectiveness. Beyond this, though, is a plan that has been proposed by TATFAR, as well as the CDC, called antibiotic stewardship programs. As was previously covered, the CDC estimates that between 30 to 50 percent of all antibiotic prescriptions are unnecessary. Stewardship programs attempt to improve the rate at which antibiotics are prescribed. By using interdisciplinary teams, improved education, new techniques, and increased feedback, healthcare providers will be able to only prescribe antibiotics when necessary, as well as make improvements in the amount of antibiotics issued in each prescription. Stewardship programs should also help doctors choose the correct antibiotic out of the gate. For decades, doctors have prescribed an array of antibiotics in an effort to find one that the infection responds to. This has led to a lot of unnecessary antibiotic exposure, which promotes the development of antibiotic resistance. The best part of stewardship programs is that they have already been proven to work. In a review of more than 20 studies, which were conducted between 1996 and 2010, stewardship programs were found to cause an 11 to 38% reduction in the defined daily dose per 1000 patient days. Unnecessary antibiotic prescriptions can also harm patients, as antibiotics reduce the amount of bacteria in the intestines and can harm the immune system, leaving the body more susceptible to other infections. By increasing the efficiency and accuracy of antibiotic prescriptions, consumers can also save money. Maryland found that stewardship programs had saved patients save $17 million over the course of 8 years. By continuing to expand the implementation of these programs, the tide of bacteria gaining antibiotic resistance can be stemmed.

Conclusion

The problems that surround the use of antibiotics will not simply disappear on their own. Antibiotic resistance will continue to be a problem, and will get worse as bacteria are continually exposed to antibiotics. Health officials and scientists have worked hard to find potential solutions to this issue, and when taken together they may lead to the antibiotics resistance crisis becoming a thing of the past. The development of new antibiotics will continue to help fight resistant bacteria. Aiding in this process is a new method for culturing bacteria, which may lead to a renewed era of rapidly discovering new classes of antibiotics. The development of new antibiotics and new antibiotic classes will be further aided by the modification of current antibiotics, which has yielded early results of incredibly more potent forms of the antibiotics.

The root of the antibiotic resistance problem, antibiotic exposure, is also being dealt with. Through increasing research in probiotics, our understanding of friendly bacteria is expanding. These friendly bacteria may be able to help in a myriad of ways, including preventing harmful bacteria from growing on food products and helping prevent infection. Promising results from the use of stewardship programs indicate that the efficiency and accuracy of antibiotic prescriptions may be on the rise. Supported by the CDC and global health organizations, stewardship programs have shown a decrease in unnecessary antibiotic resistance, a decrease in antibiotic exposure, and a decrease in costs for the consumer. All of these plans and procedures show that while the antibiotic resistance crisis is serious and only getting worse, there is a response to it from health officials. Although the progress may be slow at the moment, we are moving in the right direction.

 

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