Antibiotic therapy with extended anaerobic coverage (EAC) was not associated with a survival benefit in patients with community-acquired aspiration pneumonia, according to results from a retrospective cohort study that support current guidelines.
Across 18 hospitals in Canada, in-hospital mortality rates were 30.3% for patients treated with antibiotic therapy with limited anaerobic coverage (LAC) and 32.1% for those treated with EAC, rates that were statistically no different after adjustment, reported Anthony Bai, MD, MSc, of Queen’s University in Kingston, Ontario, and coauthors in CHESTopens in a new tab or window.
EAC antibiotics were in fact associated with more harm than good: Clostridioides difficile colitis was seen in 0.2% or less of the LAC patient population and 0.8-1.1% of the EAC population, a 1% risk difference after adjustment (95% CI 0.3-1.7).
The present study supports skipping anaerobic coverage for aspiration pneumonia and relying on ceftriaxone or levofloxacin alone, Bai and colleagues concluded. They noted that the findings from their relatively large study, counting nearly 4,000 people, are consistent with previous studies while specifically including only patients receiving first-line antibiotics.
“Hopefully, this study will promote further adoption of the most recent guidelines relating to aspiration pneumonia, with resultant improvement in patient care, specifically decreased risk of side effects (C. difficile colitis), and potentially decreased antibiotic resistance in the community,” commented Mark Yoder, MD, of Rush University Medical Center in Chicago, who was not involved in the research.
In 2019, despite the absence of strong trial-level evidence, the American Thoracic Society and Infectious Diseases Society of America released guidelines that did not recommend routinely giving anaerobic coverageopens in a new tab or window to patients with aspiration pneumonia. The guidelines instead endorsed first-line antibiotics, like ceftriaxone or levofloxacin, for general treatment of patients with community-acquired pneumonia (CAP).
Indeed, the Canadian study showed a steady increase of aspiration pneumonia patients getting LAC antibiotics from 2015 to 2021.
“We have generally changed our practice accordingly and recommended against routine anaerobic coverage for CAP due to the risks of C. difficile infection and the need to avoid unnecessarily broad antibiotic use,” said Rebekah Moehring, MD, MPH, of Duke University in Durham, North Carolina, who was not involved in the study. “We routinely face antibiotic resistance scenarios in our practice and thus a lot of emphasis has been placed on judicious use of antibiotics.”
The study authors noted that antibiotic coverage for aspiration pneumonia “has been debated and changed over time” and that historically, anaerobic bacteria were thought to be the predominant pathogen.
Yoder and Bai’s group both emphasized that anaerobic bacteria are isolated in only a minority of cases of aspiration pneumonia nowadays.
“Conceptually, almost all cases of pneumonia are due to aspiration of bacteria colonizing the oropharynx (mouth and throat), and the treatment of community-acquired as well as hospital-acquired and ventilator-associated pneumonia does not routinely include coverage of anaerobic pathogens,” Yoder told MedPage Today via email.
The study included 3,999 consecutive adults hospitalized for aspiration pneumonia at 18 acute care hospitals in Ontario from 2015 to 2022. An ICD diagnosis code was used to search records of pneumonitis due to food and vomit including aspiration pneumonia not otherwise specified, or due to food, gastric secretions, milk, or vomit.
Bai and colleagues split participants into LAC (67.1%) and EAC (32.9%) groups based on the initial antibiotic they received within 2 days of admission. Ceftriaxone, cefotaxime, and levofloxacin counted as LAC; amoxicillin-clavulanate, moxifloxacin, metronidazole, and clindamycin were defined as EAC.
Baseline characteristics were well balanced between the two treatment groups. The patient population was approximately 40% women, and the average age was about 80 years old. Fewer than a fourth of patients were from long-term care facilities.
Among the most commonly used antibiotics were ceftriaxone, metronidazole, moxifloxacin, and macrolides.
Median length of stay was 6.7 days in the LAC group and 7.6 days in the EAC group. Among patients discharged alive, 18.5% of the LAC group and 18.3% of the EAC group were readmitted to the hospital within 30 days.
The investigators acknowledged that their database did not capture cases of aspiration pneumonitis that did not require antibiotic treatment. Other study limitations included the inability to count deaths or any C.difficile colitis diagnoses after hospital discharge.
“The avoidance of unnecessary antibiotic can decrease the risk of antibiotic adverse effects, especially C. difficile colitis,” Bai’s team nonetheless noted. “On a larger scale, limiting unnecessary antibiotic use may lower antibiotic selective pressure and result in less antibiotic resistance. In hospitals, antimicrobial stewardship programs can implement targeted interventions to de-escalate antibiotic therapy for aspiration pneumonia.”
T. thermophilus HB27 strain expressing Cfr-like methylase.
Scientists at the University of Illinois Chicago and Harvard University have developed an antibiotic that could give medicine a new weapon to fight drug-resistant bacteria and the diseases they cause.
The antibiotic, cresomycin, described in Science, effectively suppresses pathogenic bacteria that have become resistant to many commonly prescribed antimicrobial drugs.
The promising novel antibiotic is the latest finding for a longtime research partnership between the group of Yury Polikanov, associate professor of biological sciences at UIC, and colleagues at Harvard. The UIC scientists provide critical insights into cellular mechanisms and structure that help the researchers at Harvard design and synthesize new drugs.
In developing the new antibiotic, the group focused on how many antibiotics interact with a common cellular target—the ribosome—and how drug-resistant bacteria modify their ribosomes to defend themselves.
More than half of all antibiotics inhibit growth of pathogenic bacteria by interfering with their protein biosynthesis—a complex process catalyzed by the ribosome, which is akin to “a 3D printer that makes all the proteins in a cell,” Polikanov said. Antibiotics bind to bacterial ribosomes and disrupt this protein-manufacturing process, causing bacterial invaders to die.
But many bacterial species evolved simple defenses against this attack. In one defense, they interfere with antibiotic activity by adding a single methyl group of one carbon and three hydrogen atoms to their ribosomes.
Scientists speculated that this defense was simply bacteria physically blocking the site where drugs bind to the ribosome, “like putting a push pin on a chair,” Polikanov said. But the researchers found a more complicated story, as they described in a paper published last month in Nature Chemical Biology.
By using a method called X-ray crystallography to visualize drug-resistant ribosomes with nearly atomic precision, they discovered two defensive tactics. The methyl group, they found, physically blocks the binding site, but it also changes the shape of the ribosome’s inner “guts,” further disrupting antibiotic activity.
Polikanov’s laboratory then used X-ray crystallography to investigate how certain drugs, including one published in Nature by the UIC/Harvard collaboration in 2021, circumvent this common form of bacterial resistance.
“By determining the actual structure of antibiotics interacting with two types of drug-resistant ribosomes, we saw what could not have been predicted by the available structural data or by computer modeling,” Polikanov said. “It’s always better to see it once than hear about it 1,000 times, and our structures were important for designing this promising new antibiotic and understanding how it manages to escape the most common types of resistance.”
Cresomycin, the new antibiotic, is synthetic. It’s preorganized to avoid the methyl-group interference and attach strongly to ribosomes, disrupting their function. This process involves locking the drug into a shape that is pre-optimized to bind to the ribosome, which helps it get around bacterial defenses.
“It simply binds to the ribosomes and acts as if it doesn’t care whether there was this methylation or not,” Polikanov said. “It overcomes several of the most common types of drug resistance easily.”
In animal experiments conducted at Harvard, the drug protected against infections with multidrug-resistant strains of common disease drivers including Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Based on these promising results, the next step is to assess the effectiveness and safety of cresomycin in humans.
But even at this early stage, the process demonstrates the critical role that structural biology plays in designing the next generation of antibiotics and other life-saving medicines, according to Polikanov.
“Without the structures, we would be blind in terms of how these drugs bind and act upon modified drug-resistant ribosomes,” Polikanov said. “The structures that we determined provided fundamental insight into the molecular mechanisms that allow these drugs to evade the resistance.”
Carbohydrate intolerance, commonly linked to the consumption of lactose, fructose, or sorbitol, affects up to 30% of the population in high-income countries. Although sorbitol intolerance is attributed to malabsorption, the underlying mechanism remains unresolved. Here, we show that a history of antibiotic exposure combined with high fat intake triggered long-lasting sorbitol intolerance in mice by reducing Clostridia abundance, which impaired microbial sorbitol catabolism. The restoration of sorbitol catabolism by inoculation with probiotic Escherichia coli protected mice against sorbitol intolerance but did not restore Clostridia abundance. Inoculation with the butyrate producer Anaerostipes caccae restored a normal Clostridia abundance, which protected mice against sorbitol-induced diarrhea even when the probiotic was cleared. Butyrate restored Clostridia abundance by stimulating epithelial peroxisome proliferator-activated receptor-gamma (PPAR-γ) signaling to restore epithelial hypoxia in the colon. Collectively, these mechanistic insights identify microbial sorbitol catabolism as a potential target for approaches for the diagnosis, treatment, and prevention of sorbitol intolerance.
Graphical abstract
Introduction
Sorbitol is a naturally occurring polyol that is poorly absorbed by the small intestine, resulting in a low caloric content. Therefore, sorbitol is used as low-calorie sweetener in “sugar-free” foods, such as sugar-free chewing gum, candy, mints, jam, diet drinks, and chocolate.
which comes mostly from its use as sweetener, but sorbitol is also naturally present at low concentrations in some fruits of the Rosaceae family, such as apples, pears, and apricots.
Excessive consumption of polyols can trap fluid in the colonic lumen to trigger osmotic diarrhea.
For example, ingestion of 20 g sorbitol can induce symptoms of carbohydrate intolerance in healthy volunteers, including diarrhea, abdominal distention, and flatulence, but most volunteers ingesting 5 g sorbitol do not develop such symptoms.
Susceptibility to polyol-induced diarrhea varies among individuals, resulting in heightened intolerance in patients with irritable bowel syndrome (IBS)
or quiescent inflammatory bowel disease (IBD).
For example, ingesting 5 g of sorbitol can intensify gastrointestinal symptoms in individuals with IBS,
whereas consuming 3 g of sorbitol can exacerbate gastrointestinal symptoms in IBD patients.
Antibiotic treatment can transiently heighten polyol intolerance by disrupting the gut microbiota, which can impair metabolic functions that remove osmotically active solutes.
In a mouse model of antibiotic-induced sorbitol intolerance, the addition of 5% sorbitol to the drinking water increases fecal water content during treatment with ampicillin or streptomycin (Str), but not in the absence of antibiotic treatment.
a transient disruption of the microbiota by antibiotics does not explain the prolonged carbohydrate intolerance in patients with IBS or quiescent IBD.
Treatment of prolonged polyol intolerance therefore relies on dietary interventions that reduce the intake of polyols and other poorly absorbed mono-, di-, and oligosaccharides.
A recent history of antibiotic usage (between 4 and 56 weeks prior to enrollment) in combination with high fat intake is an environmental risk factor in adult patients for developing diarrhea, abdominal distention, and flatulence.
These individuals can be differentiated from IBS patients by their elevated fecal calprotectin levels (between 50 and 200 μg/g feces), which is a marker of intestinal inflammation. However, intestinal inflammation in these individuals does not rise to the level of IBD, which is characterized by fecal calprotectin levels exceeding 250 μg/g feces during active disease.
Patients with low grade mucosal inflammation that is associated with a history of antibiotics and high fat intake thus represents a syndrome located at the intersection of the clinical spectra of IBS and IBD.
Elevated fecal calprotectin levels and diarrhea observed in these patients can be recapitulated in mice exposed to high fat intake in combination with a history of Str treatment.
When antibiotics are combined with maintaining mice on a high-fat (HF) diet, microbiota recovery is impaired even 4 weeks after Str treatment, as indicated by increased Enterobacterales (ord. nov.,
phylum Proteobacteria) and reduced Clostridia (phylum Firmicutes) abundance. These changes in the microbiota composition match those in the feces of patients with a history of antibiotics and high fat intake,
As mice with a history of antibiotic treatment and high fat intake recapitulate signs of disease seen in patients with diarrhea, abdominal distention, and flatulence, we wanted to investigate whether exposure to these environmental risk factors creates a mouse model for prolonged sorbitol intolerance that can be used to explore approaches for diagnosis, treatment, and prevention.
Highlights
•Low fecal SDH is a potential biomarker for sorbitol intolerance
•High fat intake after antibiotics impairs microbiota recovery to lower fecal SDH level
•Abundant sorbitol-consuming probiotics deplete sorbitol to protect against intolerance
Carbohydrate intolerance, commonly linked to the consumption of lactose, fructose, or sorbitol, affects up to 30% of the population in high-income countries. Although sorbitol intolerance is attributed to malabsorption, the underlying mechanism remains unresolved. Here, we show that a history of antibiotic exposure combined with high fat intake triggered long-lasting sorbitol intolerance in mice by reducing Clostridia abundance, which impaired microbial sorbitol catabolism. The restoration of sorbitol catabolism by inoculation with probiotic Escherichia coli protected mice against sorbitol intolerance but did not restore Clostridia abundance. Inoculation with the butyrate producer Anaerostipes caccae restored a normal Clostridia abundance, which protected mice against sorbitol-induced diarrhea even when the probiotic was cleared. Butyrate restored Clostridia abundance by stimulating epithelial peroxisome proliferator-activated receptor-gamma (PPAR-γ) signaling to restore epithelial hypoxia in the colon. Collectively, these mechanistic insights identify microbial sorbitol catabolism as a potential target for approaches for the diagnosis, treatment, and prevention of sorbitol intolerance.
Sorbitol is a naturally occurring polyol that is poorly absorbed by the small intestine, resulting in a low caloric content. Therefore, sorbitol is used as low-calorie sweetener in “sugar-free” foods, such as sugar-free chewing gum, candy, mints, jam, diet drinks, and chocolate.
which comes mostly from its use as sweetener, but sorbitol is also naturally present at low concentrations in some fruits of the Rosaceae family, such as apples, pears, and apricots.
For example, ingestion of 20 g sorbitol can induce symptoms of carbohydrate intolerance in healthy volunteers, including diarrhea, abdominal distention, and flatulence, but most volunteers ingesting 5 g sorbitol do not develop such symptoms.
Susceptibility to polyol-induced diarrhea varies among individuals, resulting in heightened intolerance in patients with irritable bowel syndrome (IBS)
Antibiotic treatment can transiently heighten polyol intolerance by disrupting the gut microbiota, which can impair metabolic functions that remove osmotically active solutes.
In a mouse model of antibiotic-induced sorbitol intolerance, the addition of 5% sorbitol to the drinking water increases fecal water content during treatment with ampicillin or streptomycin (Str), but not in the absence of antibiotic treatment.
However, antibiotic-induced changes in the microbiota composition are short lived, as the gut microbiota regains its normal composition within 5 days after withdrawing Str.
Treatment of prolonged polyol intolerance therefore relies on dietary interventions that reduce the intake of polyols and other poorly absorbed mono-, di-, and oligosaccharides.
A recent history of antibiotic usage (between 4 and 56 weeks prior to enrollment) in combination with high fat intake is an environmental risk factor in adult patients for developing diarrhea, abdominal distention, and flatulence.
These individuals can be differentiated from IBS patients by their elevated fecal calprotectin levels (between 50 and 200 μg/g feces), which is a marker of intestinal inflammation. However, intestinal inflammation in these individuals does not rise to the level of IBD, which is characterized by fecal calprotectin levels exceeding 250 μg/g feces during active disease.
Patients with low grade mucosal inflammation that is associated with a history of antibiotics and high fat intake thus represents a syndrome located at the intersection of the clinical spectra of IBS and IBD.
Elevated fecal calprotectin levels and diarrhea observed in these patients can be recapitulated in mice exposed to high fat intake in combination with a history of Str treatment.
When antibiotics are combined with maintaining mice on a high-fat (HF) diet, microbiota recovery is impaired even 4 weeks after Str treatment, as indicated by increased Enterobacterales (ord. nov.,
phylum Proteobacteria) and reduced Clostridia (phylum Firmicutes) abundance. These changes in the microbiota composition match those in the feces of patients with a history of antibiotics and high fat intake,
As mice with a history of antibiotic treatment and high fat intake recapitulate signs of disease seen in patients with diarrhea, abdominal distention, and flatulence, we wanted to investigate whether exposure to these environmental risk factors creates a mouse model for prolonged sorbitol intolerance that can be used to explore approaches for diagnosis, treatment, and prevention.
A new antibiotic class that works against multidrug-resistant bacteria has been discovered, offering new opportunities to tackle these dangerous microbes.
The macrocyclic peptide zosurabalpin showed promising antibacterial activity against Carbapenem-resistant Acinetobacterbaumannii (CRAB), according to two papers published in the journal Nature.
The Gram-negative bacteria is deemed an urgent threat by the U.S. Centers for Disease Control and Prevention and has also been classified as a priority 1 critical pathogen by the World Health Organization.
“The new molecule overcomes the existing drug-resistance mechanisms that the currently available antibiotics are failing to address,” said Kenneth Bradley, global head of infectious disease discovery at Roche pharma research & early development, which worked with Harvard researchers to establish the mechanism of action for the compound.
“With this significant breakthrough, zosurabalpin has the potential to address a major unmet need in the fight against antimicrobial resistance.”
Gram-negative bacteria are particularly difficult to kill because they are encased in both inner and outer membranes that are challenging for most antibiotics to cross. The cytoplasmic membrane is surrounded by an outer membrane containing lipopolysaccharide (LPS), which blocks the entry of most antibiotics.
Zosurabalpin traps this LPS during its transport to the outer membrane by inhibiting a complex of proteins called the LptB2FGC complex.
Specifically, the clinical candidate binds to both LPS and a transport complex that facilitates movement to its destination. The LPS transport complex is trapped in a substrate-bound state, which leaves it unable to move LPS and results in death of the bacterium.
A team led by Claudia Zampaloni, PhD, senior principal scientist in infectious diseases at Roche, initially examined around 45,000 tethered macrocyclic peptides, which have greater molecular weights than most antibiotics.
The researchers identified one that selectively killed A. baumannii, which was further honed for efficacy and tolerability using a new type of test based on blood-plasma compatibility, culminating in the discovery of zosurabalpin.
The drug was effective against more than 100 CRAB clinical samples tested in the lab and in multiple mouse infection models, including sepsis and thigh and lung infection induced by CRAB strains.
In another research article, Karanbir Pahil, PhD, from Harvard University, and colleagues use X-ray techniques to identify structures that show zosurabalpin engages LptB2FGC only when the complex is bound to LPS, indicating the importance of the latter for its action.
The basis for its specificity against A. baumannii lies in this protein complex, explaining why it is ineffective against other bacteria whose Lpt proteins may have different amino-acid sequences.
This previously unknown mode of antibiotic action suggests that pre-existing resistance is unlikely, note Morgan Gugger and Paul Hergenrother, PhD, both from the University of Illinois at Urbana-Champaign, in accompanying News and Views article.
They point out that the U.S. Food and Drug Administration has not approved any new classes of antibiotic for harmful Gram-negative bacteria in more than 50 years.
“Treatment options for CRAB infections continue to dwindle as mortality rates are rising, with some estimated death rates reaching approximately 50% for invasive infections,” they warn.
The commentators add that zosurabalpin might not have the damaging effect on normal gut microbes seen with most antibiotics, given its high specificity for A. baumannii.
“The movement towards bacterium-specific antibiotics is a new development, and one that can be facilitated by diagnostics that can rapidly identify specific harmful bacteria in infected individuals,” they wrote.
“Given that zosurabalpin is already being tested in clinical trials, the future looks promising, with the possibility of a new antibiotic class being finally on the horizon for invasive CRAB infections.”
In animal studies, zosurabalpin was shown effective against a harmful bacteria that primarily affects hospital patients
Fox News medical contributor Dr. Marc Siegel on what is causing antibiotic resistance including outdated drugs, food, and over-prescribing
Scientists in Switzerland have announced the discovery of a new class of antibiotics shown to be effective against deadly, drug-resistant bacteria.
The antibiotic, called zosurabalpin, works by blocking a bacterial molecule called lipopolysaccharide (LPS), which is responsible for creating the outer membrane that protects a harmful bacteria, Acinetobacter baumannii.
Acinetobacter is a “gram-negative” bacteria, which means it is resistant to most antibiotics and other drugs.
It can cause infections in the blood, lungs, urinary tract and other parts of the body, according to the Centers for Disease Control and Prevention (CDC).
Scientists in Switzerland have announced the discovery of a new class of antibiotics that shown to be effective against deadly, drug-resistant bacteria. (iStock)
In animal studies, zosurabalpin successfully killed drug-resistant strains of Acinetobacter.
The research, conducted at Roche Pharma Research & Early Development in Switzerland, was published in the journal Nature on Jan. 3.”This new class of antibiotics prevents bacteria from creating their outer membrane, which provide structure to the bacteria and help them survive in harsh environments and cause infection,” Kenneth Bradley, the Switzerland-based global head of infectious disease discovery at Roche, told Fox News Digital via email.
Without the ability to transport LPS — the bacteria die.
“The new molecule overcomes the existing drug-resistance mechanisms that the currently available antibiotics are failing to address,” Bradley said.
Kenneth Bradley, the Switzerland-based global head of infectious disease discovery at Roche, provided input on the antibiotic’s discovery. (Roche Pharma Research & Early Development (pRED))
This is the first time in over 50 years that a new class of antibiotic has been identified to treat infections by gram-negative bacteria, he noted.
Zosurabalpin specifically targets Acinetobacter.
“The specificity of zosurabalpin is due to the unique way in which it binds to the drug target in these bacteria,” Bradley said.
The antibiotic, called zosurabalpin, works by blocking a bacterial molecule called lipopolysaccharide (LPS), which is responsible for creating the outer membrane that protects harmful bacteria, Acinetobacter baumannii (not pictured). (iStock)
The hope is that this finding could help eventually to fight other drug-resistant bacteria.
“Discovery of the mode of action of zosurabalpin in Acinetobacter may enable the identification of other drugs that work in the same way in other antibiotic-resistant bacteria,” Bradley told Fox News Digital.
Zosurabalpin is currently in a phase 1 clinical trial, which will evaluate the “safety, tolerability and pharmacokinetics” of the molecule, according to the researcher.
“These data, as well as data from future pivotal phase 3 clinical studies, would be needed to determine the safety and efficacy profile of the molecule,” he added.
The discovery of zosurabalpin, which Bradley calls a “scientific breakthrough,” will help researchers learn more about the construction of bacterial membranes, knowledge that could enable new drugs to kill bacteria.
The finding is especially significant, given that resistance to antibiotics has been on the rise in various gram-negative bacteria for several decades, he said.
Acinetobacter infections are most commonly seen in hospital patients, mainly affecting those who are on ventilators, have surgical wounds, are in intensive care units or have catheters, according to the CDC. (iStock)
“Any new antibiotic class that has the ability to treat infections caused by multi-drug-resistant bacteria such as carbapenem-resistant Acinetobacter baumannii (CRAB) would be a significant breakthrough,” he added.
Michael Lobritz, the Switzerland-based head of infectious diseases at Roche, referred in a press release to antimicrobial resistance as a “silent pandemic.”
“Over the next 30 years, it is projected to claim more lives than those taken by cancer today, according to the report of the economist Jim O’Neill,” Lobritz said.
Over the next 30 years, antimicrobial resistance is “projected to claim more lives than those taken by cancer today,” an expert said.
Dr. Marc Siegel, clinical professor of medicine at NYU Langone Medical Center and a Fox News medical contributor, agreed that the growing resistance of gram-negative bacteria is a “huge problem.”
“Our last line of defense for decades now in the hospital has been the carbapenem drugs, specifically Imipenem and Mirapenem,” he told Fox News Digital.
The research was done at Roche Pharma Research & Early Development in Switzerland. (iStock)
“But now there is an increase of carbapenem-resistant strains — including carbapenem-resistant Acinobacter baumannii, or CRAB — which are very difficult to treat.”
Siegel also acknowledged the importance of the newly discovered zosurabalpin.
“It interferes with a lipid transport mechanism at the surface of the bacteria,” he said. “This is very important, as there are now millions of deaths a year worldwide due to antibiotic resistance.”
Zosurabalpin has only been tested in animals so far, Siegel noted, with human trials underway.
What to know about Acinetobacter
Acinetobacter infections are most commonly seen in hospital patients, mainly affecting those who are on ventilators, have surgical wounds, are in intensive care units or have catheters, according to the CDC.
Those with lung disease, diabetes or weakened immune systems are at a higher risk of infection. (iStock)
Those with lung disease, diabetes or weakened immune systems are at a higher risk of infection.
The bacteria can spread from person to person or via contact with contaminated surfaces.
Acinetobacter baumannii, along with other gram-negative bacteria, is tracked by the CDC as part of its Emerging Infections Program.
Looking ahead, Siegel said he expects that artificial intelligence will help speed up the process of developing new antibiotics and make it “more effective and streamlined.”
Researchers report that a new type of antibiotic has proved its mettle against a deadly superbug.
Acinetobacter baumannii, a bacteria that goes by the nickname CRAB when it becomes antibiotic-resistant, can trigger serious infections in the lungs, urinary tract and blood, according to the U.S. Centers for Disease Control and Prevention. Unfortunately, it’s resistant to a class of powerful broad-spectrum antibiotics called carbapenems.
Now, in a study published Jan. 3 in the journal Nature, researchers from Harvard University and the pharmaceutical company Hoffmann-La Roche discovered that a new type of antibiotic, zosurabalpin, can kill A. baumannii.
Zosurabalpin employs a unique method of action, researcher Dr. Kenneth Bradley, global head of infectious disease discovery with Roche Pharma Research and Early Development, told CNN.
“This is a novel approach, both in terms of the compound itself but as well as the mechanism by which it kills bacteria,” he explained. A. baumannii is a Gram-negative bacteria, meaning it is protected by both inner and outer membranes, making it difficult to attack.
In this study, the scientists first tried to identify and then fine-tune a molecule that could cross those double membranes and eliminate the bacteria.
After years of improving the potency and safety of a number of compounds, the researchers chose one modified molecule.
How does it work? Zosurabalpin prevents the movement of large molecules called lipopolysaccharides to the outer membrane of the bacteria, where they keep the protective membrane intact. This causes the molecules to accumulate inside the bacteria’s cell to the point where the cell becomes so toxic that it dies.
In the study, zosurabalpin worked against more than 100 CRAB samples. It also reduced the levels of bacteria in mice with CRAB-induced pneumonia and prevented the death of mice with sepsis triggered by the bacteria.
Zosurabalpin is now being tested in phase 1 clinical trials, to assess its safety in humans, the researchers told CNN.
Still, the public health threat of antimicrobial resistance remains a huge problem globally due to a lack of effective treatments, Dr. Michael Lobritz, worldwide leader of infectious diseases at Roche Pharma Research and Early Development, told CNN.
In the United States, there are more than 2.8 million antimicrobial-resistant infections each year. More than 35,000 people die as a result, according to the CDC’s 2019 Antibiotic Resistance Threats Report.
Even though zosurabalpin is years away from human use, it’s an extremely promising development, Dr. César de la Fuente, presidential assistant professor at the University of Pennsylvania, told CNN.
“I think from an academic perspective, it is exciting to see a new type of molecule that kills bacteria in a different way,” de la Fuente said. “We certainly need new out-of-the-box ways of thinking about antibiotic discovery, and I think this is a good example of that.”
The only drawback to the discovery is that the modified molecule will work only against the specific bacteria it is designed to kill, the researchers noted.
However, de la Fuente said this new method could turn out to be better than many broad-spectrum antibiotics.
“For decades, we’ve been obsessed with creating or discovering broad-spectrum antibiotics that kill everything,” he noted. “Why not try to come up with specific, more targeted antibiotics that only target the pathogen that is causing the infection and not all the other things that might be good for us?”
The discovery was made while surveilling the untreated waters of Los Angeles’ largest treatment plants—the Joint Water Pollution Control Plant in Carson and the Hyperion Water Reclamation Plant in Playa del Rey— a practice that began following Covid pandemic.
STORY HIGHLIGHTS
It has alarmed scientists as this antibiotic—for which evidence of resistance has been found—is used when all other drugs, especially penicillin, fail to respond
Researchers in Los Angeles have for the first time found bacteria that is highly resistant to colistin, considered to be the “last resort” antibiotic, in the US county’s wastewaters.
The discovery was made while surveilling the untreated waters of Los Angeles’ largest treatment plants—the Joint Water Pollution Control Plant in Carson and the Hyperion Water Reclamation Plant in Playa del Rey— a practice that began following Covid pandemic.
Both facilities serve a total of about 7.5 million people, the Los Angeles Times newspaper reported.
It has alarmed scientists as this antibiotic—for which evidence of resistance has been found—is used when all other drugs, especially penicillin, fail to respond.
“Testing found antibiotic resistance genes on two novel small plasmids, circular pieces of DNA that can be shared among different types of unrelated bacteria,” said researcher Adam Smith, associate professor of environmental engineering at USC, whose findings were published in Environmental Science & Technology Letters.
“This is probably the scariest aspect: the potential for this resistance to spread widely across different bacterial populations,” Smith said.
He noted that this type of antibiotic resistant gene has been found in “six of seven continents”, but this is the first time that traces of this antibiotic resistance have been found in LA.
According to the World Health Organisation (WHO), antibiotic resistance is one of the major threats to global health, food security, and development.
Although it occurs naturally, misuse of antibiotics in humans and animals is believed to be triggering the process.
The global health agency noted that it is becoming difficult to treat a growing number of infections, such as pneumonia, tuberculosis, gonorrhea, and salmonellosis, as antibotics are becoming less effective.
“We could get to the point where we can’t combat infections with antibiotics,” Smith said, “so we’re entering sort of a post-antibiotic world.”
What’s particularly concerning is that antibiotic resistance leads to longer hospital stays, higher medical costs and increased mortality.
Colistin was originally discovered in 2015 in China and has been documented on every continent except Antarctica, Smith said.
That includes in Los Angeles, where a resident who died in 2016 was found to have been infected with E. coli bacteria that carried a colistin resistance gene.
Antibiotic resistance is an increasingly significant public health issue in the United States. The problem is rapidly growing and is predicted to kill 10 million people every year by 2050 (pdf).
Some pathogens have already become “superbugs” that are resistant to many types of antibiotics.
“Diseases that have been treatable may become incurable as time goes on,” warned Dr. Miriam Smith, chief of infectious disease at Long Island Jewish Forest Hills, part of Northwell Health in New York.
Already Causing Thousands of Deaths Every Year
According to the U.S. Centers for Disease Control and Prevention (CDC), about three million people in the United States currently acquire antibiotic-resistant infections each year, causing over 35,000 deaths annually.
Antibiotic resistance, a main part of antimicrobial resistance (AMR), occurs when bacteria evolve and become resistant to the drugs used to treat them. This happens when bacteria mutate or acquire resistance genes, making them able to survive exposure to antibiotics.
Overuse and misuse of antibiotics have contributed to the development of antibiotic resistance. This includes using antibiotics when they are not needed, such as for viral infections like the common cold, and failing to complete a full course of antibiotics as prescribed.
In addition, the use of antibiotics in livestock and agriculture can also contribute to the development of antibiotic-resistant bacteria.
Some people are more vulnerable to antibiotic-resistant infections.
These include individuals with weakened immune systems, such as cancer patients and transplant recipients, as well as elderly individuals and young children.
Additionally, people who live or work in health care settings, such as hospitals and long-term care facilities, are at an increased risk of developing antibiotic-resistant infections due to the frequent use of antibiotics in these environments.
One of the most concerning antibiotic-resistant infections is Methicillin-resistant Staphylococcus aureus (MRSA), a type of bacteria that is resistant to many commonly used antibiotics.
MRSA infections can range from mild skin infections to life-threatening bloodstream infections and are especially common in health care settings.
Another example is carbapenem-resistant Enterobacteriaceae (CRE), which is a group of bacteria that is resistant to some of the strongest antibiotics available.
We’ve Lost Ground Since the Pandemic
It was reported that among 191 COVID-19 hospitalized patients in Wuhan, 95 percent were treated with antibiotics.
A recent review of studies conducted worldwide finds that antibiotics like macrolides, cephalosporins, fluoroquinolones, and penicillin have been prescribed to a large number of COVID–19 patients to treat secondary bacterial infections. Consequently, the possibility of increasing “antimicrobial resistance and its associated fatalities” soon can’t be ruled out.
Smith said the U.S. pandemic response was very similar and worsened the problem of antibiotic resistance.
The United States lost progress in combating antimicrobial resistance in 2020 due, in large part, to the effects of the COVID-19 pandemic. A 2022 report finds progress made on antibiotic stewardship (pdf) was reversed as antibiotics were often the first option given to treat patients with lung infection-related fever.
“Infection prevention methods and control of antibiotic use demonstrated an 18 percent reduction in mortality due to antimicrobial-resistant organisms between 2012 and 2017,” said Smith. “The U.S. lost ground combating antimicrobial resistance during the COVID pandemic.”
She explained that the setbacks were due to multiple factors, including the increased use of antibiotics at the beginning of the pandemic for pneumonia that was thought to be bacterial in origin.
Another issue was that the CDC and local departments of health that had been focusing on antimicrobial resistance were repurposed to deal with COVID.
“This dramatically accelerated vaccine development and implementation,” said Smith. “These efforts were remarkable but detracted from the fight against increasing antimicrobial resistance.”
The Era of Rapid Development Has Ended
“Early on, 40 or 50 years ago, as antibiotics started to be used and resistances accumulated, the pharmaceutical drug industry was able to discover, and/or create new antibiotics,” said Dr. William Schaffner, professor of preventive medicine in the Department of Health Policy, and professor of medicine in the Division of Infectious Diseases at Vanderbilt University Medical Center.
“So we were able to ‘stay ahead’ of antibiotic resistance because we always had a new antibiotic that we could pull off the proverbial shelf and use,” he continued.
In those early days of drug development, the “easy” antibiotics were discovered, but we’re in a difficult situation now, and advances have slowed.
“So we can’t just research our way out of a problem by creating new antibiotics,” said Schaffner. “Therefore, our options for appropriate therapy become diminished.”
Schaffner said three solutions are being implemented to address the looming crisis:
The first is that physicians are taught to be more prudent in the use of antibiotics. Virtually every hospital now has an antibiotic stewardship program, which supervises the use of antibiotics, and takes corrective action if overuse is detected.
The second is infection prevention, and there are two ways to do that. One is for hospitals to maintain sophisticated infection control programs, and for the general population to keep good hygienic practices.
“We’re constantly making recommendations to the general population about how to shelter your cough, to encourage hand hygiene, all those things to reduce infections so we won’t have to treat,” he said.
The third is through vaccinations.
“There are clearly some vaccines that have been deployed, particularly among children, and they clearly have helped turn around antibiotic resistance in certain bacterial strains,” said Schaffner.
“There was an increasing development of resistance among some pneumococcal strains,” he explained. “These were included in the vaccines, and once they were deployed, the occurrence of those [resistant] strains virtually disappeared.”
Treatment Is Becoming ‘More Complicated’
Schaffner noted other pathogens that are becoming more antibiotic resistant. These include:
E-Coli
Enterobacter
Acinetobacter
“These are gram-negative bacteria that can complicate the treatment of particularly very sick people who will have intravenous lines; they’re being treated with ventilators, catheters to help drain their bladders,” he said.
He added that the treatment of gonorrhea is also becoming “more complicated,” meaning that it’s harder to find drugs that work against the disease, and prescription regimes are more involved.
“The antibiotics we have are more restricted and they have to be given over a period of time,” he explained. “It’s not just one-dose treatment, and of course, compliance with treatment is not always assured, and that becomes a big problem.”
Nearly 87 percent (pdf) of patients don’t comply with doctors’ instructions for antimicrobial therapy, which increases the risk that a pathogen evolves antibiotic resistance.
He said a new threat on the national and international scene is not a bacteria, but a yeast: Candida auris, which is very drug resistant.
“It occurred around the globe in several different locations and once it gets into a hospital, it can be very vexing to try to get rid of,” said Schaffner.
Another factor is related to the increasing cost of health care in the United States, particularly surgical procedures, which forces some people to seek less expensive treatment abroad. “They can come back to this country with infections that are multidrug resistant,” Schaffner noted. “What’s over there can be over here very quickly.”
AZALEA trial highlights overuse of antibiotics in asthma attacks
Adding the antibiotic azithromycin to standard treatment for asthma exacerbations in adults had no significant therapeutic benefit in the AZALEA randomized clinical trial.
Findings were consistently negative across different symptom and quality-of-life scores, and treatment with the antibiotic also had no measurable impact on lung function, including FEV1, wrote researcher Sebastian L. Johnston, PhD, of the Imperial College London, and colleagues in JAMA Internal Medicine, published online Sept. 19.
The negative findings contrast with the TELICAST study, also reported by Johnston and colleagues, which demonstrated a positive clinical benefit for another macrolide antibiotic — telithromycin — for asthma exacerbations. Severe adverse reactions — especially liver toxicity — limit the use of this drug to patients with life-threatening infections.
Treatment guidelines, included those recently published by the Global Initiative for Asthma (GINA), do not recommend routine antibiotic use for asthma exacerbations. Yet, in the current trial, the investigators had to exclude nearly half of those screened because they had recently received antibiotics.
The Azithromycin Against Placebo in Exacerbations of Asthma (AZALEA) study was conducted to examine the activity of the semisynthetic macrolide antibiotic azithromycin on asthma exacerbations.
“Macrolide antibiotics might benefit asthma exacerbations through antimicrobial activity and/or anti-inflammatory properties; and azithromycin, but not telithromycin, has been shown to have antiviral properties, augmenting production of interferons that are deficiency in patients with asthma,” the researchers wrote.
The study, conducted in the United Kingdom, included adults with a history of asthma for more than six months who were recruited within 48 hours of presenting at one of 31 treatment centers for an asthma exacerbation requiring a course of oral and/or systemic corticosteroids.
Of 4,582 patients screened, just 199 were eligible for randomization, barely half of the 380 the investigators had hoped to enroll. More than 2,000 were excluded because of antibiotic use within the previous 4 weeks.
In addition to usual treatment, for exacerbations, the patients were randomized 1:1 to receive azithromycin at 500 mg daily for three days, or a matched placebo.
Median time from presentation to drug administration was 22 hours (interquartile range 14-28 hours) and exacerbation characteristics were similar in the two treatment groups.
Among the main study findings:
Primary outcome asthma symptom scores averaged 4.14 (SD 1.38) at exacerbation and 2.09 (SD 1.71) at 10 days for the azithromycin group and 4.18 (SD 1.48) and 2.20 (SD 1.51) for the placebo group, respectively
Using multilevel modeling, there was no significant difference in symptom scores between azithromycin and placebo at day 10 (difference −0.166; 95% CI −0.670 to 0.337). No difference was seen on any day between exacerbation and day 10
No significant between-group differences were shown in quality-of-life questionnaire responses or lung function between exacerbation and day 10, or in time to 50% reduction in symptom score
The researchers noted that recruitment was a major challenge, and that this might have influenced the findings.
“A remarkable finding of this study was the number of patients (n=2,044) excluded because they were already receiving antibiotic therapy for their asthma exacerbation despite treatment guidelines recommending that such therapy not be routinely given,” they wrote.
“This important finding has obvious and worrying implications regarding antibiotic stewardship; in addition, such high antibiotic use rates may also have directly influenced the study outcome because it is possible that patients who might potentially have benefitted from antibiotic therapy for their asthma exacerbations were excluded from the study through already having received them,” the researchers wrote.
In an editorial published with the study, Guy Brusselle, MD, PhD, and Eva Van Braeckel, MD, PhD, of Ghent University Hospital in Belgium, called the overuse of antibiotics in adult patients with acute asthma exacerbations a “striking finding,” given that treatment guidelines recommend against the practice and several Cochrane reviews, including one published last year, have been negative.
Strategies recommended by the authors to reduce antibiotic use in this population included:
Raising awareness among both prescribers and patients
Implementing asthma guideline recommendations against the routine use of antibiotics in asthma exacerbations
Performing studies in primary and secondary care to examine if a subset of patients with asthma exacerbations might benefit from antibiotics.
Validating known biomarkers such as C-reactive protein and procalcitonin; and developing novel biomarkers for guiding targeted antibiotic treatments
“Further study of azithromycin treatment in acute exacerbations of asthma in adults and children in settings of low rates of antibiotic use and stratifying on blood and/or sputum cell counts seems justified,” they concluded.
By Robin Foster HealthDay Reporter
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