Battling Bacteria: Back to Square 1?
CDC director Dr. Thomas Frieden grimly predicted: “The medicine cabinet is empty for some patients. We may have come to the end of the road for antibiotics.”
Urgent headlines across the U.S. crystallized the concerns of the Centers for Disease Control and Prevention (CDC) officials who steward the battle against multidrug-resistant “superbug” bacteria in the U.S.
In May 2017, a 49-year-old Pennsylvania woman arrived at a clinic with a dread mutated strain of Escherichia coli (E. coli) bacteria. It was the first time this bacterial strain had ever been detected in the United States, though it had previously been identified in Europe, Canada and China. How she contracted the infection is unknown, as she had not recently traveled out of the U.S. Fortunately for the patient, she responded to other antibiotic treatment and was released. CDC officials and the Pennsylvania Department of Health quickly mobilized to investigate the case.
Not all in the family of E. coli germs are as lethal as was this woman’s mutated bacteria. But that woman’s rare mutant strain of E. coli bacteria carries a gene for antibiotic resistance that rides on a small fragment of DNA called a plasmid. The plasmids enable the bacterial genes to move over to other bacteria, and to different species of bacteria, breeding resistance to antibiotics and transforming these bacteria into a potentially untreatable superbug.
Most troubling is that this mutant bacterial strain has been found to be resistant to an antibiotic called Colistin, regarded as a last-resort antibiotic for life threatening superbugs such as the multi-drug resistant CRE bacteria (Carbapenem-resistant Enterobacteriaceae), which CDC officials have dubbed “nightmare bacteria.”
CRE bacteria — which include families of intractable bacteria such as Klebsiella pneumoniae and E. coli, among others — are most typically acquired by patients in hospitals or medical facilities.
Resistant superbugs may not start out as devastating infections. Previously susceptible to antibiotics, bacteria can initiate as simple infections, such as a urinary tract infection (UTI), which might become resistant to the preferred narrow-spectrum first-line antibiotics (which are effective against only a specific group of bacteria). With prolonged antibiotic use, bacteria evolve and mutate into more resistant forms — the ultimate “smart bugs” — necessitating treatment with potent broad-spectrum antibiotics, as a second- or third-line defense antimicrobial treatment. Through repeated exposure to antibiotics, these dangerous bacteria proliferate, spreading resistance genes through the bacterial population.
According to the CDC, at least two million people in the United States are sickened annually with infectious multi-drug-resistant bacteria superbugs and at least 23,000 people die each year as a result of those infections. A British study estimates that globally, there are 700,000 deaths annually from antibiotic-resistant infections, and projects that if left unchecked, by 2050, there can be 10 million casualties worldwide, each year.
In September 2016, in Reno, Nevada, a woman in her 70s with Klebsiella pneumoniae was resistant to 26 antibiotics used in the U.S. to treat her superbug infection. She had been on an extended visit to India, where she had broken a thighbone and subsequently underwent several hospitalizations in India because of consequent resistant infection. When the patient was ultimately admitted to the Reno hospital, it was discovered she had a CRE infection and was resistant to every antibiotic that was available in the U.S. She later died of multiple organ failure and sepsis (blood stream infection).
Dr. Alexander Kallen, a CDC medical officer, stated about that case: “Although this isn’t the first time someone in the U.S. has been infected with pan-resistant bacteria, at this point it is not common. It is, however, alarming.”
A DOCTOR’S PROGNOSIS
Dr. Zachary A. Rubin is Associate Clinical Professor of Infectious Diseases and Medical Director of Clinical Epidemiology and Infection Prevention at the Ronald Reagan UCLA Medical Center in Los Angeles, California.
Dr. Rubin shed light on universal pitfalls which drive antibiotic resistance, explaining to Hamodia: “Antibiotic resistance is truly a global problem and has many causes. Overuse of antibiotics in the hospital is a concern in hospitals in the U.S. and in Europe, but it is an even larger problem in developing nations, as in south Asia and China.”
He further cautioned that “with the ease of movement around the globe, we are now seeing resistance spreading around the world also.” Antibiotic-resistant superbugs imported by travelers overseas are only a plane ride away.
Dr. Rubin pointed out another practice that fuels antibiotic resistance: agricultural methods employed by farmers of feeding antibiotics to livestock to promote their growth, which people afterward consume. Moreover, the global ecosystem absorbs antibiotics, too, spurring greater antibiotic resistance, as quantities of unneeded, expired, spoiled, or unused antibiotics are dumped by medical facilities or by pharmaceutical companies into wastewater which streams into rivers or in irrigation and consequently infiltrates our drinking water.
Resistant bacteria may be related to either Gram-negative or Gram-positive bacterial species. The species differ primarily in the structure and composition of their cell wall, which makes them react to antibiotics quite differently. Dr. Rubin explained more about the more resilient and dangerous Gram-negative bacteria: “What we are seeing on a large scale is that Gram-negative bacteria, which largely live in the colon, are able to transmit resistance to each other more easily, probably related to closer contact in the colon. Additionally, antibiotics for Gram-negative bacteria seem to be harder to develop and have shorter life spans than Gram-positive antibiotics in general, leading to more difficulty treating Gram-negative infections over the last decade.
“Exacerbating the problem,” he added, “is that drug companies are developing fewer antibiotics largely due to economic factors.”
Pharmaceutical companies’ profit margins are not inflated by launching new classes of antibiotics and they rather focus on producing drugs for diseases that will boost revenues. The heyday of new antibiotic classes emerged principally in the decades of the 1940s, ’50s and ’60s. Conversely, within the past 30 years, there has been a shortfall of antibiotic innovations to combat the stranglehold of multi-drug bacterial resistance.
Dr. Rubin warned that models of drug resistance demonstrate that as the rates of resistance increase in patient populations, the greater the number of people who die of infections.
“If you think about the world in the early 20th century before we had antibiotics, patients died of even simple infections like Staphylococcus and Streptococcus infections that are easy to treat now with antibiotics. Though we aren’t there yet, the concern is that as resistance increases in the population, we may find ourselves in a situation more like the pre-antibiotic era,” Dr. Rubin said.
Pundits posit that a post-antibiotic apocalypse would herald the risks of the pre-antibiotic era, as antibiotics are a crucial adjunct to surgical procedures and medical treatments. Surgery would be far riskier to patients if they would not respond to antibiotics. Antibiotic resistance can spawn casualties among chemotherapy patients with suppressed immune systems. Even a minor infected scratch can engender dire consequences due to antibiotic resistance. Seemingly, a post-antibiotic era may all too eerily ring of the perilous pre-antibiotic epoch before Alexander Fleming discovered the first antibiotic, penicillin, in 1928.
A patient Dr. Rubin treated needed a surgical procedure and subsequently developed a blood stream infection (sepsis) of CRE bacteria. Dr. Rubin started her on multiple broad-spectrum antibiotics. “At the initial diagnosis, the CRE bacteria was susceptible only to one antibiotic, yet the patient continued to have a persistent infection despite treatment with the antibiotic,” he said.
As there were no other antibiotic options, Dr. Rubin contacted the manufacturers of two antibiotics that had not yet been FDA approved at that time. Working with the FDA via an emergency investigational new drug application, pharmaceutical companies delivered one drug from France and another from England for treatment of his patient. Dr. Rubin’s patient ultimately died of complications of the resistant infection, despite administration of the new antibiotics.
“Telling a patient or family members that we have no other options to treat an infection that should be treatable is very upsetting, especially when the infection should be susceptible to the antibiotic,” Dr. Rubin disclosed to Hamodia. “Luckily, the FDA in the U.S. has helped expand the pipeline for new antibiotics over the last couple of years, which is helping.”
Dr. Rubin underscored, “in many cases, the bacteria are evolving more rapidly than researchers can come up with new drugs.”
Susan Bermish of Staten Island, N.Y., shared with Hamodia her mother’s close call with Methicillin-resistant Staphylococcus aureus (MRSA), which almost felled Blanche Wrubel.
In 1997, Wrubel, 75, a New York City resident, was a “healthy, active person who walked, shopped, cooked, visited and was engaged in life,” maintained Bermish. The only flaw on her clear health records was a hip replacement she had undergone years earlier.
This, until the day Blanche Wrubel called her daughter, indicating that she wasn’t feeling well, that “her stomach and her shoulder hurt.” Concerned that she was having a heart attack, Wrubel was rushed to the hospital. After physicians did diagnostic bloodwork on Wrubel, they ascertained that she wasn’t having a heart attack, but, rather, harbored a raging MRSA infection.
“The doctor looked as if a heart attack would have been preferable to this type of infection,” recalled Bermish to Hamodia.
Blanche Wrubel was started on intravenous Vancomycin, a powerful broad-spectrum antibiotic, while physicians surgically removed a pocket of infection in her shoulder, the cause for her pain. She was treated with that IV antibiotic both in the hospital and then at home over the ensuing months.
Wrubel was again hospitalized with fevers, pain, lethargy and even hallucinations as the MRSA infection spread to her other organs, including her spine and a previous hip replacement (later necessitating a revision hip replacement). When Blanche Wrubel’s body was overcome with sepsis and her vital organs were failing, she was near death.
Susan Bermish recounted to Hamodia: “This crisis happened at around the time of Tishah B’Av. The doctors told our family to prepare for the worst.”
A new infectious-disease physician placed her mother on a cocktail of IV antibiotics, to which, miraculously, Blanche Wrubel responded. Although the elder woman survived, remaining on oral antibiotics for another decade, she is now in a wheelchair with an aide, having lost her independence and mobility.
Susan Bermish emphasized to Hamodia: “My mother was a completely healthy woman before the MRSA. Had she had a heart or a kidney problem, or any other medical issues, she would never have survived!”
She worries: “My mother’s experience frightens me because anyone can get a simple infection which doesn’t respond to antibiotics and it can turn into a full-blown life-threatening bacterial infection. I have children and grandchildren, and I see that my grandchildren do not respond to medication as my children did a generation earlier.”
Elkie Trenk is co-founder of the nursing division of Infusion Options, in Brooklyn, N.Y., a home-care infusion agency which provides home-care antibiotic infusions according to doctors’ directives.
Although now retired, Trenk is a veteran nurse of over 25 years, having worked in the Brooklyn, N.Y., hospital of Maimonides Medical Center [with which Infusion Options is affiliated], in the Intensive Care Unit and the Emergency Room, among the hospital’s other departments.
Trenk observed to Hamodia: “I call antibiotics a necessary evil. We don’t want to overuse it, but when a patient has a bacterial infection, we’ve got to treat it with antibiotics.”
Elkie Trenk pointed out that abuse of antibiotics is often propelled by overuse of conventional oral antibiotics, which are a mainstay of the medical profession, for when patients have a viral infection, such as a sore throat accompanying a viral cold or flu, they may be started on antibiotics as a pre-emptive measure to prevent bacterial infection.
“But they have a viral infection,” she explained, “so the unnecessary antibiotics build up resistance, because they’re used inappropriately. So when a patient needs IV antibiotics most, they can be ineffective!”
This seasoned nurse maintained that “patients may be given an antibiotic, to which they respond the initial three times, but by the fourth time taking that antibiotic, it might not be effective, and they need stronger antibiotic treatments because they became resistant.”
She singled out superbugs, such as MRSA, as chiefly hospital-acquired infections. “Hospital physicians will administer a broad-spectrum IV antibiotic until lab cultures show a specific infection, and then the doctors will narrow down to a more specific antibiotic,” she said. “But that’s what has to be done.”
“Why would we return to an era where people are again dying because antibiotics are now failing to work?” Ellie Trenk wondered. “I can’t imagine going back to a time when someone would catch a cold, develop pneumonia and die. But with antibiotic resistance, it can start again.”
A WATERSHED IN RESEARCH STUDIES
Trailblazing research studies of diverse approaches, recently published in peer-reviewed science journals, are poised to combat antibiotic resistance. Hamodia interviewed these leading researchers, each at the helm of his study.
Assistant Professors Prashant Nagpal and Anushree Chatterjee of the Department of Chemical and Biological Engineering in the University of Colorado Boulder, whose studies were published in the science journals Nature Materials and Science Advances.
“Our approach is a two-pronged strategy to fight antibiotic-drug resistance,” Professor Nagpal told Hamodia. “In a study published last year, we showed that quantum dots [made out of semiconducting material] can be developed as antibiotics and treat infections. In a recent study we further showed the potential of designed quantum dots to also reactivate existing antibiotics and work effectively with conventional antibiotics.”
These quantum dots are tiny, light-activated nanoparticles, around 10,000 times smaller than the thickness of a single strand of hair. When these nanoparticles are illuminated with light, it produces a biochemical reaction in superbug-resistant bacteria that empowers existing antibiotics to effectively fight against multi-drug-resistant bacteria.
“Our goal is to develop a whole range of quantum dots [as antibiotic therapies] against resistant superbugs,” says Professor Nagpal. “These quantum dots can be scaled easily and can be produced in a gram or larger, to adjust to the bacteria [strain].
“The quantum dots will be tailored rapidly, and by adjusting the size or material of the quantum dots we can obtain a new therapy against resistant bacteria. The quantum dots work together with a range of antibiotics, to prevent further spread of antibiotic resistance.”
The objective is “to stay steps ahead of these fast-evolving very smart bugs that we are currently 10 steps or more behind. This gives us a fighting chance in a race we cannot afford to lose, since antibiotics are an important pillar of modern medicine and crucial for our survival, health and wellbeing.”
The antibiotic therapies necessary to administer in conjunction with the quantum dots “are enabled to be 1,000 to 100,000 times less than current antibiotic therapies,” he maintained.
Professors Chatterjee and Nagpal’s prospective scientific treatment of an antibiotic-resistant superbug seems like science fiction, except that their research studies are very real and science evidenced. They project that their quantum dots treatment could be fast tracked in a few years to clinical trials given adequate resources, since funding is “currently our biggest hurdle in translating and testing this therapy to combat superbugs.”
Professor Nagpal said that his and Professor Chatterjee’s vision as to how the quantum dots would work: The dots will be either inhaled as an aerosol spray or infused intravenously into patients with a superbug-resistant infection, and can be taken together with conventional antibiotics administered at a lesser dose than currently given. The patient will be asked to sit in an illuminated room, with lights, or could sit outside in the sun while enjoying the outdoors, or asked to wear a jacket or other apparel lined with LED lights emitting visible light. The outer fabric can be standard opaque fabric while the inside will be lined with LED lights. “After being exposed to these lights the patients can go through their normal routine day. The infection should be cleared fast and the patient will recover,” he said.
Professor Nagpal averred that they have tested quantum dots against clinical patient isolates [pure strains of bacteria isolated from patients’ lab specimens], such as MRSA, Salmonella, Staph, and strains of E. coli, which were designated by the CDC and the World Health Organization (WHO) as “critical” class-1 priority pathogens. “Our therapy worked remarkably well against them, in lab cultures, infection models and small nematode animal models [worms] used for high-throughput screening [a wide-scale, automated method for experimentation].”
Professor Nagpal outlined that they have tested their quantum dot therapies with a range of different bacteria. “We tested pathogens that are resistant to two or more antibiotics, and pathogens of really potent bacterial strains, resistant to more than 20 antibiotics, [and also] with a range of lab strains of patient clinical isolates. Our quantum dots work against a large number — more than 80 percent — of tested pathogens.
“If our therapy is as effective in clinical trials against the pathogens and a broad range of clinical strains we tested in vitro [in laboratory tubes], we could see a dramatic reduction, perhaps even more than half, in fatality rates from antimicrobial resistance!” he affirmed.
Professor Nagpal explained that as this therapy targets an essential cellular process rather than a specific target like most small-molecule antibiotics, which bacteria can fight by evolving, “we think this is a harder therapy for bacteria to fight. Therefore, we have high hopes for this novel therapy, which we are very eager to test in clinical trials and see if it can translate as a viable therapy to combat this imminent and imposing public health crisis of antimicrobial drug-resistance.”
The professor thanked Hamodia for disseminating this public health concern. “We want to remind your readers that antibiotic resistance is not a nightmare scenario we could face in the future. It is very real and it exists right now — as all these strains [that were tested] were patient isolates from outbreaks in Colorado. The only thing preventing it from being a pandemic infection is their spread, and it could turn into a very serious and impending health crisis. So the time to act is now!”
USING COMPUTER ALGORITHM AND GRANZYME B TO COMPLEMENT THE IMMUNE SYSTEM
Hamodia interviewed Sriram Chandrasekaran, Assistant Professor of Biomedical Engineering in the University of Michigan, about his studies published in the science journals Cell and Molecular Systems Biology.
Professor Chandrasekaran told Hamodia about his revolutionary approach. “We are trying to solve the antibiotic resistance crisis by taking two different approaches. First, we are searching for combinations of existing drugs that are effective in killing pathogens. The idea behind using combinations of drugs is that the probability of pathogens becoming resistant to all the drugs in a combination simultaneously is very low. Further, by choosing the combinations smartly, we can greatly reduce the rate at which resistance occurs.
“We have now developed a computer algorithm [a highly complex computational formula] that can search through thousands of potential drug combinations and identify those that are best at eliminating pathogens and reduce the rise of resistance.
“A second approach we are using is by trying to understand how the immune system eliminates pathogens. This can tell us if the immune system eliminates bacteria in a different way, compared to existing antibiotics, and identify new strategies to kill bacteria as the immune system has done for thousands of years. Understanding this process can also help us design new drugs that work in synergy with the immune system.
“For our research, we focused on a specific type of immune cells called T-cells, which eliminates several pathogens, including those that cause E. coli, listeriosis and tuberculosis infections. They kill these bacteria by producing an enzyme called ‘granzyme B.’ Most antibiotics kill bacteria by preventing them from making new proteins, or stopping them from duplicating their DNA or by breaking their cell wall.
“A surprising discovery from our research is that unlike antibiotics that specifically block a single process in the pathogen, granzyme B uses a multi-pronged approach and targets multiple vital processes in the bacteria. Bacteria, when exposed to this enzyme, were unable to develop resistance to this multi-pronged attack even after exposing them to multiple generations [which would ordinarily encourage resistance].”
A bacterial generation happens each time a population of bacteria divides and doubles — and this cycle happens quickly. Generation time tends to vary with different organisms. E. coli divides every 20 minutes — hence its generation time is 20 minutes, and for Staphylococcus aureus it is 30 minutes.
Professor Chandrasekaran explained their goal is to develop a computer algorithm that can predict in real time for a specific patient and type of infection (derived from a bacterial DNA) what combination of drugs would be the most effective.
“Currently, patients are either given a combination of drugs with the hope that one of them will be effective, or the clinic needs to do a time-consuming sensitivity test by growing the pathogen in a lab to predict what drugs will be effective for each multi-drug-resistant infection.”
Professor Chandrasekaran said: “My research has so far demonstrated that the computer algorithm we developed can identify effective therapies in the lab, rather than blindly searching through all possible combinations of drugs. Our next goal is to design combinations that complement the immune system.”
Asked about a projected time frame for his study’s use in clinical trials, the professor responded: “We are now optimizing effective drug combinations for drug-sensitive and drug-resistant tuberculosis. The next steps are to test promising treatments in the lab and with mice, and subsequently proceed to testing in humans. With many roadblocks along the way, it is difficult to give a time frame for clinical use. We are optimistic that we have a strategy now that we can follow to design treatments.”
Professor Chandrasekaran explained that his work is focused on many drug-resistant strains such as E. coli, Staph aureus and M. tuberculosis (a major pathogen in developing countries). “So in theory our research can address most drug-resistant infections. We are primarily focused on ways to reduce the rise of drug resistance.”
The professor concluded to Hamodia: “The use of computational algorithms to design treatments tailored for each patient and the knowledge of the strategy used by the immune system can help us design treatment that can complement the immune system.”
THE IMPORTANCE OF ASYMMETRY IN BACTERIA TO COMBAT ANTIBIOTIC RESISTANCE
Hamodia interviewed Professor Bert van den Berg of Newcastle University in the United Kingdom, about his breakthrough research. He is Professor of Membrane Protein Structural Biology within the Institute for Cell and Molecular Biosciences. Professor van den Berg published his study in the science journal Nature Microbiology.
Professor Bert van den Berg: “To fulfill their role, antibiotics have to penetrate the bacterial cell by crossing the cell envelope which forms a protective barrier around the [bacterial] cell. For an antibiotic to be effective, it needs to cross this barrier rapidly and efficiently. Thus, the more we know about this barrier and how drugs move across it, the better, because this should allow us to design antibiotics with good permeation [crossing] properties. The bacterial cell envelope is a very complex structure which, in the case of the most problematic bacteria [Gram-negative bacteria], consists of two membranes [lipid bilayers] called the inner and outer membrane (OM). The OM is mainly responsible for the barrier function of the cell envelope. It is a very special membrane because it is asymmetric, and this asymmetry is crucial for the barrier function.
“However, natural processes in the bacteria tend to disrupt the asymmetry — analogous to making holes in a wall — thereby compromising the barrier function which makes the bacterium more vulnerable to toxic molecules such as antibiotics [allowing for the antibiotics to work].”
Professor van den Berg explained that bacteria have a system of six proteins that together maintain the asymmetry of the OM, called Mla (maintenance of lipid asymmetry). “Our research is focused to understand how the Mla system maintains the OM asymmetry. The idea is that by understanding how it works, we can try to disrupt the function of the Mla system so that antibiotics become more effective.”
That is, because in his study, his team discovered that one of the Mla components (MlaA) works as a kind of vacuum cleaner, vacuuming out, or removing the “hole forming” molecules from the membrane, and thereby preserving asymmetry.
“We also found that by removing the MlaA protein — which is analogous to the action of an efficient drug — several antibiotics become more effective in killing E. coli, our bacterial model system. Thus our study also provides a proof of principle.”
He conveyed: “Our research suggests that by shutting down — or inhibiting — the Mla system we could make the cells more permeable to antibiotics that are already in clinical use, making conventional antibiotics more effective again. It would also extend the number of antibiotics that could be used, opening up new possibilities for treatment of various infections.”
Professor van den Berg added: “Of course, all this would require that we can shut down the Mla system — and this would mean a new drug would first have to be developed that would do this. For us, as an academic lab, the challenge is to generate data that would convince the pharmaceutical companies to put time and money into developing a drug against the Mla system.”
He extrapolated a time frame for his team’s discovery to be utilized in clinical trials. “The complexity of this type of research and the need to guarantee the safety of patients make these projects very long. We would normally be speaking of a time frame of five to 10 years.”
Professor van den Berg summed up: “As basic scientists, we are most excited about gaining an understanding into the workings of nature. We will therefore continue to work on understanding various basic aspects of the Mla system, but will also explore the ‘next step’ and investigate if this system can be utilized as a drug target.”
USING SMALL MOLECULES TO PREVENT INFLAMMATION
Reports issued in a press release from the University of Maryland School of Medicine (UMSOM) in Baltimore contain research on antibiotic resistance to serious wounds and systemic infections, a growing concern particularly for those injured in combat, as in the military.
Researchers headed by Allen Cross, MD, will focus on MRSA, Klebsiella pneumoniae, and Pseudomonas aeruginosa and are studying how to fend off infections by targeting the body’s immune response to dangerous resistant bacteria. Rather than fighting the bacteria once infection is already present, researchers are instead using small molecules, or peptides, to change how the body’s immune system responds when it is exposed to them.
Dr. Cross’s team will develop novel peptides to keep the immune system from responding with the typical inflammation that takes place when the body is exposed to pathogens and is trying to fight off infection. In previous research, Dr. Cross discovered that preventing this inflammatory response enables the body’s immune system to better fight infections.
“What we have been focusing on is not to deal with the bacteria, but the host response to the bacteria,” said Dr. Cross. “This approach could pave the way toward treating a wide range of infections.”
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