Study results from Switzerland come as clinical laboratory scientists seek new ways to tackle the problem of antimicrobial resistance in hospitals
Microbiologists and clinical laboratory scientists engaged in the fight against antibiotic-resistant (aka, antimicrobial resistant) bacteria will be interested in a recent study conducted at the University of Basel and University Hospital Basel in Switzerland. The epidemiologists involved in the study discovered that some of these so-called “superbugs” can remain in the body for as long as nine years continuing to infect the host and others.
The researchers wanted to see how two species of drug-resistant bacteria—K. pneumoniae and E. coli—changed over time in the body, according to a press release from the university. They analyzed samples of the bacteria collected from patients who were admitted to the hospital over a 10-year period, focusing on older individuals with pre-existing conditions. They found that K. pneumoniae persisted for up to 4.5 years (1,704 days) and E. coli persisted for up to nine years (3,376 days).
“These patients not only repeatedly become ill themselves, but they also act as a source of infection for other people—a reservoir for these pathogens,” said Lisandra Aguilar-Bultet, PhD, the study’s lead author, in the press release.
“This is crucial information for choosing a treatment,” explained Sarah Tschudin Sutter, MD, Head of the Division of Infectious Diseases and Hospital Epidemiology, and of the Division of Hospital Epidemiology, who specializes in hospital-acquired infections and drug-resistant pathogens. Sutter led the Basel University study.
“The issue is that when patients have infections with these drug-resistant bacteria, they can still carry that organism in or on their bodies even after treatment,” said epidemiologist Maroya Spalding Walters, MD (above), who leads the Antimicrobial Resistance Team in the Division of Healthcare Quality Promotion at the federal Centers for Disease Control and Prevention (CDC). “They don’t show any signs or symptoms of illness, but they can get infections again, and they can also transmit the bacteria to other people.” Clinical laboratories working with microbiologists on antibiotic resistance will want to follow the research conducted into these deadly pathogens. (Photo copyright: Centers for Disease Control and Prevention.)
COVID-19 Pandemic Increased Antibiotic Resistance
The Basel researchers looked at 76 K. pneumoniae isolates recovered from 19 patients and 284 E. coli isolates taken from 61 patients, all between 2008 and 2018. The study was limited to patients in which the bacterial strains were detected from at least two consecutive screenings on admission to the hospital.
“DNA analysis indicates that the bacteria initially adapt quite quickly to the conditions in the colonized parts of the body, but undergo few genetic changes thereafter,” the Basel University press release states.
The researchers also discovered that some of the samples, including those from different species, had identical mechanisms of drug resistance, suggesting that the bacteria transmitted mobile genetic elements such as plasmids to each other.
One limitation of the study, the authors acknowledged, was that they could not assess the patients’ exposure to antibiotics.
Meanwhile, recent data from the World Health Organization (WHO) suggests that the COVID-19 pandemic might have exacerbated the challenges of antibiotic resistance. Even though COVID-19 is a viral infection, WHO scientists found that high percentages of patients hospitalized with the disease between 2020 and 2023 received antibiotics.
“While only 8% of hospitalized patients with COVID-19 had bacterial co-infections requiring antibiotics, three out of four or some 75% of patients have been treated with antibiotics ‘just in case’ they help,” the WHO stated in a press release.
WHO uses an antibiotic categorization system known as AWaRe (Access, Watch, Reserve) to classify antibiotics based on risk of resistance. The most frequently prescribed antibiotics were in the “Watch” group, indicating that they are “more prone to be a target of antibiotic resistance and thus prioritized as targets of stewardship programs and monitoring.”
“When a patient requires antibiotics, the benefits often outweigh the risks associated with side effects or antibiotic resistance,” said Silvia Bertagnolio, MD, Unit Head in the Antimicrobial resistance (AMR) Division at the WHO in the press release. “However, when they are unnecessary, they offer no benefit while posing risks, and their use contributes to the emergence and spread of antimicrobial resistance.”
Citing research from the National Institutes of Health (NIH), NPR reported that in the US, hospital-acquired antibiotic-resistant infections increased 32% during the pandemic compared with data from just before the outbreak.
“While that number has dropped, it still hasn’t returned to pre-pandemic levels,” NPR noted.
The UPenn researchers have already developed an antimicrobial treatment derived from guava plants that has proved effective in mice, Vox reported. They’ve also trained an AI model to scan the proteomes of extinct organisms.
“The AI identified peptides from the woolly mammoth and the ancient sea cow, among other ancient animals, as promising candidates,” Vox noted. These, too, showed antimicrobial properties in tests on mice.
These findings can be used by clinical laboratories and microbiologists in their work with hospital infection control teams to better identify patients with antibiotic resistant strains of bacteria who, after discharge, may show up at the hospital months or years later.
New technology could enable genetic scientists to identify antibiotic resistant genes and help physicians choose better treatments for genetic diseases
Genomic scientists at the Icahn School of Medicine at Mount Sinai Medical Center in New York City have developed what they call a “smart tweezer” that enables researchers to isolate a single bacterium from a patient’s microbiome in preparation for genetic sequencing. Though primarily intended for research purposes, the new technology could someday be used by clinical laboratories and microbiologists to help physicians diagnose chronic disease and choose appropriate genetic therapies.
The researchers designed their new technology—called mEnrich-seq—to improve the effectiveness of research into the complex communities of microorganisms that reside in the microbiomes within the human body. The discovery “ushers in a new era of precision in microbiome research,” according to a Mount Sinai Hospital press release.
“Imagine you’re a scientist who needs to study one particular type of bacteria in a complex environment. It’s like trying to find a needle in a large haystack,” said the study’s senior author Gang Fang, PhD (above), Professor of Genetics and Genomic Sciences at Icahn School of Medicine at Mount Sinai Medical Center, in a press release. “mEnrich-seq essentially gives researchers a ‘smart tweezer’ to pick up the needle they’re interested in,” he added. Might smart tweezers one day be used to help physicians and clinical laboratories diagnose and treat genetic diseases? (Photo copyright: Icahn School of Medicine.)
Addressing a Technology Gap in Genetic Research
Any imbalance or decrease in the variety of the body’s microorganisms can lead to an increased risk of illness and disease.
In researching the microbiome, many scientists “focus on studying specific types of bacteria within a sample, rather than looking at each type of bacteria present,” the press release states. The limitation of this method is that a specific bacterium is just one part of a complicated environment that includes other bacteria, viruses, fungi and host cells, each with their own unique DNA.
“mEnrich-seq effectively distinguishes bacteria of interest from the vast background by exploiting the ‘secret codes’ written on bacterial DNA that bacteria use naturally to differentiate among each other as part of their native immune systems,” the press release notes. “This new strategy addresses a critical technology gap, as previously researchers would need to isolate specific bacterial strains from a given sample using culture media that selectively grow the specific bacterium—a time-consuming process that works for some bacteria, but not others. mEnrich-seq, in contrast, can directly recover the genome(s) of bacteria of interest from the microbiome sample without culturing.”
Isolating Hard to Culture Bacteria
To conduct their study, the Icahn researchers used mEnrich-seq to analyze urine samples taken from three patients with urinary tract infections (UTIs) to reconstruct Escherichia coli (E. Coli) genomes. They discovered their “smart tweezer” covered more than 99.97% of the genomes across all samples. This facilitated a comprehensive examination of antibiotic-resistant genes in each genome. They found mEnrich-seq had better sensitivity than standard study methods of the urine microbiome.
They also used mEnrich-seq to selectively examine the genomes of Akkermansia muciniphila (A. muciniphila), a bacterium that colonizes the intestinal tract and has been shown to have benefits for obesity and Type 2 diabetes as well as a response to cancer immunotherapies.
“Akkermansia is very hard to culture,” Fang told GenomeWeb. “It would take weeks for you to culture it, and you need special equipment, special expertise. It’s very tedious.”
mEnrich-seq was able to quickly segregate it from more than 99.7% of A. muciniphila genomes in the samples.
Combatting Antibiotic Resistance Worldwide
According to the press release, mEnrich-seq could potentially be beneficial to future microbiome research due to:
Cost-Effectiveness: It offers a more economical approach to microbiome research, particularly beneficial in large-scale studies where resources may be limited.
Broad Applicability: The method can focus on a wide range of bacteria, making it a versatile tool for both research and clinical applications.
Medical Breakthroughs: By enabling more targeted research, mEnrich-seq could accelerate the development of new diagnostic tools and treatments.
“One of the most exciting aspects of mEnrich-seq is its potential to uncover previously missed details, like antibiotic resistance genes that traditional sequencing methods couldn’t detect due to a lack of sensitivity,” Fang said in the news release. “This could be a significant step forward in combating the global issue of antibiotic resistance.”
More research and clinical trials are needed before mEnrich-seq can be used in the medical field. The Icahn researchers plan to refine their novel genetic tool to improve its efficiency and broaden its range of applications. They also intend to collaborate with physicians and other healthcare professionals to validate how it could be used in clinical environments.
Should all this come to pass, hospital infection control teams, clinical laboratories, and microbiology labs would welcome a technology that would improve their ability to detect details—such as antibiotic resistant genes—that enable a faster and more accurate diagnosis of a patient’s infection. In turn, that could contribute to better patient outcomes.
New vaccine could give clinical laboratories and antimicrobial stewardship programs the tool they need to dramatically reduce hospital-acquired infections
The innovative approach focuses on bolstering the patient’s immune system itself, rather than relying on proteins to fight infections, according to a USC Today article.
Developed by senior study author Brad Spellberg, MD, Chief Medical Officer at the Los Angeles General Medical Center, and colleagues, “The experimental vaccine takes an entirely different approach: It gooses the body’s preexisting supply of pathogen-gobbling immune cells called macrophages, which engulf and digest bacteria, fungi, and other bad actors. These activated fighters, found in all tissues, quickly neutralize incoming invaders which might otherwise multiply rapidly and overwhelm the body’s defenses,” USC Today reported.
“This is very different from developing new antibiotics,” Jun Yan, a doctoral student at Keck School of Medicine and the study’s first author, told USC Today. “This is using our own immune system to fight against different superbugs, which is a different approach than everybody else.”
To develop the vaccine [the USC researchers] formed a biotechnology startup called ExBaq LLC in Bethesda, Md.
“The pandemic stimulated unprecedented innovation in vaccine development, where federal funding and university-industry partnerships were game changers for translating promising discoveries from academic labs for the good of all,” said Ishwar K. Puri, PhD (above), senior vice president of research and innovation at USC. “We are both pleased and proud of the critical support the USC Stevens Center provided to enable the development of ExBaq’s experimental vaccine that protects vulnerable populations from serious infections.” Clinical laboratories that work with hospitals in the fight against hospital-acquired infections understand the importance of this discovery. (Photo copyright: University of Southern California.)
USC Vaccine Details
The USC team developed a “protein-free vaccine, composed of aluminum hydroxide, monophosphoryl lipid A, and fungal mannan, that stimulates the innate immune system and confers protection,” the researchers wrote in Science Translational Medicine.
“Tested in two independent labs, the vaccine works within 24 hours and lasts for up to 28 days. In lab models, the number of pathogen-eating immune cells in the blood increased dramatically, and survival time of invasive blood and lung infections improved. Early data suggest that a second dose could extend the window to prevent infection,” USC Today reported.
Unlike anything currently available, the new vaccine focuses on boosting the body itself instead of creating antibodies against certain pathogens. A mere dose of the vaccine is described to “provide rapid protection against nine different bacteria and fungi species,” USC Today noted.
“It’s an early warning system. It’s like Homeland Security putting out a terror alert. Everybody, keep your eyes open. Keep an eye out for suspicious packages. You’re alerting the soldiers and tanks of your immune system. The vaccine activates them,” Spellberg told USC Today.
“The vaccine acted through stimulation of the innate, rather than the adaptive, immune system, as demonstrated by efficacy in the absence of lymphocytes that were abrogated by macrophage depletion. A role for macrophages was further supported by the finding that vaccination induced macrophage epigenetic alterations that modulated phagocytosis and the inflammatory response to infection. Together, these data show that this protein-free vaccine is a promising strategy to prevent deadly antimicrobial-resistant healthcare-associated infections,” the researchers wrote in Science Translational Medicine.
“Patients who acquire infections from surgery spend, on average, an additional 6.5 days in the hospital, are five times more likely to be readmitted after discharge and twice as likely to die. Moreover, surgical patients who develop infections are 60% more likely to require admission to a hospital’s intensive care unit. Surgical infections are believed to account for up to 10 billion dollars annually in healthcare expenditures,” the CDC reports.
“All hospitalized patients are susceptible to contracting a [hospital-acquired] infection. Some patients are at greater risk than others: young children, the elderly, and persons with compromised immune systems are more likely to get an infection. Other risk factors are long hospital stays, the use of indwelling catheters, failure of healthcare workers to wash their hands, and overuse of antibiotics,” the CDC notes.
Therefore, USC’s new vaccine may be just what the doctor ordered to protect patients in hospitals and other healthcare settings from deadly HAIs.
Looking Ahead
There are currently no vaccines that are FDA-approved that treat “the most serious antibiotic resistant infections,” USC Today reported.
“Even if there were such vaccines, multiple vaccines would have to be deployed simultaneously to protect against the full slate of antibiotic-resistant microbes that cause healthcare-acquired infections,” Brian Luna, PhD, assistant professor of molecular microbiology and immunology at USC’s Keck School of Medicine, told USC Today.
Thus, USC’s new vaccine could be a boon to hospital antimicrobial stewardship programs. But so far, it has only been tested on mice.
“The next step is getting guidance from the US Food and Drug Administration (FDA) on the design of a clinical trial. The first such trial would be done in healthy volunteers to find the right dose of vaccine that is safe and triggers the same kind of immune response in people as seen in the mice,” USC Today reported.
ExBaq LLC has begun talking with potential larger partners who might be willing to help develop the vaccine into clinical testing.
For years hospitals and other healthcare settings—such as long-term care facilities, urgent care clinics, and clinical laboratories—have fought an uphill battle against superbugs. So, for a vaccine to be on the horizon that can prevent life-threatening hospital-acquired infections would be a game changer.
With antimicrobial stewardships being a requirement in all hospitals, medical laboratory managers and microbiologists may celebrate this new development and its potential to be a useful tool in fighting antimicrobial resistant bacteria in their facilities.
Study findings could lead to new biomarker targets for clinical laboratories working to identify AMR bacteria
Reducing and managing antimicrobial resistance (AMR) is a major goal of researchers and health systems across the globe. And it is the job of microbiologists and clinical laboratories to identify microbes that are AMR and those which are not to guide physicians as to the most appropriate therapies for patients with bacterial infections.
“AMR is a silent pandemic of much greater risk to society than COVID-19. In addition to 10 million deaths per year by 2050, the WHO estimates AMR will cost the global economy $100 trillion if we can’t find a way to combat antibiotic failure,” Timothy Barnett, PhD (above), Deputy Director and head of the Strep A Pathogenesis and Diagnostics team at Wesfarmers Centre of Vaccines and Infectious Diseases, told News Medical. Additional research may provide new targets for clinical laboratories tasked with identifying antimicrobial resistant bacteria. (Photo copyright: University of Western Australia.)
Rendering an Antibiotic Ineffective
According to the University of Oxford, about 1.2 million people died worldwide in 2019 due to AMR, and antimicrobial-resistant infections played a role in as many as 4.95 million deaths that same year. The World Health Organization (WHO) declared AMR one of the top ten global public health threats facing humanity.
While investigating antibiotic sensitivity of Group A Streptococcus—a potentially deadly bacteria often detected on the skin and in the throat—the Australian researchers uncovered a mechanism that enabled bacteria to absorb nutrients from their human host and evade the antibiotic sulfamethoxazole, a commonly-prescribed treatment for Group A Strep.
“Bacteria need to make their own folates to grow and, in turn, cause disease. Some antibiotics work by blocking this folate production to stop bacteria growing and treat the infection,” Timothy Barnett, PhD, Deputy Director of the Wesfarmers Centre of Vaccines and Infectious Diseases and head of the Strep A Pathogenesis and Diagnostics team, told News Medical.
“When looking at an antibiotic commonly prescribed to treat Group A Strep skin infections, we found a mechanism of resistance where, for the first time ever, the bacteria demonstrated the ability to take folates directly from its human host when blocked from producing their own. This makes the antibiotic ineffective and the infection would likely worsen when the patient should be getting better,” he added.
According to their study, the researchers identified an energy-coupling (ECF) factor transporter S component gene that allows Group A Strep to acquire extracellular reduced folate compounds that likely “expands the substrate specificity of an endogenous ECF transporter to acquire reduced folate compounds directly from the host, thereby bypassing the inhibition of folate biosynthesis by sulfamethoxazole.”
The study indicates that this new form of antibiotic resistance is indistinguishable under traditional testing used in microbiology and clinical laboratories, which in turn makes it difficult for clinicians to prescribe effective antibiotics to fight an infection.
Understanding AMR before It Is Too Late
The research suggests that understanding AMR is more complicated and intricate than previously thought. Barnett and his team believe their discovery is just the “tip of the iceberg” and that it will prove to be a far-reaching issue across other bacterial pathogens in addition to Group A Strep.
“Without antibiotics, we face a world where there will be no way to stop deadly infections, cancer patients won’t be able to have chemotherapy and people won’t have access to have life-saving surgeries,” Barnett told News Medical. “In order to preserve the long-term efficacy of antibiotics, we need to further identify and understand new mechanisms of antibiotic resistance, which will aid in the discovery of new antibiotics and allow us to monitor AMR as it arises.”
More research and clinical studies are needed before this discovery can become technology that clinical laboratories can use to test if microbes are AMR. The scientists at Wesfarmers Centre of Vaccines and Infectious Diseases are now developing testing methods to detect the presence of the antibiotic resistant mechanism and determine the best treatment options.
“It is vital we stay one step ahead of the challenges of AMR and, as researchers, we should continue to explore how resistance develops in pathogens and design rapid accurate diagnostic methods and therapeutics,” Kalindu Rodrigo, a PhD student in the Barnett lab and one of the authors of the study told News Medical. “On the other hand, equal efforts should be taken at all levels of the society including patients, health professionals, and policymakers to help reduce the impacts of AMR.”
Clinical laboratory data was key in identifying antibiotic-resistant bacteria responsible for surge in BSIs in hospitals and other healthcare facilities in 2020 and 2021
Clinical laboratory data compiled by the European Antimicrobial Resistance Surveillance Network (EARS-Net) shows that a massive increase in bloodstream infections (BSIs) occurred among EU nations during the first two years of the COVID-19 pandemic. The study found that BSIs caused by certain antimicrobial-resistant (AMR) pathogens, known as superbugs, more than doubled in EU hospitals and healthcare facilities in 2020 and 2021.
Microbiologists and clinical laboratory managers in the US may find it valuable to examine this peer-reviewed study into AMR involved in blood stream infections. It could contain useful insights for diagnosing patients suspected of BSIs in US hospitals where sepsis prevention and antibiotic stewardship programs are major priorities.
“Antimicrobial resistance undermines modern medicine and puts millions of lives at risk,” said Tedros Adhanom Ghebreyesus, PhD, Director-General, World Health Organization, in a WHO press release. “To truly understand the extent of the global threat and mount an effective public health response to [antimicrobial resistance], we must scale up microbiology testing and provide quality-assured data across all countries, not just wealthier ones.” Clinical laboratories in the US may be called upon to submit data on bloodstream infections in this country. (Photo copyright: WHO.)
Clinical Laboratories in EU Report Huge Increase in Carbapenem Resistance
To perform their study, researchers measured the increase in Acinetobacter BSIs between 2020 and 2021, the first two years of the COVID-19 pandemic. Their data originated from qualitative regular antimicrobial susceptibility testing (AST) from blood samples collected by local clinical laboratories in the European Union/European economic area (EU/EEA) nations.
The researchers limited their dataset to Acinetobacter BSI information from the European medical laboratories that documented results of carbapenem susceptibility testing for the bacterial species.
Carbapenems are a class of very powerful antibiotics that are typically used to treat severe bacterial infections. A total of 255 EU/EEA clinical laboratories reported their data for the study. The scientists found that the percentages of Acinetobacter resistance varied considerably between EU/EEA nations, so they separated the countries into three different groups:
Nations in Group One—The Netherlands, Belgium, Austria, Estonia, Denmark, Germany, Iceland, Finland, Luxembourg, Ireland, Norway, Sweden, and Malta—experienced less than 10% resistance to carbapenems.
Nations in Group Two—Slovenia, Czech Republic, and Portugal—had carbapenem resistance between 10% and 50%.
Nations in Group Three—Croatia, Bulgaria, Greece, Cyprus, Italy, Hungary, Lithuania, Latvia, Romania, Poland, Spain, and Slovakia—demonstrated carbapenem resistance equal or greater than 50%.
The study also found that Acinetobacter BSIs rose by 57% and case counts increased by 114% in 2020 and 2021 when compared to 2018 and 2019. The percentage of resistance to carbapenems rose to 66% in 2020 and 2021, up from 48% in 2018 and 2019.
Antimicrobial Resistance Especially High in Hospital Settings
The researchers further arranged the data into three hospital ward types: intensive care unit (ICU), non-ICU, and unknown. The increase in BSIs caused by Acinetobacter species resistant to carbapenems was greater in ICU-admitted individuals (144%) than non-ICU-admitted individuals (41%).
There are more than 50 species of Acinetobacter bacteria and various strains are often resistant to many types of commonly-used antibiotics. Symptoms of an Acinetobacter infection usually appear within 12 days after a person comes into contact with the bacteria. These symptoms may include:
Blood infections,
Urinary tract infections,
Pneumonia, and
Wound infections.
Healthy people have a low risk of contracting an Acinetobacter infection with the highest number of these infections occurring in hospitals and other healthcare settings. Acinetobacter bacteria can survive for a long time on surfaces and equipment, and those working in healthcare or receiving treatment are in the highest risk category.
The prevalence of this type of bacteria increases in relation to the use of medical equipment, such as ventilators and catheters, as well as antibiotic treatments.
WHO Report Validates EARS-Net Research
In December of 2022, the World Health Organization (WHO) issued a Global Antimicrobial Resistance and Use Surveillance System (GLASS) report that revealed the presence of an increasing resistance to antibiotics in some bacterial infections. That report showed high levels (above 50%) of resistance in bacteria that frequently caused bloodstream infections in hospitals, such as Klebsiella pneumonia and Acinetobacter.
The WHO report examined data collected during 2020 from 87 different countries and found that common bacterial infections are becoming increasingly resistant to treatments. Both Klebsiella pneumoniae and Acinetobacter can be life threatening and often require treatment with strong antibiotics, such as carbapenems.
More research is needed to determine the reasons behind increases in Acinetobacter infections as reported in European hospitals and other healthcare settings, and to ascertain the extent to which they are related to hospitalizations and the upsurge in antimicrobial resistance during the COVID-19 pandemic.
Microbiologists and clinical laboratory managers in the US may want to learn more about the fIndings of this European study involving AMR and use those insights to plan accordingly for any future increase in bloodstream infections in this country.
