HEALTHCARE SCIENCE

A Solution For The Antibiotic Resistance Crisis

Synergistic Antibiotics: The treatment with great potential

Photo by CDC on Unsplash

The prevalence of antibiotic resistance is often overlooked by healthcare systems worldwide. Disease-inducing bacteria are increasingly becoming resistant to antibiotics at a faster rate than we can produce them. Without proper intervention, this global crisis can lead to 10 million deaths annually by 2050.

But even today, antibiotic resistance poses a huge threat and is one of the greatest worldwide challenges to modern medicine and society at large. According to a report released in The Lancet, antimicrobial resistance was responsible for at least 1.27 million deaths in 2019. From that number, antibiotic resistance alone accounted for 700,000 deaths. The World Health Organization (WHO) has now classified this crisis as a “serious threat [that] is no longer a prediction for the future.”

As of now, this field of medicine is significantly underinvested as opposed to the newer, more attractive forms of therapy being offered in other areas of healthcare.

To prevent us from further heading into a post-antibiotic era where common infections can be lethal, coordinated efforts must be made to combat this global crisis. This includes implementing new policies such as the Antibiotic Stewardship Pledge, or renewing/ investing more in research. Considering the devasting impact COVID-19 brought on us for these last few years, it’s clear that a world with overwhelming antibiotic resistance can have a substantially greater toll on life than we’ve ever experienced before.

An Overview of Antibiotics

An antibiotic is a type of antimicrobial substance used to treat bacterial infections by either killing or inhibiting the growth of bacteria. The first modern-day antibiotic, penicillin, was discovered in 1928 by Alexander Fleming. This initial discovery proved to be incredibly beneficial during wartime as bacteria-induced diseases were quite common. Since then, the development of antibiotics took off and they’ve become one of our most precious medical resources.

Today there are hundreds of different types of antibiotics, all classified based on their chemical structure, mechanism of action, and the type of bacterial infections they treat. Here are the six common types of antibiotics:

• Penicillins — Used to treat a wide range of infections including urinary tract infections, chest infections, and skin infections. They are classified as beta-lactam antibiotics, meaning their chemical structure contains a beta-lactam ring which inhibits enzymes required for bacterial cell wall synthesis. Examples are penicillin, ampicillin, amoxicillin.
• Aminoglycosides — Used to treat very serious illnesses such as bacteremia, endocarditis, as well as infections of the abdomen and the urinary tract. They work by binding to ribosomes within the 30S ribosomal subunit, interfering with the bacteria’s ability to read genetic code. Examples are tobramycin, neomycin, and gentamycin.
• Cephalosporins — Used to treat a wide variety of infections such as skin and sinus infections but can also be effective for treating more serious infections such as meningitis and pneumonia. Like penicillins, they are also classified as beta-lactam antibiotics. They inhibit the production of enzymes which are critical for synthesizing the bacteria’s cell wall. Examples are cefazolin and cephalexin.
• Macrolides — Used particularly to treat lung and chest infections or as an alternative to penicillin. They interfere with the bacteria’s ability to synthesize essential proteins by binding to the 50S ribosomal subunit. Examples are azithromycin, clarithromycin, and erythromycin.
• Tetracyclines — Used to treat a wide range of infections but are often used to treat skin conditions. Similar to macrolides, they work by inhibiting protein synthesis, this time by reversibly binding to the 30S ribosomal subunit. Examples are tetracycline, doxycycline, and minocycline.
• Fluoroquinolones — Used to treat serious infections such as pneumonia, bronchitis, septicemia, and urinary tract infections. They inhibit two enzymes involved in bacterial DNA replication, thereby preventing the bacteria from properly replicating and producing new proteins. Examples are moxifloxacin, ciprofloxacin, and levofloxacin.

The Antibiotic Resistance Crisis

As effective and easy-access many antibiotics are, the overuse and misuse of these drugs accelerate the process of what we know as antibiotic resistance. Antibiotic resistance occurs when bacteria change in response to the effects of antibiotic drugs and become resistant to them.

The accumulation of this resistance threatens our ability to treat common infectious diseases and causes the more serious ones such as blood poisoning, or tuberculosis to be harder, if not, impossible to treat. An infection that previously could be treated at home can now require hospital admission.

The first signs of antibiotic resistance were hinted shortly after the discovery of Penicillin, which explains the reason behind the rapid development of new antibiotics since then. Furthermore, in 1945, Alexander Fleming informed public health regarding the overuse of these drugs, and the consequences that come along with it. Epidemiological studies were then carried out to understand the mechanism by which antibiotic resistance is induced. It was discovered that there are a number of factors that contribute to antibiotic resistance, the five main ones being:

• Misuse of antibiotics — Bacteria are able to rapidly multiply the second they get a chance, meaning that stopping treatment too soon, using incorrect antibiotics, or even missing a single dose can cause bacteria to reproduce. In doing so, they can also mutate to become more resistant to the antibiotic.
• Overuse of antibiotics — Taking unnecessary amounts of antibiotics when they’re not needed or are ineffective can contribute to resistance. For example, repeating the same antibiotic treatment where resistance already occurred will make it even worse.
• Spontaneous resistance — The DNA of some bacteria naturally changes or mutates over time, thereby becoming resistant to the antibiotic as it isn’t recognized anymore. The change/ mutation can also help the bacteria develop a defense mechanism against certain antibiotics.
• Transmitted resistance — Like many infections, drug-resistant bacteria are contagious, meaning that antibiotic resistance can be passed on to other people. Over time this makes the drug-resistant bacteria harder to treat.
• Agricultural use — It’s estimated that around 66% of all antibiotics are used for livestock. Bacteria in animals can also become antibiotic-resistant as much as they can in humans.

As time passes, the level of antibiotic resistance will only increase and become more and more difficult to treat. Currently, bacteria such as clostridioides difficile or acinetobacter are urgent public health threats that require immediate action.

There are steps being taken to prescribe antibiotics only when necessary, and improve overall hygiene/ infection control. However, it’s only a matter of time before we run out of antibiotics to treat these overwhelming amounts of drug-resistant bacteria. Newer strategies such as developing/ prescribing synergistic drug combinations must be implemented.

Synergistic Antibiotic Combinations

Synergistic antibiotic combinations are two or more antibiotics combined to form an effect greater than the sum of their predicted individual effects. These combinations allow for lower doses of the constituents followed by greatly enhanced effects. This is achieved by each antibiotic targeting a different aspect of the bacterium, providing a more comprehensive approach to treating the infection. The specific combination of antibiotics being used and their mechanism of action will depend on the type and severity of the infection being treated.

An example of a synergistic combination involves amoxicillin and clavulanic acid, which are commonly used together to treat lower respiratory tract infections such as bronchitis or pneumonia. Amoxicillin is a beta-lactam antibiotic, used to treat a wide range of infections including urinary tract infections, chest infections, and skin infections. It works by interrupting the construction of the bacteria’s cell wall, ultimately leading to the lysis (destruction) of the bacteria. Clavulanic acid on the other hand, has little to no antibiotic properties but instead protects beta-lactams from bacterial destruction. The combination of the two (amoxiclav) restores the full antibiotic effect of amoxicillin.

Previous studies show that drug combinations with synergy (like amoxiclav) are highly successful in treating infections caused by drug-resistant bacteria. For example, the combination of rifampin and doxycycline was found to effectively treat diseases such as brucellosis.

But for the longest time, this particular field in the pharmaceutical industry was cold-heartedly ignored and lacked the necessary research. The combinations require lower amounts of constituents for the same, or even better treatment, making them unattractive from the business perspective.

But as antibiotic resistance becomes a bigger issue, we can expect to see some of the synergistic combinations come to life. Because at the end of the day, it’s the health and well-being of our people that really matters.