Use of Antibiotics : Dangerous or Helpful Aids?

Introduction:

Although, broad spectrum drugs are effective against a wide range of bacteria they also drive antibiotic resistance. When physicians are unsure of the type of infection they are dealing with they use these 'last resort antibiotics'. (A) E.coli for example, which is a type of bacteria that lives in the intestines but, some types of E.coli such as E.coli 0157:H7 causes intestinal infections. Diarrhea, abdominal pain, and fever are just some of the symptoms. Sometimes these symptoms although rare can lead to bloody diarrhea, dehydration, and kidney failure. Intestinal infections are commonly caused by contaminated food or water. Most infections can be treated at home and usually resolve within a few days to a week. (D)

Then there is Klebsiella pneumoniae which is a type of gram negative bacteria that causes different types of healthcare-associated infections. (some examples include: pneumonia, bloodstream infections, wound/surgical site infections, and meningitis) The Klebsiella bacteria have developed antimicrobial resistance to a class of antibiotics known as carbapenems. Just like E.coli, Klebsiella is found in the intestines, but also in human feces. Patients who are recieving care in hospital/healthcare settings through devices such as ventilators, intravenous vein catheters, and those taking antibiotics are at highest risk of a Klebsiella infection. (E)

In recent reports there can be seen an overall rise in consumption of antibiotics through surgeries whereas the number of perscriptions are falling. Between the years of 2010 to 2014 blood stream infections from E.coli and Klebsiella pneumoniae have increased from 13.5% to 17.2%.  Between 2011-14, there was a 6.5% rise in total antibiotic consumption (defined as doses of antibiotics per 1,000 people per day).(A) 

Streptococcus Pneumoniae infections are just some of the small group of bacteria that have shown good results in cutting infections. Their infections have fallen by 23% between 2010 to 2014 which seem to be related to have increased pneumococcal vaccination rates. If one was to look at the molecular level, these forms of mutations can actually prevent an antibiotic from entering the bacterial cell at all. By changing the target molecules that do not bind to the antibiotic or enhancing the efficiency of efflux of mechanisms in the bacteria that allows it to pump a drug back out again. Specific genes can actively degrade antibiotics by limiting their effectiveness once they have entered the cell.

The World Health Organization (WHO) has reported on the global antibiotic resistance because of the serious concern that there could very soon be a very serious threat to public health which has been recently rapidly growing. Diseases that we have thought to be treatable or far from concern could very possibly be a scary new reality. Everyone could be affected by this not just individuals living in poverty or developing countries. Tuberculosis is an example of a disease that used to be of the past is considered fatal now.

Research:

In 2014, most antibiotics in England were prescribed in general practice (74%), followed by prescribing for hospital inpatients (11%), hospital outpatients (7%), patients seen in dental practices (5%) and patients in other community settings (3%). Antibiotic prescribing to hospital inpatients increased significantly by 11.7% and to hospital outpatients by 8.5% between 2011-14. With the exception of general dental practice, antibiotic prescribing increased across the NHS in 2014.

The rising resistance to antibiotics routinely used to prevent patients getting infections during and after surgery is disastrous. It will mean increased risk for operations such as caesareans, hip replacements and appendix removal, and also treatment for cancer patients, who are given antibiotics because chemotherapy drugs undermine their immune system, making them vulnerable to infections.

 

About 32 percent of patients believe that they should stop taking antibiotics when they feel better rather than completing the prescribed course by their physicians, meanwhile over 76 percent of patients think that resistance occurs when the body itself becomes resistant. However, scientific research shows that bacteria grow resistant to antibiotics not humans or animals.

When the PHE released a second annual report on antimicrobial resistance, it supported WHO's survey that revealed a widespread public misunderstanding of antibiotics. The results showed that 64 percent of individuals have the misconception that antibiotics can actually cure common cold and flue whereas antibiotics have no impact on viruses. Subsequently, it is clear to see how antimicrobial resistance is quickly becoming a major threat to delivery of healthcare across the globe. 

The Ebola epidemic in West Africa puts into perspective the global antibiotic resistance pandemic. In 2014, the Ebola virus accounted for over 11,000 fatalities making it officially the most devastating outbreak virus in history. A rough estimate of 700,000 lives have lead to death worldwide because of the antibiotic resistant bacteria. Unless drastic changes are made, this number of annual deaths is predicted to rise to 10 million by 2050 where numbers of bacteria which are already fully resistant to every clinical antibiotic available are growing.

Scientists from San Diego Institute of Oceaneography have collected samples of marine life from the ocean floor, 20,000 feet below the surface of the pacific ocean in the coast of California. Within the small clumps of sediment, they found micro-organisms that can one day give us an answer to one of the most urgent issues in modern healthcare.

Professor Otto Cars described resistance to antibiotics as “a silent tsunami, crumbling down the pillars upon which modern medicine is built.” Cars, who has spent decades campaigning for awareness on the topic, describes the problem as one of complacency. While antibiotic consumption has increased by 36% in the past decade, no new classes of these drugs have been discovered since the 1980s. In June, the World Health Organisation unveiled a global action plan to tackle antibiotic resistance. One of the stated aims is to have a whole new class of antibiotics in development by 2019.

Over the past 80 years, the main focal point of the search for new antibiotics has been soil microbes, and the variety of substances they produce to kill each other as part of their ongoing chemical warfare. But until recently, we haven’t been especially adept at keeping them alive in the lab for long enough to obtain their weapons for our own use.

Meanwhile, scientists in Germany as well as in the United States have developed a method that has led to the discovery of teixobactin. This substance is believed to have the potential of becoming the very first new antibiotic since 1987. It has the ability to destroy some of the most dangerous drug resistant bacteria (i.e MRSA). Teixobactin has a very low potential for developing a resistance but it is ineffective against the most difficult to treat family of all bacteria, the gram-negative bacteria. Gram negative bacteria develop resistance at an incredible rate due to their rapid DNA sharing. This has evolved in gram negative bacteria as an extra protective membrane and a sophisticated efflux.

Scientists have been shifting their focus to organisms who live thousands of feet beneath the ocean surface. These specific organisms have evolved their own ways of defending against microbes where most of them are still unknown. Anthracimycin is a compound that is produced by a bacterium living in the pacific ocean which has given scientists potential however finding such compounds is just a minor aspect of the challenge.

The number one problem is finding compounds that are not toxic or harmful to humans. It is well known that bacteria, humans as well as all living creatures have the same biochemical mechanisms essential to life. This is what antibiotics usually target. Killing a bacterium is to poke a hole in its membrane. However, discovering something that specifically pokes holes in bacteria and NOT human cells is another challenge.

Gibbons feels the WHO’s 2019 deadline is unrealistic. “There’s a lot of work from simple testing to safety testing, and then animal models involving mice or rabbits, before you even think about a clinical trial. And you have to prove that you can generate enough of the substance itself. So I doubt we’ll see any new classes of antibiotics until 2021 or 2022 at the very least.”

Others are instead looking at redesigning old, discarded antibiotics to increase their stability and effectiveness. Some were originally abandoned because they only worked on a small handful of bacteria, but now it’s thought that a range of more narrow spectrum treatments may be a better way to avoid driving resistance.Lee is currently researching spectinomycin, an antibiotic introduced in the 1960s to treat gonorrhoea, before being cast aside as it only worked in massive doses. He believes that a remodeled version has the potential to work well against a range of respiratory tract infections and sexually transmitted diseases.

“The drug has always been very safe, and fifty years on we now know its crystal structure,” he says. “So we can exploit that along with all the old knowledge from the pharmaceutical companies who tried to develop it in the 1980s, to improve its design and help it access the target bacteria more effectively.” Of course, some bacteria will eventually become resistant to spectinomycin and other old antibiotics, but Lee believes that it is possible to design these drugs so this comes at an evolutionary cost to the bacteria.

Tuberculosis:

Tuberculosis should be treatable within 6 month period once individuals are given a prescribed course of drugs including isoniazid and rifampicin antibiotics. However, there is a resistance to these medications as well as a wide range of pharmaceuticals used to treat the disease. Because of this recent obstacle, a multi drug resistant TB has emerged, "XDR-TB" and a total drug resistant TB officially confirmed in India. Many countries have run out of treatment options for their patients such as those in South Africa and have to choice but to discharge the patients from the hospitals without proper treatment. As of today, 92 countries are reported to being resistant to TB hitting the global scale mark with XDR-TB.

Gonorrhoea: 

Gonorrhoea is a sexually transmitted infection. It used to be easily treatable but once penicillin and tetracycline, however since the bacteria behind the disease developed high levels of resistance that now there is only one drug left to treat it. Even this antibiotic, ceftriaxone, is becoming less effective. With last-resort drugs losing their impact, this sexually transmitted infection (STI) could spread throughout the population.

Klebsiella:

Klebsiella is a common bacterium that is part of the group of bacteria with the 'apt' acronym of Eskape. that causes a range of conditions such as pneumonia, UTIs, septicaemia, meningitis, as well as diarrhea. Their ability to avoid the effects of antibiotics which are used against them. The 'apt' acronym stands for the names within the bacterial group members: Enterococcus faecium, Staphylococcus aureus; Klebsiella pneumoniae: Acinetobacter baumannii; Pseudomonas aeruginosa; and Enterobacter. Klebsiella are just some examples of this group. Although MRSA is a concern it is declining in hospitals. Eskape pathogens are causing more and more problems. As the WHO report highlighted, routine hospital visits or treatments could result in these previously treatable bacteria having fatal consequences.

Typhoid:

Typhoid is a somewhat rare disease for humans because of the routine vaccinations against typhoid are performed. There are a large amount of people affected by typhoid, around 21.5 million people per year.  Since people are always traveling to developing countries and travel to  areas with increased sources of infection has become more common. This has affected more than 5,000 American lives as they have become infected after ingesting contaminated foods or drinks.

Typhoid consists of a typhoid fever where the bacterium salmonella typhi although typically treated with antibiotics have been increasing their resistance to multiple antibiotics. Reduced susceptibility to fluoroquinolone class of drugs and the emerging of multi drug resistance has complicated the treatment of infections. (especially those from South Asia). There is good news as the vaccination for typhoid does in fact exist, however it is critical for people to be vaccinated before getting onto a plane. 

Syphillis and Diphtheria:

Although resistance to these diseases is yet to emerge, public awareness of them has reduced as a result of effective treatments. But in an era of resistance there is always the potential for them to return as a serious public health threat. Although rates of syphilis are low, they have been increasing in the UK since 1997. This STI is currently treated by a single injection with penicillin, but resistance to this antibiotic has developed in other diseases. Imagine the impact if it happened again. The fever and chills of diphtheria are mainly prevalent in the developing world, but with travelers contracting typhoid even though a vaccine is available, the same could happen with diphtheria.

CONCLUSION:

“The most common way this happens is through the acquisition of genes from other resistant bacteria,” says Gerry Wright, a chemical biologist at McMaster University in Ontario, Canada. “Bacteria are very promiscuous and the most shocking thing we’ve realised over the past 60 years is just how rapidly this gene sharing occurs. They often acquire these resistance genes in packages, giving them resistance to multiple antibiotics at the same time, and that’s a major problem in hospitals. Resistance also develops through chance mutations during DNA copying when bacteria reproduce. This is believed to be how bacteria became resistant to rifampin, a drug used to treat tuberculosis.”

Since antibiotics are harder for bacteria to develop a resistance against, mutated bacteria can bypass the drug however they do not live very long. So you could become infected but it won’t be as virulent and threatening. Developing a new product from scratch or even rewiring an old one comes with substantial costs and challenges, and so there are many scientists focusing exclusively on ways to make our existing antibiotics useful once more against resistant bacteria. One popular idea is combination therapy – combining multiple drugs together to form a cocktail mix which is both more potent and difficult to evade.

By continuing the discovery of specific genes essential for the life of the bacterium that interact with multiple other genes in the cell in a complex web-like fashion. By combining antibiotics with other molecules and using these combinations to target this web in various random fashions, perhaps we can unexpectedly improve antibiotic activity or overcome bacterial resistance in new ways. Such random screening required vast numbers of drug combinations to be tried and tested, a thankless needle-in-a-haystack task which would have taken years of labor in decades gone by. But with 21st century robotics technology, Wright and his colleague Eric Brown are able to screen thousands in a mere afternoon.

There can still be unexpected drawbacks as it is often hard to match the exposure of two drugs at the site of infection to see the desired effect.. Wright and Brown thought they’d struck gold with a combination of the antibiotic tetracycline with a drug called imodium, used to treat diarrhea. Imodium enhanced tetracycline’s ability to penetrate bacteria, but further testing showed this only worked in the gut, limiting its usefulness.  “The alternative is to have one drug that simultaneously hits several , often related bacterial targets making resistance harder to develop,” Lee says. “This is a serendipitous strategy applied by many currently successful antibacterial agents including fluoroquinolones and beta-lactam antibiotics. But from a de novo discovery angle this is technically much harder to do.”

As a result, some feel the right combinations of drugs have major advantages when it comes to developing viable products. Given that the individual drugs themselves are known to be safe, and can be produced in large quantities at a reasonable cost, the path from lab to clinic should, in theory, be much faster and less expensive. Wright believes combination therapy is the main way forward, just as combinations of antiviral drugs proved to be the way to control HIV. “With multiple molecules, bacteria often have to develop resistance to each one. And with three or even four molecules together, there’s less and less chance of this actually happening.”

Antibiotic resistance is a problem we can all help to reduce. Good hand hygiene when visiting people in hospital helps. Only taking antibiotics when prescribed by a doctor is crucial; as is always completing a full course if you do have to take them. In addition, doctors themselves should only be prescribing these medicines when patients truly need them. These may be small things, but if we all do them it will have an impact and maybe prevent a future where treatable diseases become fatal once more.

Links:

(A) http://www.theguardian.com/society/2015/nov/16/last-resort-antibiotics-growing-threat-healthcare-report

(B)http://www.theguardian.com/society/blog/2015/aug/21/antibiotic-resistance-the-race-to-stop-the-silent-tsunami-facing-modern-medicine

(C) http://www.theguardian.com/commentisfree/2014/may/09/6-diseases-becoming-resistant-to-antibiotics

(D) http://www.healthline.com/health/e-coli-infection#Overview1

(E)http://www.cdc.gov/HAI/organisms/klebsiella/klebsiella.html

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