Antibiotic Resistance

Did you know that each year there are over 154 million antibiotics prescribed by doctor’s offices and emergency rooms in America? While some of these prescriptions are needed, it is estimated that 47 million of these are unnecessary and could be contributing to the growing problem of antibiotic resistance throughout the world. Each year in the U.S. at least 2 million people are infected with resistant bacteria and at least 23,000 die because of the infection. Bacteria that cause pneumonia, tuberculosis, blood poisoning and gonorrhea are becoming more difficult to treat and the list is continuing to grow. Antibiotic resistance occurs when an antibiotic has lost its ability to effectively eliminate a bacterium. These resistant bacteria will continue to not only thrive, but multiply even in the presence of the therapeutic levels of an antibiotic. This is a major concern in the health field because infections that were once easily treatable are now becoming incurable, resulting in serious complications and sometimes even death. 

              In bacterial colonies, antibiotic resistance can occur when bacteria change in ways that cause a decline in the effectiveness of an antibiotic. Once this small number of bacterial cells become resistant to the antibiotic they will survive and reproduce to create more bacterial cells that are resistant to the bacteria. Another major concern, is the ability of bacteria to obtain bacterial resistance from other bacteria. In some cases, the bacteria transfer their genetic material, including genes encoding for resistance to antibiotics, via a

mating process called conjugation from one bacteria to another. The emergence of antibiotic resistance has occurred in part due to the misuse and overuse of antibiotics in the healthcare field. Each time a person uses antibiotics resistant bacteria is left behind, if these bacteria are left alone they will continue multiply, and repopulate the environment. Once these bacteria repopulate, another antibiotic will be prescribed which can cause the process to repeat itself leading to multi-resistant bacteria or “super bugs.” 

                 

Colonies of bacteria that are resistant to antibiotics (Right) compared to bacteria treated with bacteria in which they are killers (Left).

    Bacteria can become resistant to antibiotics in many ways. Some bacteria can destroy the antibiotic by simply neutralizing them which can make it harmful to the individual. Another method bacteria can use is to prevent the antibiotic from getting to its target. This is done by the bacteria pumping the antibiotic back outside of the cell before it takes it effect on the bacteria. Bacteria can also change their targets by changing their outside appearance so the antibiotic cannot bind to the target rendering the antibiotic ineffective.

                So, what is being done to prevent a world where antibiotic resistance bacteria are dominant? The Centers for Disease Control and Prevention (CDC) and The World Health Organization (WHO) are working to improve awareness about antibiotic resistance and how healthcare professional can prevent antibiotic resistance. This awareness includes ways in to prevent different infection in the first place, and if an infection is established to create guidelines on how antibiotics should be prescribed and dispensed. The consequences of a continuing growth in antibiotic resistance will lead to the need for more expensive drugs, increase cost in health care, and possibly an increase in infections and death due to antibiotic resistance.

Bibliography

Center For Disease Control . Antibiotic Resistance Questions and Answers. 25 September 2017. 22 October 2017. <https://www.cdc.gov/antibiotic-use/community/about/antibiotic-resistance-faqs.html>.

Kuiper, Randy L. "Overuse of antibiotics leads to bacterial resistance." Great Falls Tribune May 19 2014: 1-3.

Ventol, C. Lee. "The Antibiotic Resistance Crisis." Pharmacy and Therapeutics (2015): 227-283.

World Health Organization . Antibiotic resistance. October 2017. 22 October 2017. <http://www.who.int/mediacentre/factsheets/antibiotic-resistance/en/>.

 By:  Maya Hines, MSMS Graduate Student 

Innovative approaches in drug development

We all know that it takes great amount of resources and time to develop an effective drug. Pharmaceutical companies must go through very costly trials to refine a drug with best effectiveness. According to ‘Tufts Center for the Study of Drug Development’, the cost of developing new drugs and bringing it to market has significantly increased since 1970 from few hundred million to 3 billion over the course of 40 years. This increasing cost of research also increases the cost of treatment on public. [1]

According to Food and Drug Administration, there are multiple stages involved in drug development process such as drug discovery, studying its chemical property, preclinical research, clinical trials on human with small scale Phase 1 to large scale Phase 3. The goal of preclinical research is to find outs drug’s toxicity by testing it in vivo and in vitro; then drug is tested on human during clinical trial stage. In other word, human cells don’t usually see a drug until it reaches phase-1 of clinical trial and until now, we were relying on data using animal models. Researchers has come to notice that every patient is different and understands that there may not be one drug for all patients. These ideas lead to concept of precision medicine which involves personalized therapies based on patient’s individual needs. The new technique developed by Stanford university called “clinical trials in a dish” uses patient-specific induced pluripotent stem (iPS) cells to predicts if specific patients will benefit from a drug or not. [2]

The current in vitro research involves genetic modifications (mutations) of a human embryonic kidney cells or Chinese hamster ovarian cells to generate a tissue that resemble a tissue with disease. However, the new technique allows researchers to test drugs directly on human cells which includes hereditary mutation instead of kidney or hamster cells with induced mutations. The iPS cells are generated by reprogramming skin cells into stem cell state and then these stem cells are induced to differentiate into variety of cells such as neuron, liver cell or cardiac cell. This non-invasive technique provides researcher unlimited supply of patient derived specific tissue cells and since iPS cells retains DNA of a patient it can be used to evaluate personalized drug responses. One of the study by Stanford University used iPS cell derived cardiomyocytes (heart cells) and successfully predicted if Doxorubicin, chemotherapy drug will cause any toxicity to a cardiac tissue. [3]

I attended the seminar by Dr. Donald Ingber, who was the guest speaker at University

 Source:  Wyss Institute at Harvard University
Organ on a chip

of Kentucky during 2014 Naff Symposium. He provided the earlier insights on biologically inspired engineering to build an ‘organ-on-a-chip’. The chip is a size of AA battery with living cells with its microenvironment to mimic the physiological environment. Dr Ingber showed that their lab currently has bone marrow, liver, intestine, lung, heart and kidney on a chip. These chips can even be combined with another organ chip to study the inter-organ interactions. These chips can also be personalized using patient derived iPS cells which will reduce the need for lengthy and costly clinical trials. The chip is programmed and run by a computer simulation and this technique will easily replaces in vitro method to in silico. [4]

Something that was merely a dream few years back is now taking its shape and it’s going to revolutionize drug development industry. Recently, on April 11^th, 2017 FDA has made agreement to work with researchers to test the potentials of this organ-on-chips in drug development. Although only liver-chip is currently being evaluating by FDA, they are hoping to expand it to other organs including kidney, intestine and lung model. [5]

The benefits of these new techniques will provide researchers better tools to develop drug toxicity model and drug efficacy model. Since these tools will eliminate the need of animal model, it won’t raise any ethical issues and it will also keep PETA happy since there won’t be any animal cruelty. These techniques will predict how patient will react to a specific drug, thus increasing their chance of survival and decreasing the lethal side effects before patients are given such treatments. Although this new tool comes with great advantage, it is not without its limitation. These tools cannot predict if patients will have some side effects such as mood swing or insomnia.

References

[1] Commissioner, Office of the. “The Drug Development Process.” US FDA Home Page, Office of the Commissioner, 24 June 2015, www.fda.gov/ForPatients/Approvals/Drugs/default.htm.

[2]  Strauss, D.G. and K. Blinova, Clinical Trials in a Dish. Trends Pharmacol Sci, 2017. 38(1): p. 4-7

[3] Burridge, P. W., Li, Y. F., Matsa, E., Wu, H., Ong, S. G., Sharma, A., . . . Wu, J. C. (2016). Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity. Nat Med, 22(5), 547-556. doi:10.1038/nm.4087

[4] Bhatia, S. N., & Ingber, D. E. (2014). Microfluidic organs-on-chips. Nat Biotech, 32(8), 760-772. doi:10.1038/nbt.2989

 [5] Center for Food Safety and Applied Nutrition. “Constituent Updates - FDA Researchers to Evaluate 'Organs-on-Chips' Technology.” US FDA, Center for Food Safety and Applied Nutrition, 11 Apr. 2017, www.fda.gov/food/newsevents/constituentupdates/ucm551503.htm.

By Falak Patel, Master's of Medical Science Student, University of Kentucky