Antimicrobial-resistant infections

A group of researchers from the University of Pennsylvania, Philadelphia, has developed a messenger RNA (mRNA) vaccine, delivered via lipid nanoparticles (LNPs) — the same type as the COVID-19 vaccine produced by Moderna and Pfizer — targeting Clostridioides difficile (formerly Clostridium difficile). According to the authors, the results of their preclinical study, published in Science, demonstrated this technology as a promising platform for C difficile vaccine development and could be the starting point for curbing intestinal infections that, in their most severe forms (pseudomembranous colitis, toxic megacolon), can be fatal.

An Increasingly Pressing Issue

C difficile is the leading cause of infectious diarrhea acquired in healthcare settings. In recent years, community-acquired C difficile infections have also become more frequent. The increase in infections has been attributed to the emergence of highly virulent and antibiotic-resistant strains.

A 2019 study reported a global incidence of C difficile infections at 2.2 per 1000 hospital admissions per year and 3.5 per 10,000 patient-days per year.
 

The Vaccine Candidate

Vaccine candidates tested so far have used toxoids or recombinant proteins targeting the combined repetitive oligopeptide (CROP) or receptor-binding domain (RBD) of the two primary C difficile toxins, TcdA and TcdB. The US researchers are now exploring the mRNA-LNP vaccine approach to target multiple antigens simultaneously. They developed a bivalent vaccine (including the CROP and RBD domains of both toxins) and a trivalent vaccine (with an additional virulence factor, the metalloprotease Pro-Pro endopeptidase-1).

Mice vaccinated with the bivalent and trivalent vaccines produced immunoglobulin G antibody titers two to four times higher than those elicited by recombinant protein with an adjuvant. The vaccination stimulated the proliferation of follicular T helper cells and the antigen-specific response of B lymphocytes, laying the foundation for a strong and long-lasting humoral response. The vaccines were also immunogenic in hamsters.

Vaccinated mice not only survived a toxin dose five times higher than the 100% lethal dose but also demonstrated the vaccine’s protective effect through serum transfer; unvaccinated mice given serum from vaccinated mice survived the lethal challenge. More importantly, when exposed to a lethal dose of the bacterium itself, all vaccinated mice survived.

To demonstrate the vaccine’s efficacy in patients with a history of C difficile infection and high recurrence risk — ideal candidates for vaccination — the researchers vaccinated mice that had previously survived a sublethal infection. Six months after the initial infection and vaccination, these mice remained protected against mortality when reexposed to the bacterium.

Additionally, a quadrivalent vaccine that included an immunogen targeting C difficile spores — key agents in transmission — also proved effective. Low levels of bacteria and toxins in the feces of mice vaccinated in this way suggested that spore vaccination could limit initial colonization.

In tests with nonhuman primates, two doses of the vaccines targeting either the vegetative form or the spores elicited strong immune responses against bacterial toxins and virulence factors. Human trials may indeed be on the horizon.
 

This story was translated from Univadis Italy using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

A group of researchers from the University of Pennsylvania, Philadelphia, has developed a messenger RNA (mRNA) vaccine, delivered via lipid nanoparticles (LNPs) — the same type as the COVID-19 vaccine produced by Moderna and Pfizer — targeting Clostridioides difficile (formerly Clostridium difficile). According to the authors, the results of their preclinical study, published in Science, demonstrated this technology as a promising platform for C difficile vaccine development and could be the starting point for curbing intestinal infections that, in their most severe forms (pseudomembranous colitis, toxic megacolon), can be fatal.

An Increasingly Pressing Issue

C difficile is the leading cause of infectious diarrhea acquired in healthcare settings. In recent years, community-acquired C difficile infections have also become more frequent. The increase in infections has been attributed to the emergence of highly virulent and antibiotic-resistant strains.

A 2019 study reported a global incidence of C difficile infections at 2.2 per 1000 hospital admissions per year and 3.5 per 10,000 patient-days per year.
 

The Vaccine Candidate

Vaccine candidates tested so far have used toxoids or recombinant proteins targeting the combined repetitive oligopeptide (CROP) or receptor-binding domain (RBD) of the two primary C difficile toxins, TcdA and TcdB. The US researchers are now exploring the mRNA-LNP vaccine approach to target multiple antigens simultaneously. They developed a bivalent vaccine (including the CROP and RBD domains of both toxins) and a trivalent vaccine (with an additional virulence factor, the metalloprotease Pro-Pro endopeptidase-1).

Mice vaccinated with the bivalent and trivalent vaccines produced immunoglobulin G antibody titers two to four times higher than those elicited by recombinant protein with an adjuvant. The vaccination stimulated the proliferation of follicular T helper cells and the antigen-specific response of B lymphocytes, laying the foundation for a strong and long-lasting humoral response. The vaccines were also immunogenic in hamsters.

Vaccinated mice not only survived a toxin dose five times higher than the 100% lethal dose but also demonstrated the vaccine’s protective effect through serum transfer; unvaccinated mice given serum from vaccinated mice survived the lethal challenge. More importantly, when exposed to a lethal dose of the bacterium itself, all vaccinated mice survived.

To demonstrate the vaccine’s efficacy in patients with a history of C difficile infection and high recurrence risk — ideal candidates for vaccination — the researchers vaccinated mice that had previously survived a sublethal infection. Six months after the initial infection and vaccination, these mice remained protected against mortality when reexposed to the bacterium.

Additionally, a quadrivalent vaccine that included an immunogen targeting C difficile spores — key agents in transmission — also proved effective. Low levels of bacteria and toxins in the feces of mice vaccinated in this way suggested that spore vaccination could limit initial colonization.

In tests with nonhuman primates, two doses of the vaccines targeting either the vegetative form or the spores elicited strong immune responses against bacterial toxins and virulence factors. Human trials may indeed be on the horizon.
 

This story was translated from Univadis Italy using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

A group of researchers from the University of Pennsylvania, Philadelphia, has developed a messenger RNA (mRNA) vaccine, delivered via lipid nanoparticles (LNPs) — the same type as the COVID-19 vaccine produced by Moderna and Pfizer — targeting Clostridioides difficile (formerly Clostridium difficile). According to the authors, the results of their preclinical study, published in Science, demonstrated this technology as a promising platform for C difficile vaccine development and could be the starting point for curbing intestinal infections that, in their most severe forms (pseudomembranous colitis, toxic megacolon), can be fatal.

An Increasingly Pressing Issue

C difficile is the leading cause of infectious diarrhea acquired in healthcare settings. In recent years, community-acquired C difficile infections have also become more frequent. The increase in infections has been attributed to the emergence of highly virulent and antibiotic-resistant strains.

A 2019 study reported a global incidence of C difficile infections at 2.2 per 1000 hospital admissions per year and 3.5 per 10,000 patient-days per year.
 

The Vaccine Candidate

Vaccine candidates tested so far have used toxoids or recombinant proteins targeting the combined repetitive oligopeptide (CROP) or receptor-binding domain (RBD) of the two primary C difficile toxins, TcdA and TcdB. The US researchers are now exploring the mRNA-LNP vaccine approach to target multiple antigens simultaneously. They developed a bivalent vaccine (including the CROP and RBD domains of both toxins) and a trivalent vaccine (with an additional virulence factor, the metalloprotease Pro-Pro endopeptidase-1).

Mice vaccinated with the bivalent and trivalent vaccines produced immunoglobulin G antibody titers two to four times higher than those elicited by recombinant protein with an adjuvant. The vaccination stimulated the proliferation of follicular T helper cells and the antigen-specific response of B lymphocytes, laying the foundation for a strong and long-lasting humoral response. The vaccines were also immunogenic in hamsters.

Vaccinated mice not only survived a toxin dose five times higher than the 100% lethal dose but also demonstrated the vaccine’s protective effect through serum transfer; unvaccinated mice given serum from vaccinated mice survived the lethal challenge. More importantly, when exposed to a lethal dose of the bacterium itself, all vaccinated mice survived.

To demonstrate the vaccine’s efficacy in patients with a history of C difficile infection and high recurrence risk — ideal candidates for vaccination — the researchers vaccinated mice that had previously survived a sublethal infection. Six months after the initial infection and vaccination, these mice remained protected against mortality when reexposed to the bacterium.

Additionally, a quadrivalent vaccine that included an immunogen targeting C difficile spores — key agents in transmission — also proved effective. Low levels of bacteria and toxins in the feces of mice vaccinated in this way suggested that spore vaccination could limit initial colonization.

In tests with nonhuman primates, two doses of the vaccines targeting either the vegetative form or the spores elicited strong immune responses against bacterial toxins and virulence factors. Human trials may indeed be on the horizon.
 

This story was translated from Univadis Italy using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Peering through his microscope in 1910, Franco-Canadian microbiologist Félix d’Hérelle noticed some “clear spots” in his bacterial cultures, an anomaly that turned out to be viruses preying on the bacteria. Years later, Mr. d’Hérelle would come to use these viruses, which he called bacteriophages, to treat patients plagued with dysentery after World War I.

In the decades that followed, Mr. d’Hérelle and others used this phage therapy to treat bubonic plague and other bacterial infections until the technique fell into disuse after the widespread adoption of antibiotics in the 1940s.

But now, with bacteria evolving resistance to more and more antibiotics, phage therapy is drawing a second look from researchers — sometimes with a novel twist. Instead of simply using the phages to kill bacteria directly, the new strategy aims to catch the bacteria in an evolutionary dilemma — one in which they cannot evade phages and antibiotics simultaneously.

This plan, which uses something called “phage steering,” has shown promising results in initial tests, but the scope of its usefulness remains to be proven.

There’s certainly need to find new ways to respond to bacterial infections. More than 70% of hospital-acquired bacterial infections in the United States are resistant to at least one type of antibiotic. And some pathogens, such as Acinetobacter, Pseudomonas, Escherichia coli, and Klebsiella — classified by the World Health Organization as some of the biggest threats to human health — are resistant to multiple antibiotics. In 2019, antibacterial resistance was linked to 4.95 million deaths globally, heightening the call for more effective treatment options.

One of the ways that bacteria can evolve resistance to antibiotics is by using structures in their membranes that are designed to move unwanted molecules out of the cell. By modifying these “efflux pumps” to recognize the antibiotic, bacteria can eliminate the drug before it poisons them.

As it turns out, some phages appear to use these same efflux pumps to invade the bacterial cell. The phage presumably attaches its tail to the outer portion of the pump protein, like a key slipping into a lock, and then injects its genetic material into the cell. This lucky coincidence led Paul Turner, PhD, an evolutionary biologist at Yale University, New Haven, Connecticut, to suggest that treating a patient with phages and antibiotics simultaneously could trap bacteria in a no-win situation: If they evolve to modify their efflux pumps so the phage can’t bind, the pumps will no longer expel antibiotics, and the bacteria will lose their resistance. But if they retain their antibiotic resistance, the phages will kill them, as Dr. Turner and colleagues explained in the 2023 Annual Review of Virology.

The result, in other words, is a two-pronged attack, said Michael Hochberg, PhD, an evolutionary biologist at the French National Centre for Scientific Research who studies how to prevent the evolution of bacterial resistance. “It’s kind of like a crisscross effect.” The same principle can target other bacterial molecules that play a dual role in resistance to viruses and antibiotics.

Turner tested this hypothesis on multidrug-resistant Pseudomonas aeruginosa, which causes dangerous infections, especially in healthcare settings. This bacterium has four efflux pumps involved in antibiotic resistance, and Dr. Turner predicted that if he could find a phage that used one of the pumps as a way into the cell, the bacterium would be forced to slam the door on the phage by mutating the receptor — thereby impeding its ability to pump out antibiotics.

Sampling from the environment, Dr. Turner’s team collected 42 phage strains that infect P aeruginosa. Out of all the phages, one, OMKO1, bound to an efflux pump, making it the perfect candidate for the experiment.

The researchers then cultured antibiotic-resistant P aeruginosa together with OMKO1, hoping this would force the bacterium to modify its efflux pump to resist the phage. They exposed these phage-resistant bacteria, as well as their normal, phage-sensitive counterparts, to four antibiotics the bacteria had been resistant to: tetracycline, erythromycin, ciprofloxacin, and ceftazidime.

As the theory predicted, the bacteria that had evolved resistance to the phage were more sensitive to the antibiotics than those that had not been exposed to the phage. This suggests that the bacteria had, indeed, been forced to lose their antibiotic resistance through their need to fight off the phage.

Other researchers have also shown that phage steering can resensitize bacteria to common antibiotics they’d become resistant to. One study, by an international research team, showed that a phage called Phab24 can be used to restore sensitivity to the antibiotic colistin in Acinetobacter baumannii, which causes life-threatening diseases.

In a second study, researchers at Monash University in Australia sampled infectious bacteria from patients. They found that several phages, including strains known as phi-FG02 and phi-CO01, were already present in some of the samples, and that A baumannii bacteria exposed to the phages had inactivated a gene that helps create the microbe’s important outer layer, or capsule. This layer serves as the entry point for the phages, but it also helps the bacterium to form biofilms that keep out antibiotics — so removing the layer rendered A baumannii susceptible to several antibiotics that it was previously resistant to.

In a third study, researchers from the University of Liverpool discovered that, when a P aeruginosa strain that was resistant to all antibiotics was exposed to phages, the bacterium became sensitive to two antibiotics that were otherwise considered ineffective against P aeruginosa.

Dr. Turner’s team has used phage steering in dozens of cases of personalized therapy in clinical settings, said Benjamin Chan, PhD, a microbiologist at Yale University who works with Dr. Turner. The results, many still unpublished, have been promising so far. Nonrespiratory infections are relatively easy to clear off, and lung infections, which the phage steering approach wouldn’t be expected to eradicate completely, often show some improvement.

“I would say that we have been quite successful in using phage steering to treat difficult-to-manage infections, reducing antimicrobial resistance in many cases,” he said. But he notes that it is sometimes difficult to determine whether phage steering really was responsible for the cures.
 

Devil in the details

Phage therapy may not work for all antibiotic-resistant bacteria, said molecular biologist Graham Hatfull, PhD, of the University of Pittsburgh in Pennsylvania. That’s because phages are very host specific, and for most phages, no one knows what target they bind to on the bacterial cell surface. For phage steering to work against antibiotic resistance, the phage has to bind to a molecule that’s involved in that resistance — and it’s not clear how often that fortuitous coincidence occurs.

Jason Gill, PhD, who studies bacteriophage biology at Texas A&M University, College Station, said that it is not easy to predict if a phage will induce antibiotic sensitivity. So you always have to hunt for the right virus each time.

Dr. Gill knows from experience how complicated the approach can get. He was part of a team of researchers and doctors who used phages to treat a patient with a multidrug-resistant A baumannii infection. Less than 4 days after the team administered phages intravenously and through the skin, the patient woke up from a coma and became responsive to the previously ineffective antibiotic minocycline — a striking success.

But when Dr. Gill tried a similar experiment in cell cultures, he got a different result. The A baumannii developed resistance to the phages, but they also maintained their resistance to minocycline. “There’s not a complete mechanistic understanding,” said Dr. Gill. “The linkage between phage resistance and antibiotic sensitivity probably varies by bacterial strain, phage and antibiotic.” That means phage steering may not always work.

Dr. Turner, for his part, pointed out another potential problem: That phages could work too well. If phage therapy kills large amounts of bacteria and deposits their remains in the bloodstream quickly, for example, this could trigger septic shock in patients. Scientists do not yet know how to address this problem.

Another concern is that doctors have less precise control over phages than antibiotics. “Phages can mutate, they can adapt, they have a genome,” said Dr. Hochberg. Safety concerns, he notes, are one factor inhibiting the routine use of phage therapy in countries like the United States, restricting it to case-by-case applications such as Dr. Turner and Dr. Chan’s.

Phage therapy may have been too high-tech for the 1940s, and even today, scientists grapple with how to use it. What we need now, said Dr. Turner, are rigorous experiments that will teach us how to make it work.

This article originally appeared in Knowable Magazine on September 09, 2024. Knowable Magazine is an independent journalistic endeavor from Annual Reviews, a nonprofit publisher dedicated to synthesizing and integrating knowledge for the progress of science and the benefit of society. Sign up for Knowable Magazine’s newsletter. A version of this article appeared on Medscape.com.

Peering through his microscope in 1910, Franco-Canadian microbiologist Félix d’Hérelle noticed some “clear spots” in his bacterial cultures, an anomaly that turned out to be viruses preying on the bacteria. Years later, Mr. d’Hérelle would come to use these viruses, which he called bacteriophages, to treat patients plagued with dysentery after World War I.

In the decades that followed, Mr. d’Hérelle and others used this phage therapy to treat bubonic plague and other bacterial infections until the technique fell into disuse after the widespread adoption of antibiotics in the 1940s.

But now, with bacteria evolving resistance to more and more antibiotics, phage therapy is drawing a second look from researchers — sometimes with a novel twist. Instead of simply using the phages to kill bacteria directly, the new strategy aims to catch the bacteria in an evolutionary dilemma — one in which they cannot evade phages and antibiotics simultaneously.

This plan, which uses something called “phage steering,” has shown promising results in initial tests, but the scope of its usefulness remains to be proven.

There’s certainly need to find new ways to respond to bacterial infections. More than 70% of hospital-acquired bacterial infections in the United States are resistant to at least one type of antibiotic. And some pathogens, such as Acinetobacter, Pseudomonas, Escherichia coli, and Klebsiella — classified by the World Health Organization as some of the biggest threats to human health — are resistant to multiple antibiotics. In 2019, antibacterial resistance was linked to 4.95 million deaths globally, heightening the call for more effective treatment options.

One of the ways that bacteria can evolve resistance to antibiotics is by using structures in their membranes that are designed to move unwanted molecules out of the cell. By modifying these “efflux pumps” to recognize the antibiotic, bacteria can eliminate the drug before it poisons them.

As it turns out, some phages appear to use these same efflux pumps to invade the bacterial cell. The phage presumably attaches its tail to the outer portion of the pump protein, like a key slipping into a lock, and then injects its genetic material into the cell. This lucky coincidence led Paul Turner, PhD, an evolutionary biologist at Yale University, New Haven, Connecticut, to suggest that treating a patient with phages and antibiotics simultaneously could trap bacteria in a no-win situation: If they evolve to modify their efflux pumps so the phage can’t bind, the pumps will no longer expel antibiotics, and the bacteria will lose their resistance. But if they retain their antibiotic resistance, the phages will kill them, as Dr. Turner and colleagues explained in the 2023 Annual Review of Virology.

The result, in other words, is a two-pronged attack, said Michael Hochberg, PhD, an evolutionary biologist at the French National Centre for Scientific Research who studies how to prevent the evolution of bacterial resistance. “It’s kind of like a crisscross effect.” The same principle can target other bacterial molecules that play a dual role in resistance to viruses and antibiotics.

Turner tested this hypothesis on multidrug-resistant Pseudomonas aeruginosa, which causes dangerous infections, especially in healthcare settings. This bacterium has four efflux pumps involved in antibiotic resistance, and Dr. Turner predicted that if he could find a phage that used one of the pumps as a way into the cell, the bacterium would be forced to slam the door on the phage by mutating the receptor — thereby impeding its ability to pump out antibiotics.

Sampling from the environment, Dr. Turner’s team collected 42 phage strains that infect P aeruginosa. Out of all the phages, one, OMKO1, bound to an efflux pump, making it the perfect candidate for the experiment.

The researchers then cultured antibiotic-resistant P aeruginosa together with OMKO1, hoping this would force the bacterium to modify its efflux pump to resist the phage. They exposed these phage-resistant bacteria, as well as their normal, phage-sensitive counterparts, to four antibiotics the bacteria had been resistant to: tetracycline, erythromycin, ciprofloxacin, and ceftazidime.

As the theory predicted, the bacteria that had evolved resistance to the phage were more sensitive to the antibiotics than those that had not been exposed to the phage. This suggests that the bacteria had, indeed, been forced to lose their antibiotic resistance through their need to fight off the phage.

Other researchers have also shown that phage steering can resensitize bacteria to common antibiotics they’d become resistant to. One study, by an international research team, showed that a phage called Phab24 can be used to restore sensitivity to the antibiotic colistin in Acinetobacter baumannii, which causes life-threatening diseases.

In a second study, researchers at Monash University in Australia sampled infectious bacteria from patients. They found that several phages, including strains known as phi-FG02 and phi-CO01, were already present in some of the samples, and that A baumannii bacteria exposed to the phages had inactivated a gene that helps create the microbe’s important outer layer, or capsule. This layer serves as the entry point for the phages, but it also helps the bacterium to form biofilms that keep out antibiotics — so removing the layer rendered A baumannii susceptible to several antibiotics that it was previously resistant to.

In a third study, researchers from the University of Liverpool discovered that, when a P aeruginosa strain that was resistant to all antibiotics was exposed to phages, the bacterium became sensitive to two antibiotics that were otherwise considered ineffective against P aeruginosa.

Dr. Turner’s team has used phage steering in dozens of cases of personalized therapy in clinical settings, said Benjamin Chan, PhD, a microbiologist at Yale University who works with Dr. Turner. The results, many still unpublished, have been promising so far. Nonrespiratory infections are relatively easy to clear off, and lung infections, which the phage steering approach wouldn’t be expected to eradicate completely, often show some improvement.

“I would say that we have been quite successful in using phage steering to treat difficult-to-manage infections, reducing antimicrobial resistance in many cases,” he said. But he notes that it is sometimes difficult to determine whether phage steering really was responsible for the cures.
 

Devil in the details

Phage therapy may not work for all antibiotic-resistant bacteria, said molecular biologist Graham Hatfull, PhD, of the University of Pittsburgh in Pennsylvania. That’s because phages are very host specific, and for most phages, no one knows what target they bind to on the bacterial cell surface. For phage steering to work against antibiotic resistance, the phage has to bind to a molecule that’s involved in that resistance — and it’s not clear how often that fortuitous coincidence occurs.

Jason Gill, PhD, who studies bacteriophage biology at Texas A&M University, College Station, said that it is not easy to predict if a phage will induce antibiotic sensitivity. So you always have to hunt for the right virus each time.

Dr. Gill knows from experience how complicated the approach can get. He was part of a team of researchers and doctors who used phages to treat a patient with a multidrug-resistant A baumannii infection. Less than 4 days after the team administered phages intravenously and through the skin, the patient woke up from a coma and became responsive to the previously ineffective antibiotic minocycline — a striking success.

But when Dr. Gill tried a similar experiment in cell cultures, he got a different result. The A baumannii developed resistance to the phages, but they also maintained their resistance to minocycline. “There’s not a complete mechanistic understanding,” said Dr. Gill. “The linkage between phage resistance and antibiotic sensitivity probably varies by bacterial strain, phage and antibiotic.” That means phage steering may not always work.

Dr. Turner, for his part, pointed out another potential problem: That phages could work too well. If phage therapy kills large amounts of bacteria and deposits their remains in the bloodstream quickly, for example, this could trigger septic shock in patients. Scientists do not yet know how to address this problem.

Another concern is that doctors have less precise control over phages than antibiotics. “Phages can mutate, they can adapt, they have a genome,” said Dr. Hochberg. Safety concerns, he notes, are one factor inhibiting the routine use of phage therapy in countries like the United States, restricting it to case-by-case applications such as Dr. Turner and Dr. Chan’s.

Phage therapy may have been too high-tech for the 1940s, and even today, scientists grapple with how to use it. What we need now, said Dr. Turner, are rigorous experiments that will teach us how to make it work.

This article originally appeared in Knowable Magazine on September 09, 2024. Knowable Magazine is an independent journalistic endeavor from Annual Reviews, a nonprofit publisher dedicated to synthesizing and integrating knowledge for the progress of science and the benefit of society. Sign up for Knowable Magazine’s newsletter. A version of this article appeared on Medscape.com.

Peering through his microscope in 1910, Franco-Canadian microbiologist Félix d’Hérelle noticed some “clear spots” in his bacterial cultures, an anomaly that turned out to be viruses preying on the bacteria. Years later, Mr. d’Hérelle would come to use these viruses, which he called bacteriophages, to treat patients plagued with dysentery after World War I.

In the decades that followed, Mr. d’Hérelle and others used this phage therapy to treat bubonic plague and other bacterial infections until the technique fell into disuse after the widespread adoption of antibiotics in the 1940s.

But now, with bacteria evolving resistance to more and more antibiotics, phage therapy is drawing a second look from researchers — sometimes with a novel twist. Instead of simply using the phages to kill bacteria directly, the new strategy aims to catch the bacteria in an evolutionary dilemma — one in which they cannot evade phages and antibiotics simultaneously.

This plan, which uses something called “phage steering,” has shown promising results in initial tests, but the scope of its usefulness remains to be proven.

There’s certainly need to find new ways to respond to bacterial infections. More than 70% of hospital-acquired bacterial infections in the United States are resistant to at least one type of antibiotic. And some pathogens, such as Acinetobacter, Pseudomonas, Escherichia coli, and Klebsiella — classified by the World Health Organization as some of the biggest threats to human health — are resistant to multiple antibiotics. In 2019, antibacterial resistance was linked to 4.95 million deaths globally, heightening the call for more effective treatment options.

One of the ways that bacteria can evolve resistance to antibiotics is by using structures in their membranes that are designed to move unwanted molecules out of the cell. By modifying these “efflux pumps” to recognize the antibiotic, bacteria can eliminate the drug before it poisons them.

As it turns out, some phages appear to use these same efflux pumps to invade the bacterial cell. The phage presumably attaches its tail to the outer portion of the pump protein, like a key slipping into a lock, and then injects its genetic material into the cell. This lucky coincidence led Paul Turner, PhD, an evolutionary biologist at Yale University, New Haven, Connecticut, to suggest that treating a patient with phages and antibiotics simultaneously could trap bacteria in a no-win situation: If they evolve to modify their efflux pumps so the phage can’t bind, the pumps will no longer expel antibiotics, and the bacteria will lose their resistance. But if they retain their antibiotic resistance, the phages will kill them, as Dr. Turner and colleagues explained in the 2023 Annual Review of Virology.

The result, in other words, is a two-pronged attack, said Michael Hochberg, PhD, an evolutionary biologist at the French National Centre for Scientific Research who studies how to prevent the evolution of bacterial resistance. “It’s kind of like a crisscross effect.” The same principle can target other bacterial molecules that play a dual role in resistance to viruses and antibiotics.

Turner tested this hypothesis on multidrug-resistant Pseudomonas aeruginosa, which causes dangerous infections, especially in healthcare settings. This bacterium has four efflux pumps involved in antibiotic resistance, and Dr. Turner predicted that if he could find a phage that used one of the pumps as a way into the cell, the bacterium would be forced to slam the door on the phage by mutating the receptor — thereby impeding its ability to pump out antibiotics.

Sampling from the environment, Dr. Turner’s team collected 42 phage strains that infect P aeruginosa. Out of all the phages, one, OMKO1, bound to an efflux pump, making it the perfect candidate for the experiment.

The researchers then cultured antibiotic-resistant P aeruginosa together with OMKO1, hoping this would force the bacterium to modify its efflux pump to resist the phage. They exposed these phage-resistant bacteria, as well as their normal, phage-sensitive counterparts, to four antibiotics the bacteria had been resistant to: tetracycline, erythromycin, ciprofloxacin, and ceftazidime.

As the theory predicted, the bacteria that had evolved resistance to the phage were more sensitive to the antibiotics than those that had not been exposed to the phage. This suggests that the bacteria had, indeed, been forced to lose their antibiotic resistance through their need to fight off the phage.

Other researchers have also shown that phage steering can resensitize bacteria to common antibiotics they’d become resistant to. One study, by an international research team, showed that a phage called Phab24 can be used to restore sensitivity to the antibiotic colistin in Acinetobacter baumannii, which causes life-threatening diseases.

In a second study, researchers at Monash University in Australia sampled infectious bacteria from patients. They found that several phages, including strains known as phi-FG02 and phi-CO01, were already present in some of the samples, and that A baumannii bacteria exposed to the phages had inactivated a gene that helps create the microbe’s important outer layer, or capsule. This layer serves as the entry point for the phages, but it also helps the bacterium to form biofilms that keep out antibiotics — so removing the layer rendered A baumannii susceptible to several antibiotics that it was previously resistant to.

In a third study, researchers from the University of Liverpool discovered that, when a P aeruginosa strain that was resistant to all antibiotics was exposed to phages, the bacterium became sensitive to two antibiotics that were otherwise considered ineffective against P aeruginosa.

Dr. Turner’s team has used phage steering in dozens of cases of personalized therapy in clinical settings, said Benjamin Chan, PhD, a microbiologist at Yale University who works with Dr. Turner. The results, many still unpublished, have been promising so far. Nonrespiratory infections are relatively easy to clear off, and lung infections, which the phage steering approach wouldn’t be expected to eradicate completely, often show some improvement.

“I would say that we have been quite successful in using phage steering to treat difficult-to-manage infections, reducing antimicrobial resistance in many cases,” he said. But he notes that it is sometimes difficult to determine whether phage steering really was responsible for the cures.
 

Devil in the details

Phage therapy may not work for all antibiotic-resistant bacteria, said molecular biologist Graham Hatfull, PhD, of the University of Pittsburgh in Pennsylvania. That’s because phages are very host specific, and for most phages, no one knows what target they bind to on the bacterial cell surface. For phage steering to work against antibiotic resistance, the phage has to bind to a molecule that’s involved in that resistance — and it’s not clear how often that fortuitous coincidence occurs.

Jason Gill, PhD, who studies bacteriophage biology at Texas A&M University, College Station, said that it is not easy to predict if a phage will induce antibiotic sensitivity. So you always have to hunt for the right virus each time.

Dr. Gill knows from experience how complicated the approach can get. He was part of a team of researchers and doctors who used phages to treat a patient with a multidrug-resistant A baumannii infection. Less than 4 days after the team administered phages intravenously and through the skin, the patient woke up from a coma and became responsive to the previously ineffective antibiotic minocycline — a striking success.

But when Dr. Gill tried a similar experiment in cell cultures, he got a different result. The A baumannii developed resistance to the phages, but they also maintained their resistance to minocycline. “There’s not a complete mechanistic understanding,” said Dr. Gill. “The linkage between phage resistance and antibiotic sensitivity probably varies by bacterial strain, phage and antibiotic.” That means phage steering may not always work.

Dr. Turner, for his part, pointed out another potential problem: That phages could work too well. If phage therapy kills large amounts of bacteria and deposits their remains in the bloodstream quickly, for example, this could trigger septic shock in patients. Scientists do not yet know how to address this problem.

Another concern is that doctors have less precise control over phages than antibiotics. “Phages can mutate, they can adapt, they have a genome,” said Dr. Hochberg. Safety concerns, he notes, are one factor inhibiting the routine use of phage therapy in countries like the United States, restricting it to case-by-case applications such as Dr. Turner and Dr. Chan’s.

Phage therapy may have been too high-tech for the 1940s, and even today, scientists grapple with how to use it. What we need now, said Dr. Turner, are rigorous experiments that will teach us how to make it work.

This article originally appeared in Knowable Magazine on September 09, 2024. Knowable Magazine is an independent journalistic endeavor from Annual Reviews, a nonprofit publisher dedicated to synthesizing and integrating knowledge for the progress of science and the benefit of society. Sign up for Knowable Magazine’s newsletter. A version of this article appeared on Medscape.com.

TOPLINE:

The prevalence of recurrent urinary tract infections (rUTIs) and the use of antibiotics for prevention are substantial among women in Wales, particularly among those over the age of 57 years. A high level of resistance to two recommended antibiotics was observed, suggesting that more frequent urine cultures could better guide antibiotic selection for treatment and prophylaxis.

METHODOLOGY:

• The researchers conducted a retrospective cross-sectional study using a large databank of patients in Wales to describe the characteristics and urine profiles of women with rUTIs between 2010 and 2022.
• They created two cohorts: One with 92,213 women (median age, 60 years) who experienced rUTIs, defined as two or more acute episodes within 6 months or three or more acute episodes within 12 months.
• Another cohort comprised of 26,862 women (median age, 71 years) were prescribed prophylactic antibiotics, which was defined as receiving three or more consecutive prescriptions of the same UTI-specific antibiotic (trimethoprim, nitrofurantoin, or cefalexin), with intervals of 21-56 days between prescriptions.
• Urine culture results in the 12 months before a rUTI diagnosis and 18 months before prophylactic antibiotic initiation and all urine culture results within 7 days of an acute UTI were analyzed to assess antibiotic resistance patterns.

TAKEAWAY:

• Overall, 6% of women had rUTIs, 1.7% of which were prescribed prophylactic antibiotics with proportions increasing sharply after age 57.
• Nearly half of the women (49%) who were prescribed a prophylactic antibiotic qualified as having rUTIs in the 18 months before initiation.
• This study showed that 80.8% of women with rUTIs had a urine culture result documented in the 12 months preceding the diagnosis.
• More than half (64%) of the women taking prophylactic antibiotics had a urine culture result documented before starting treatment, and 18% of those prescribed trimethoprim had resistance to the antibiotic.

IN PRACTICE:

“More frequent urine cultures in the workup of rUTI diagnosis and prophylactic antibiotic initiation could better inform antibiotic choice,” the authors wrote.

SOURCE:

The study was led by Leigh Sanyaolu, BSc (Hons), MRCS, MRCGP, PGDip, a general practitioner from the Division of Population Medicine and PRIME Centre Wales at Cardiff University in Cardiff, and was published online in the British Journal of General Practice.

LIMITATIONS:

The study’s reliance on electronic health records may have led to coding errors and missing data. The diagnosis of UTIs may have been difficult in older women with increased frailty as they can have fewer specific symptoms and asymptomatic bacteriuria, which can be misdiagnosed as a UTI.

DISCLOSURES:

This work was supported by Health and Care Research Wales. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

The prevalence of recurrent urinary tract infections (rUTIs) and the use of antibiotics for prevention are substantial among women in Wales, particularly among those over the age of 57 years. A high level of resistance to two recommended antibiotics was observed, suggesting that more frequent urine cultures could better guide antibiotic selection for treatment and prophylaxis.

METHODOLOGY:

• The researchers conducted a retrospective cross-sectional study using a large databank of patients in Wales to describe the characteristics and urine profiles of women with rUTIs between 2010 and 2022.
• They created two cohorts: One with 92,213 women (median age, 60 years) who experienced rUTIs, defined as two or more acute episodes within 6 months or three or more acute episodes within 12 months.
• Another cohort comprised of 26,862 women (median age, 71 years) were prescribed prophylactic antibiotics, which was defined as receiving three or more consecutive prescriptions of the same UTI-specific antibiotic (trimethoprim, nitrofurantoin, or cefalexin), with intervals of 21-56 days between prescriptions.
• Urine culture results in the 12 months before a rUTI diagnosis and 18 months before prophylactic antibiotic initiation and all urine culture results within 7 days of an acute UTI were analyzed to assess antibiotic resistance patterns.

TAKEAWAY:

• Overall, 6% of women had rUTIs, 1.7% of which were prescribed prophylactic antibiotics with proportions increasing sharply after age 57.
• Nearly half of the women (49%) who were prescribed a prophylactic antibiotic qualified as having rUTIs in the 18 months before initiation.
• This study showed that 80.8% of women with rUTIs had a urine culture result documented in the 12 months preceding the diagnosis.
• More than half (64%) of the women taking prophylactic antibiotics had a urine culture result documented before starting treatment, and 18% of those prescribed trimethoprim had resistance to the antibiotic.

IN PRACTICE:

“More frequent urine cultures in the workup of rUTI diagnosis and prophylactic antibiotic initiation could better inform antibiotic choice,” the authors wrote.

SOURCE:

The study was led by Leigh Sanyaolu, BSc (Hons), MRCS, MRCGP, PGDip, a general practitioner from the Division of Population Medicine and PRIME Centre Wales at Cardiff University in Cardiff, and was published online in the British Journal of General Practice.

LIMITATIONS:

The study’s reliance on electronic health records may have led to coding errors and missing data. The diagnosis of UTIs may have been difficult in older women with increased frailty as they can have fewer specific symptoms and asymptomatic bacteriuria, which can be misdiagnosed as a UTI.

DISCLOSURES:

This work was supported by Health and Care Research Wales. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

The prevalence of recurrent urinary tract infections (rUTIs) and the use of antibiotics for prevention are substantial among women in Wales, particularly among those over the age of 57 years. A high level of resistance to two recommended antibiotics was observed, suggesting that more frequent urine cultures could better guide antibiotic selection for treatment and prophylaxis.

METHODOLOGY:

• The researchers conducted a retrospective cross-sectional study using a large databank of patients in Wales to describe the characteristics and urine profiles of women with rUTIs between 2010 and 2022.
• They created two cohorts: One with 92,213 women (median age, 60 years) who experienced rUTIs, defined as two or more acute episodes within 6 months or three or more acute episodes within 12 months.
• Another cohort comprised of 26,862 women (median age, 71 years) were prescribed prophylactic antibiotics, which was defined as receiving three or more consecutive prescriptions of the same UTI-specific antibiotic (trimethoprim, nitrofurantoin, or cefalexin), with intervals of 21-56 days between prescriptions.
• Urine culture results in the 12 months before a rUTI diagnosis and 18 months before prophylactic antibiotic initiation and all urine culture results within 7 days of an acute UTI were analyzed to assess antibiotic resistance patterns.

TAKEAWAY:

• Overall, 6% of women had rUTIs, 1.7% of which were prescribed prophylactic antibiotics with proportions increasing sharply after age 57.
• Nearly half of the women (49%) who were prescribed a prophylactic antibiotic qualified as having rUTIs in the 18 months before initiation.
• This study showed that 80.8% of women with rUTIs had a urine culture result documented in the 12 months preceding the diagnosis.
• More than half (64%) of the women taking prophylactic antibiotics had a urine culture result documented before starting treatment, and 18% of those prescribed trimethoprim had resistance to the antibiotic.

IN PRACTICE:

“More frequent urine cultures in the workup of rUTI diagnosis and prophylactic antibiotic initiation could better inform antibiotic choice,” the authors wrote.

SOURCE:

The study was led by Leigh Sanyaolu, BSc (Hons), MRCS, MRCGP, PGDip, a general practitioner from the Division of Population Medicine and PRIME Centre Wales at Cardiff University in Cardiff, and was published online in the British Journal of General Practice.

LIMITATIONS:

The study’s reliance on electronic health records may have led to coding errors and missing data. The diagnosis of UTIs may have been difficult in older women with increased frailty as they can have fewer specific symptoms and asymptomatic bacteriuria, which can be misdiagnosed as a UTI.

DISCLOSURES:

This work was supported by Health and Care Research Wales. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Scientists at Stanford University and the University of Pennsylvania have discovered a new antibiotic candidate in a surprising place: the human gut. 

In mice, the antibiotic — a peptide known as prevotellin-2 — showed antimicrobial potency on par with polymyxin B, an antibiotic medication used to treat multidrug-resistant infections. Meanwhile, the peptide mainly left commensal, or beneficial, bacteria alone. The study, published in Cell, also identified several other potent antibiotic peptides with the potential to combat antimicrobial-resistant infections.

The research is part of a larger quest to find new antibiotics that can fight drug-resistant infections, a critical public health threat with more than 2.8 million cases and 35,000 deaths annually in the United States. That quest is urgent, said study author César de la Fuente, PhD, professor of bioengineering at the University of Pennsylvania, Philadelphia. 

“The main pillars that have enabled us to almost double our lifespan in the last 100 years or so have been antibiotics, vaccines, and clean water,” said Dr. de la Fuente. “Imagine taking out one of those. I think it would be pretty dramatic.” (Dr. De la Fuente’s lab has become known for finding antibiotic candidates in unusual places, like ancient genetic information of Neanderthals and woolly mammoths.)  

The first widely used antibiotic, penicillin, was discovered in 1928, when a physician studying Staphylococcus bacteria returned to his lab after summer break to find mold growing in one of his petri dishes. But many other antibiotics — like streptomycin, tetracycline, and erythromycin — were discovered from soil bacteria, which produce variations of these substances to compete with other microorganisms. 

By looking in the gut microbiome, the researchers hoped to identify peptides that the trillions of microbes use against each other in the fight for limited resources — ideally, peptides that wouldn’t broadly kill off the entire microbiome. 
 

Kill the Bad, Spare the Good

Many traditional antibiotics are small molecules. This means they can wipe out the good bacteria in your body, and because each targets a specific bacterial function, bad bacteria can become resistant to them.

Peptide antibiotics, on the other hand, don’t diffuse into the whole body. If taken orally, they stay in the gut; if taken intravenously, they generally stay in the blood. And because of how they kill bacteria, targeting the membrane, they’re also less prone to bacterial resistance.

The microbiome is like a big reservoir of pathogens, said Ami Bhatt, MD, PhD, hematologist at Stanford University in California and one of the study’s authors. Because many antibiotics kill healthy gut bacteria, “what you have left over,” Dr. Bhatt said, “is this big open niche that gets filled up with multidrug-resistant organisms like E coli [Escherichia coli] or vancomycin-resistant Enterococcus.”

Dr. Bhatt has seen cancer patients undergo successful treatment only to die of a multidrug-resistant infection, because current antibiotics fail against those pathogens. “That’s like winning the battle to lose the war.”

By investigating the microbiome, “we wanted to see if we could identify antimicrobial peptides that might spare key members of our regular microbiome, so that we wouldn’t totally disrupt the microbiome the way we do when we use broad-spectrum, small molecule–based antibiotics,” Dr. Bhatt said.

The researchers used artificial intelligence to sift through 400,000 proteins to predict, based on known antibiotics, which peptide sequences might have antimicrobial properties. From the results, they chose 78 peptides to synthesize and test.

“The application of computational approaches combined with experimental validation is very powerful and exciting,” said Jennifer Geddes-McAlister, PhD, professor of cell biology at the University of Guelph in Ontario, Canada, who was not involved in the study. “The study is robust in its approach to microbiome sampling.” 
 

The Long Journey from Lab to Clinic

More than half of the peptides the team tested effectively inhibited the growth of harmful bacteria, and prevotellin-2 (derived from the bacteria Prevotella copri)stood out as the most powerful.

“The study validates experimental data from the lab using animal models, which moves discoveries closer to the clinic,” said Dr. Geddes-McAlister. “Further testing with clinical trials is needed, but the potential for clinical application is promising.” 

Unfortunately, that’s not likely to happen anytime soon, said Dr. de la Fuente. “There is not enough economic incentive” for companies to develop new antibiotics. Ten years is his most hopeful guess for when we might see prevotellin-2, or a similar antibiotic, complete clinical trials.

A version of this article first appeared on Medscape.com.

Scientists at Stanford University and the University of Pennsylvania have discovered a new antibiotic candidate in a surprising place: the human gut. 

In mice, the antibiotic — a peptide known as prevotellin-2 — showed antimicrobial potency on par with polymyxin B, an antibiotic medication used to treat multidrug-resistant infections. Meanwhile, the peptide mainly left commensal, or beneficial, bacteria alone. The study, published in Cell, also identified several other potent antibiotic peptides with the potential to combat antimicrobial-resistant infections.

The research is part of a larger quest to find new antibiotics that can fight drug-resistant infections, a critical public health threat with more than 2.8 million cases and 35,000 deaths annually in the United States. That quest is urgent, said study author César de la Fuente, PhD, professor of bioengineering at the University of Pennsylvania, Philadelphia. 

“The main pillars that have enabled us to almost double our lifespan in the last 100 years or so have been antibiotics, vaccines, and clean water,” said Dr. de la Fuente. “Imagine taking out one of those. I think it would be pretty dramatic.” (Dr. De la Fuente’s lab has become known for finding antibiotic candidates in unusual places, like ancient genetic information of Neanderthals and woolly mammoths.)  

The first widely used antibiotic, penicillin, was discovered in 1928, when a physician studying Staphylococcus bacteria returned to his lab after summer break to find mold growing in one of his petri dishes. But many other antibiotics — like streptomycin, tetracycline, and erythromycin — were discovered from soil bacteria, which produce variations of these substances to compete with other microorganisms. 

By looking in the gut microbiome, the researchers hoped to identify peptides that the trillions of microbes use against each other in the fight for limited resources — ideally, peptides that wouldn’t broadly kill off the entire microbiome. 
 

Kill the Bad, Spare the Good

Many traditional antibiotics are small molecules. This means they can wipe out the good bacteria in your body, and because each targets a specific bacterial function, bad bacteria can become resistant to them.

Peptide antibiotics, on the other hand, don’t diffuse into the whole body. If taken orally, they stay in the gut; if taken intravenously, they generally stay in the blood. And because of how they kill bacteria, targeting the membrane, they’re also less prone to bacterial resistance.

The microbiome is like a big reservoir of pathogens, said Ami Bhatt, MD, PhD, hematologist at Stanford University in California and one of the study’s authors. Because many antibiotics kill healthy gut bacteria, “what you have left over,” Dr. Bhatt said, “is this big open niche that gets filled up with multidrug-resistant organisms like E coli [Escherichia coli] or vancomycin-resistant Enterococcus.”

Dr. Bhatt has seen cancer patients undergo successful treatment only to die of a multidrug-resistant infection, because current antibiotics fail against those pathogens. “That’s like winning the battle to lose the war.”

By investigating the microbiome, “we wanted to see if we could identify antimicrobial peptides that might spare key members of our regular microbiome, so that we wouldn’t totally disrupt the microbiome the way we do when we use broad-spectrum, small molecule–based antibiotics,” Dr. Bhatt said.

The researchers used artificial intelligence to sift through 400,000 proteins to predict, based on known antibiotics, which peptide sequences might have antimicrobial properties. From the results, they chose 78 peptides to synthesize and test.

“The application of computational approaches combined with experimental validation is very powerful and exciting,” said Jennifer Geddes-McAlister, PhD, professor of cell biology at the University of Guelph in Ontario, Canada, who was not involved in the study. “The study is robust in its approach to microbiome sampling.” 
 

The Long Journey from Lab to Clinic

More than half of the peptides the team tested effectively inhibited the growth of harmful bacteria, and prevotellin-2 (derived from the bacteria Prevotella copri)stood out as the most powerful.

“The study validates experimental data from the lab using animal models, which moves discoveries closer to the clinic,” said Dr. Geddes-McAlister. “Further testing with clinical trials is needed, but the potential for clinical application is promising.” 

Unfortunately, that’s not likely to happen anytime soon, said Dr. de la Fuente. “There is not enough economic incentive” for companies to develop new antibiotics. Ten years is his most hopeful guess for when we might see prevotellin-2, or a similar antibiotic, complete clinical trials.

A version of this article first appeared on Medscape.com.

Scientists at Stanford University and the University of Pennsylvania have discovered a new antibiotic candidate in a surprising place: the human gut. 

In mice, the antibiotic — a peptide known as prevotellin-2 — showed antimicrobial potency on par with polymyxin B, an antibiotic medication used to treat multidrug-resistant infections. Meanwhile, the peptide mainly left commensal, or beneficial, bacteria alone. The study, published in Cell, also identified several other potent antibiotic peptides with the potential to combat antimicrobial-resistant infections.

The research is part of a larger quest to find new antibiotics that can fight drug-resistant infections, a critical public health threat with more than 2.8 million cases and 35,000 deaths annually in the United States. That quest is urgent, said study author César de la Fuente, PhD, professor of bioengineering at the University of Pennsylvania, Philadelphia. 

“The main pillars that have enabled us to almost double our lifespan in the last 100 years or so have been antibiotics, vaccines, and clean water,” said Dr. de la Fuente. “Imagine taking out one of those. I think it would be pretty dramatic.” (Dr. De la Fuente’s lab has become known for finding antibiotic candidates in unusual places, like ancient genetic information of Neanderthals and woolly mammoths.)  

The first widely used antibiotic, penicillin, was discovered in 1928, when a physician studying Staphylococcus bacteria returned to his lab after summer break to find mold growing in one of his petri dishes. But many other antibiotics — like streptomycin, tetracycline, and erythromycin — were discovered from soil bacteria, which produce variations of these substances to compete with other microorganisms. 

By looking in the gut microbiome, the researchers hoped to identify peptides that the trillions of microbes use against each other in the fight for limited resources — ideally, peptides that wouldn’t broadly kill off the entire microbiome. 
 

Kill the Bad, Spare the Good

Many traditional antibiotics are small molecules. This means they can wipe out the good bacteria in your body, and because each targets a specific bacterial function, bad bacteria can become resistant to them.

Peptide antibiotics, on the other hand, don’t diffuse into the whole body. If taken orally, they stay in the gut; if taken intravenously, they generally stay in the blood. And because of how they kill bacteria, targeting the membrane, they’re also less prone to bacterial resistance.

The microbiome is like a big reservoir of pathogens, said Ami Bhatt, MD, PhD, hematologist at Stanford University in California and one of the study’s authors. Because many antibiotics kill healthy gut bacteria, “what you have left over,” Dr. Bhatt said, “is this big open niche that gets filled up with multidrug-resistant organisms like E coli [Escherichia coli] or vancomycin-resistant Enterococcus.”

Dr. Bhatt has seen cancer patients undergo successful treatment only to die of a multidrug-resistant infection, because current antibiotics fail against those pathogens. “That’s like winning the battle to lose the war.”

By investigating the microbiome, “we wanted to see if we could identify antimicrobial peptides that might spare key members of our regular microbiome, so that we wouldn’t totally disrupt the microbiome the way we do when we use broad-spectrum, small molecule–based antibiotics,” Dr. Bhatt said.

The researchers used artificial intelligence to sift through 400,000 proteins to predict, based on known antibiotics, which peptide sequences might have antimicrobial properties. From the results, they chose 78 peptides to synthesize and test.

“The application of computational approaches combined with experimental validation is very powerful and exciting,” said Jennifer Geddes-McAlister, PhD, professor of cell biology at the University of Guelph in Ontario, Canada, who was not involved in the study. “The study is robust in its approach to microbiome sampling.” 
 

The Long Journey from Lab to Clinic

More than half of the peptides the team tested effectively inhibited the growth of harmful bacteria, and prevotellin-2 (derived from the bacteria Prevotella copri)stood out as the most powerful.

“The study validates experimental data from the lab using animal models, which moves discoveries closer to the clinic,” said Dr. Geddes-McAlister. “Further testing with clinical trials is needed, but the potential for clinical application is promising.” 

Unfortunately, that’s not likely to happen anytime soon, said Dr. de la Fuente. “There is not enough economic incentive” for companies to develop new antibiotics. Ten years is his most hopeful guess for when we might see prevotellin-2, or a similar antibiotic, complete clinical trials.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity. 

There is a helpful consensus from experts on the best management of patients with acute sore throat. This is a common problem in primary care, and one for which there is a lot of evidence, opinion, and ultimately overprescribing of antibiotics. This consensus presents a pragmatic clinical approach aimed at decreasing overprescribing, yet detecting which patients are likely to benefit from treatment with antibiotics. 

Let’s first go over the evidence that forms the basis for the recommendations, then the recommended approach. First, a sore throat can be caused by many different viruses, as well as group A streptococcus (GAS), the group C streptococcus S dysgalactiae, and fusobacterium. We sometimes think of throat cultures as telling us the definitive etiology of a sore throat. In fact, children commonly are colonized with GAS even when not infected — 35% of the time, when GAS is detected on throat swab in a child, GAS is not the cause of the sore throat. Very few adults are colonized with GAS.

Sore throats are usually self-limited, whether they are treated with antibiotics or not, but occasionally complications can occur. Suppurative complications include peritonsillar abscess, sinusitis and sepsis. Nonsuppurative complications are primarily glomerulonephritis and rheumatic fever, which can lead to rheumatic heart disease. 

Antibiotics. Antibiotics have three potential benefits in acute sore throat: to reduce the risk of developing rheumatic heart disease, reduce the duration and severity of symptoms, and treat suppurative complications. The risk for rheumatic heart disease has almost vanished in high-income countries, but not in low-income countries. Thus, antibiotic treatment of acute sore throat due to GAS may benefit those in living in, and those who recently emigrated from, low-income countries. 

Patients with suppurative complications should be identified because antibiotics are important for this group. Although antibiotics are prescribed primarily to prevent rheumatic fever in this population, they may be mildly helpful in reducing a patient’s symptoms. 

Testing. The sensitivity and specificity of high-quality point-of-care tests (POCTs) are on par with those of cultures, with the advantage that the results are available within minutes. Negative tests reduce unneeded antibiotic prescriptions.

Given this evidence, the authors recommend an approach that puts a lot of emphasis on two major things: the risk for rheumatic fever, and clinical assessment. On the basis of these factors, a decision is made about the utility of POCTs and treatment with antibiotics for GAS. The risk for rheumatic fever is based on epidemiology: If the patient is in a low-income country or has recently immigrated from one, then the risk is high, and if not, the risk is low.

Complicated vs uncomplicated? This is determined by clinical assessment of the severity of the patient’s illness, including general appearance. Uncomplicated sore throat means that the patient:

• Is not getting worse after 3 days of illness
• Has a duration of illness ≤ 5 days or is getting better after day 5
• Has mild to moderate symptom severity (bilateral throat pain, the ability to open the mouth fully, and absence of a sandpaper or scarlatiniform rash or strawberry tongue)

For patients with uncomplicated sore throat and low risk for rheumatic fever, the main goals are to reduce antibiotic use and provide symptomatic relief. For these patients, an assessment such as the Centor score can be done. Those with a low Centor score (0-2) can be treated with analgesics and there is no need for a POCT.

In patients with a higher Centor score, the consensus gives two choices: They can either be tested (and treated if the testing is positive), or it is reasonable to forgo testing and use a wait-and-see strategy, with reevaluation if they are getting worse after day 3 or not improving after day 5 days of their illness. Illnesses that last longer than 5 days with sore throat and fatigue should prompt consideration of alternative diagnoses, such as infectious mononucleosis. 

For patients with potentially complicated sore throat — including indicators such as worsening symptoms after 3 days or worsening after initiation of antibiotics, inability to open the mouth fully, unilateral neck pain or swelling, or rigors — should undergo a careful evaluation. The need for further testing in these patients, including labs and imaging, should be decided on a case-by-case basis. If the patient appears seriously ill, don’t rely solely on POCT for GAS, but think about other diagnoses. 

Rheumatic fever. The approach is very different in patients at high risk for rheumatic fever. POCT for GAS is recommended irrespective of their clinical score, and antibiotics should be prescribed if it’s positive for GAS. If a POCT is unavailable, then the consensus recommends prescribing antibiotics for all high-risk patients who have acute sore throat. 

This approach is sensible and puts a lot of emphasis on clinical evaluation, though it should be noted that this approach is considerably different from that in the 2012 Infectious Diseases Society of America guidelines. 
 

Dr. Skolnik, professor, Department of Family Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, and associate director, Department of Family Medicine, Abington Jefferson Health, Abington, Pennsylvania, disclosed ties with AstraZeneca, Teva, Eli Lilly and Company, Boehringer Ingelheim, Sanofi, Sanofi Pasteur, GlaxoSmithKline, Merck, and Bayer.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity. 

There is a helpful consensus from experts on the best management of patients with acute sore throat. This is a common problem in primary care, and one for which there is a lot of evidence, opinion, and ultimately overprescribing of antibiotics. This consensus presents a pragmatic clinical approach aimed at decreasing overprescribing, yet detecting which patients are likely to benefit from treatment with antibiotics. 

Let’s first go over the evidence that forms the basis for the recommendations, then the recommended approach. First, a sore throat can be caused by many different viruses, as well as group A streptococcus (GAS), the group C streptococcus S dysgalactiae, and fusobacterium. We sometimes think of throat cultures as telling us the definitive etiology of a sore throat. In fact, children commonly are colonized with GAS even when not infected — 35% of the time, when GAS is detected on throat swab in a child, GAS is not the cause of the sore throat. Very few adults are colonized with GAS.

Sore throats are usually self-limited, whether they are treated with antibiotics or not, but occasionally complications can occur. Suppurative complications include peritonsillar abscess, sinusitis and sepsis. Nonsuppurative complications are primarily glomerulonephritis and rheumatic fever, which can lead to rheumatic heart disease. 

Antibiotics. Antibiotics have three potential benefits in acute sore throat: to reduce the risk of developing rheumatic heart disease, reduce the duration and severity of symptoms, and treat suppurative complications. The risk for rheumatic heart disease has almost vanished in high-income countries, but not in low-income countries. Thus, antibiotic treatment of acute sore throat due to GAS may benefit those in living in, and those who recently emigrated from, low-income countries. 

Patients with suppurative complications should be identified because antibiotics are important for this group. Although antibiotics are prescribed primarily to prevent rheumatic fever in this population, they may be mildly helpful in reducing a patient’s symptoms. 

Testing. The sensitivity and specificity of high-quality point-of-care tests (POCTs) are on par with those of cultures, with the advantage that the results are available within minutes. Negative tests reduce unneeded antibiotic prescriptions.

Given this evidence, the authors recommend an approach that puts a lot of emphasis on two major things: the risk for rheumatic fever, and clinical assessment. On the basis of these factors, a decision is made about the utility of POCTs and treatment with antibiotics for GAS. The risk for rheumatic fever is based on epidemiology: If the patient is in a low-income country or has recently immigrated from one, then the risk is high, and if not, the risk is low.

Complicated vs uncomplicated? This is determined by clinical assessment of the severity of the patient’s illness, including general appearance. Uncomplicated sore throat means that the patient:

• Is not getting worse after 3 days of illness
• Has a duration of illness ≤ 5 days or is getting better after day 5
• Has mild to moderate symptom severity (bilateral throat pain, the ability to open the mouth fully, and absence of a sandpaper or scarlatiniform rash or strawberry tongue)

For patients with uncomplicated sore throat and low risk for rheumatic fever, the main goals are to reduce antibiotic use and provide symptomatic relief. For these patients, an assessment such as the Centor score can be done. Those with a low Centor score (0-2) can be treated with analgesics and there is no need for a POCT.

In patients with a higher Centor score, the consensus gives two choices: They can either be tested (and treated if the testing is positive), or it is reasonable to forgo testing and use a wait-and-see strategy, with reevaluation if they are getting worse after day 3 or not improving after day 5 days of their illness. Illnesses that last longer than 5 days with sore throat and fatigue should prompt consideration of alternative diagnoses, such as infectious mononucleosis. 

For patients with potentially complicated sore throat — including indicators such as worsening symptoms after 3 days or worsening after initiation of antibiotics, inability to open the mouth fully, unilateral neck pain or swelling, or rigors — should undergo a careful evaluation. The need for further testing in these patients, including labs and imaging, should be decided on a case-by-case basis. If the patient appears seriously ill, don’t rely solely on POCT for GAS, but think about other diagnoses. 

Rheumatic fever. The approach is very different in patients at high risk for rheumatic fever. POCT for GAS is recommended irrespective of their clinical score, and antibiotics should be prescribed if it’s positive for GAS. If a POCT is unavailable, then the consensus recommends prescribing antibiotics for all high-risk patients who have acute sore throat. 

This approach is sensible and puts a lot of emphasis on clinical evaluation, though it should be noted that this approach is considerably different from that in the 2012 Infectious Diseases Society of America guidelines. 
 

Dr. Skolnik, professor, Department of Family Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, and associate director, Department of Family Medicine, Abington Jefferson Health, Abington, Pennsylvania, disclosed ties with AstraZeneca, Teva, Eli Lilly and Company, Boehringer Ingelheim, Sanofi, Sanofi Pasteur, GlaxoSmithKline, Merck, and Bayer.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity. 

There is a helpful consensus from experts on the best management of patients with acute sore throat. This is a common problem in primary care, and one for which there is a lot of evidence, opinion, and ultimately overprescribing of antibiotics. This consensus presents a pragmatic clinical approach aimed at decreasing overprescribing, yet detecting which patients are likely to benefit from treatment with antibiotics. 

Let’s first go over the evidence that forms the basis for the recommendations, then the recommended approach. First, a sore throat can be caused by many different viruses, as well as group A streptococcus (GAS), the group C streptococcus S dysgalactiae, and fusobacterium. We sometimes think of throat cultures as telling us the definitive etiology of a sore throat. In fact, children commonly are colonized with GAS even when not infected — 35% of the time, when GAS is detected on throat swab in a child, GAS is not the cause of the sore throat. Very few adults are colonized with GAS.

Sore throats are usually self-limited, whether they are treated with antibiotics or not, but occasionally complications can occur. Suppurative complications include peritonsillar abscess, sinusitis and sepsis. Nonsuppurative complications are primarily glomerulonephritis and rheumatic fever, which can lead to rheumatic heart disease. 

Antibiotics. Antibiotics have three potential benefits in acute sore throat: to reduce the risk of developing rheumatic heart disease, reduce the duration and severity of symptoms, and treat suppurative complications. The risk for rheumatic heart disease has almost vanished in high-income countries, but not in low-income countries. Thus, antibiotic treatment of acute sore throat due to GAS may benefit those in living in, and those who recently emigrated from, low-income countries. 

Patients with suppurative complications should be identified because antibiotics are important for this group. Although antibiotics are prescribed primarily to prevent rheumatic fever in this population, they may be mildly helpful in reducing a patient’s symptoms. 

Testing. The sensitivity and specificity of high-quality point-of-care tests (POCTs) are on par with those of cultures, with the advantage that the results are available within minutes. Negative tests reduce unneeded antibiotic prescriptions.

Given this evidence, the authors recommend an approach that puts a lot of emphasis on two major things: the risk for rheumatic fever, and clinical assessment. On the basis of these factors, a decision is made about the utility of POCTs and treatment with antibiotics for GAS. The risk for rheumatic fever is based on epidemiology: If the patient is in a low-income country or has recently immigrated from one, then the risk is high, and if not, the risk is low.

Complicated vs uncomplicated? This is determined by clinical assessment of the severity of the patient’s illness, including general appearance. Uncomplicated sore throat means that the patient:

• Is not getting worse after 3 days of illness
• Has a duration of illness ≤ 5 days or is getting better after day 5
• Has mild to moderate symptom severity (bilateral throat pain, the ability to open the mouth fully, and absence of a sandpaper or scarlatiniform rash or strawberry tongue)

For patients with uncomplicated sore throat and low risk for rheumatic fever, the main goals are to reduce antibiotic use and provide symptomatic relief. For these patients, an assessment such as the Centor score can be done. Those with a low Centor score (0-2) can be treated with analgesics and there is no need for a POCT.

In patients with a higher Centor score, the consensus gives two choices: They can either be tested (and treated if the testing is positive), or it is reasonable to forgo testing and use a wait-and-see strategy, with reevaluation if they are getting worse after day 3 or not improving after day 5 days of their illness. Illnesses that last longer than 5 days with sore throat and fatigue should prompt consideration of alternative diagnoses, such as infectious mononucleosis. 

For patients with potentially complicated sore throat — including indicators such as worsening symptoms after 3 days or worsening after initiation of antibiotics, inability to open the mouth fully, unilateral neck pain or swelling, or rigors — should undergo a careful evaluation. The need for further testing in these patients, including labs and imaging, should be decided on a case-by-case basis. If the patient appears seriously ill, don’t rely solely on POCT for GAS, but think about other diagnoses. 

Rheumatic fever. The approach is very different in patients at high risk for rheumatic fever. POCT for GAS is recommended irrespective of their clinical score, and antibiotics should be prescribed if it’s positive for GAS. If a POCT is unavailable, then the consensus recommends prescribing antibiotics for all high-risk patients who have acute sore throat. 

This approach is sensible and puts a lot of emphasis on clinical evaluation, though it should be noted that this approach is considerably different from that in the 2012 Infectious Diseases Society of America guidelines. 
 

Dr. Skolnik, professor, Department of Family Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, and associate director, Department of Family Medicine, Abington Jefferson Health, Abington, Pennsylvania, disclosed ties with AstraZeneca, Teva, Eli Lilly and Company, Boehringer Ingelheim, Sanofi, Sanofi Pasteur, GlaxoSmithKline, Merck, and Bayer.

A version of this article appeared on Medscape.com.

TOPLINE:

Accurately diagnosing recurrent urinary tract infections (rUTIs) in older women is challenging and requires careful weighing of the risks and benefits of various treatments, according to a new clinical insight published in JAMA Internal Medicine.

METHODOLOGY:

• Women aged > 65 years have double the rUTI rates compared with younger women, but detecting the condition is more complicated due to age-related conditions, such as overactive bladder related to menopause.
• Overuse of antibiotics can increase their risk of contracting antibiotic-resistant organisms and can lead to pulmonary or hepatic toxic effects in women with reduced kidney function.
• Up to 20% of older women have bacteria in their urine, which may or may not reflect a rUTI.
• Diagnosing rUTIs is complicated if women have dementia or cognitive decline, which can hinder recollection of symptoms.

TAKEAWAYS:

• Clinicians should consider only testing older female patients for rUTIs when symptoms are present and consider all possibilities before making a diagnosis.
• Vaginal estrogen may be an effective treatment, although the authors of the clinical review note a lack of a uniform formulation to recommend. However, oral estrogen use is not supported by evidence, and clinicians should instead consider vaginal creams or rings.
• The drug methenamine may be as effective as antibiotics but may not be safe for women with comorbidities. Evidence supports daily use at 1 g.
• Cranberry supplements and behavioral changes may be helpful, but evidence is limited, including among women living in long-term care facilities.

IN PRACTICE:

“Shared decision-making is especially important when diagnosis of an rUTI episode in older women is unclear ... in these cases, clinicians should acknowledge limitations in the evidence and invite patients or their caregivers to discuss preferences about presumptive treatment, weighing the possibility of earlier symptom relief or decreased UTI complications against the risk of adverse drug effects or multidrug resistance.”

SOURCE:

The paper was led by Alison J. Huang, MD, MAS, an internal medicine specialist and researcher in the Department of Medicine at the University of California, San Francisco.

LIMITATIONS:

The authors reported no limitations.

DISCLOSURES:

Dr. Huang received grants from the National Institutes of Health. Other authors reported receiving grants from the Agency for Healthcare Research and Quality, the US Department of Veterans Affairs, the Kahn Foundation, and Nanovibronix.

Cranberry supplements and behavioral changes may be helpful, but evidence is limited, including among women living in long-term care facilities.

A version of this article first appeared on Medscape.com.

TOPLINE:

Accurately diagnosing recurrent urinary tract infections (rUTIs) in older women is challenging and requires careful weighing of the risks and benefits of various treatments, according to a new clinical insight published in JAMA Internal Medicine.

METHODOLOGY:

• Women aged > 65 years have double the rUTI rates compared with younger women, but detecting the condition is more complicated due to age-related conditions, such as overactive bladder related to menopause.
• Overuse of antibiotics can increase their risk of contracting antibiotic-resistant organisms and can lead to pulmonary or hepatic toxic effects in women with reduced kidney function.
• Up to 20% of older women have bacteria in their urine, which may or may not reflect a rUTI.
• Diagnosing rUTIs is complicated if women have dementia or cognitive decline, which can hinder recollection of symptoms.

TAKEAWAYS:

• Clinicians should consider only testing older female patients for rUTIs when symptoms are present and consider all possibilities before making a diagnosis.
• Vaginal estrogen may be an effective treatment, although the authors of the clinical review note a lack of a uniform formulation to recommend. However, oral estrogen use is not supported by evidence, and clinicians should instead consider vaginal creams or rings.
• The drug methenamine may be as effective as antibiotics but may not be safe for women with comorbidities. Evidence supports daily use at 1 g.
• Cranberry supplements and behavioral changes may be helpful, but evidence is limited, including among women living in long-term care facilities.

IN PRACTICE:

“Shared decision-making is especially important when diagnosis of an rUTI episode in older women is unclear ... in these cases, clinicians should acknowledge limitations in the evidence and invite patients or their caregivers to discuss preferences about presumptive treatment, weighing the possibility of earlier symptom relief or decreased UTI complications against the risk of adverse drug effects or multidrug resistance.”

SOURCE:

The paper was led by Alison J. Huang, MD, MAS, an internal medicine specialist and researcher in the Department of Medicine at the University of California, San Francisco.

LIMITATIONS:

The authors reported no limitations.

DISCLOSURES:

Dr. Huang received grants from the National Institutes of Health. Other authors reported receiving grants from the Agency for Healthcare Research and Quality, the US Department of Veterans Affairs, the Kahn Foundation, and Nanovibronix.

Cranberry supplements and behavioral changes may be helpful, but evidence is limited, including among women living in long-term care facilities.

A version of this article first appeared on Medscape.com.

TOPLINE:

Accurately diagnosing recurrent urinary tract infections (rUTIs) in older women is challenging and requires careful weighing of the risks and benefits of various treatments, according to a new clinical insight published in JAMA Internal Medicine.

METHODOLOGY:

• Women aged > 65 years have double the rUTI rates compared with younger women, but detecting the condition is more complicated due to age-related conditions, such as overactive bladder related to menopause.
• Overuse of antibiotics can increase their risk of contracting antibiotic-resistant organisms and can lead to pulmonary or hepatic toxic effects in women with reduced kidney function.
• Up to 20% of older women have bacteria in their urine, which may or may not reflect a rUTI.
• Diagnosing rUTIs is complicated if women have dementia or cognitive decline, which can hinder recollection of symptoms.

TAKEAWAYS:

• Clinicians should consider only testing older female patients for rUTIs when symptoms are present and consider all possibilities before making a diagnosis.
• Vaginal estrogen may be an effective treatment, although the authors of the clinical review note a lack of a uniform formulation to recommend. However, oral estrogen use is not supported by evidence, and clinicians should instead consider vaginal creams or rings.
• The drug methenamine may be as effective as antibiotics but may not be safe for women with comorbidities. Evidence supports daily use at 1 g.
• Cranberry supplements and behavioral changes may be helpful, but evidence is limited, including among women living in long-term care facilities.

IN PRACTICE:

“Shared decision-making is especially important when diagnosis of an rUTI episode in older women is unclear ... in these cases, clinicians should acknowledge limitations in the evidence and invite patients or their caregivers to discuss preferences about presumptive treatment, weighing the possibility of earlier symptom relief or decreased UTI complications against the risk of adverse drug effects or multidrug resistance.”

SOURCE:

The paper was led by Alison J. Huang, MD, MAS, an internal medicine specialist and researcher in the Department of Medicine at the University of California, San Francisco.

LIMITATIONS:

The authors reported no limitations.

DISCLOSURES:

Dr. Huang received grants from the National Institutes of Health. Other authors reported receiving grants from the Agency for Healthcare Research and Quality, the US Department of Veterans Affairs, the Kahn Foundation, and Nanovibronix.

Cranberry supplements and behavioral changes may be helpful, but evidence is limited, including among women living in long-term care facilities.

A version of this article first appeared on Medscape.com.

A new antibiotic uses a never-before-seen mechanism to deliver a direct hit on tough-to-treat infections while leaving beneficial microbes alone. The strategy could lead to a new class of antibiotics that attack dangerous bacteria in a powerful new way, overcoming current drug resistance while sparing the gut microbiome.

“The biggest takeaway is the double-selective component,” said co-lead author Kristen A. Muñoz, PhD, who performed the research as a doctoral student at University of Illinois at Urbana-Champaign (UIUC). “We were able to develop a drug that not only targets problematic pathogens, but because it is selective for these pathogens only, we can spare the good bacteria and preserve the integrity of the microbiome.”

The drug goes after Gram-negative bacteria — pathogens responsible for debilitating and even fatal infections like gastroenteritis, urinary tract infections, pneumonia, sepsis, and cholera. The arsenal of antibiotics against them is old, with no new classes specifically targeting these bacteria coming on the market since 1968.

Many of these bugs have become resistant to one or more antibiotics, with deadly consequences. And antibiotics against them can also wipe out beneficial gut bacteria, allowing serious secondary infections to flare up.

In a study published in Nature, the drug lolamicin knocked out or reduced 130 strains of antibiotic-resistant Gram-negative bacteria in cell cultures. It also successfully treated drug-resistant bloodstream infections and pneumonia in mice while sparing their gut microbiome.

With their microbiomes intact, the mice then fought off secondary infection with Clostridioides difficile (a leading cause of opportunistic and sometimes fatal infections in US health care facilities), while mice treated with other compounds that damaged their microbiome succumbed.
 

How It Works

Like a well-built medieval castle, Gram-negative bacteria are encased in two protective walls, or membranes. Dr. Muñoz and her team at UIUC set out to breach this defense by finding compounds that hinder the “Lol system,” which ferries lipoproteins between them. 

From one compound they constructed lolamicin, which can stop Gram-negative pathogens — with little effect on Gram-negative beneficial bacteria and no effect on Gram-positive bacteria. 

“Gram-positive bacteria do not have an outer membrane, so they do not possess the Lol system,” Dr. Muñoz said. “When we compared the sequences of the Lol system in certain Gram-negative pathogens to Gram-negative commensal [beneficial] gut bacteria, we saw that the Lol systems were pretty different.”

Tossing a monkey wrench into the Lol system may be the study’s biggest contribution to future antibiotic development, said Kim Lewis, PhD, professor of Biology and director of Antimicrobial Discovery Center at Northeastern University, Boston, who has discovered several antibiotics now in preclinical research. One, darobactin, targets Gram-negative bugs without affecting the gut microbiome. Another, teixobactin, takes down Gram-positive bacteria without causing drug resistance. 

“Lolamicin hits a novel target. I would say that’s the most significant study finding,” said Dr. Lewis, who was not involved in the study. “That is rare. If you look at antibiotics introduced since 1968, they have been modifications of existing antibiotics or, rarely, new chemically but hitting the same proven targets. This one hits something properly new, and [that’s] what I found perhaps the most original and interesting.”

Kirk E. Hevener, PharmD, PhD, associate professor of Pharmaceutical Sciences at the University of Tennessee Health Science Center, Memphis, Tennessee, agreed. (Dr. Hevener also was not involved in the study.) “Lolamicin works by targeting a unique Gram-negative transport system. No currently approved antibacterials work in this way, meaning it potentially represents the first of a new class of antibacterials with narrow-spectrum Gram-negative activity and low gastrointestinal disturbance,” said Dr. Hevener, whose research looks at new antimicrobial drug targets.

The UIUC researchers noted that lolamicin has one drawback: Bacteria frequently developed resistance to it. But in future work, it could be tweaked, combined with other antibiotics, or used as a template for finding other Lol system attackers, they said.

“There is still a good amount of work cut out for us in terms of assessing the clinical translatability of lolamicin, but we are hopeful for the future of this drug,” Dr. Muñoz said.
 

Addressing a Dire Need

Bringing such a drug to market — from discovery to Food and Drug Administration approval — could take more than a decade, said Dr. Hevener. And new agents, especially for Gram-negative bugs, are sorely needed.

Not only do these bacteria shield themselves with a double membrane but they also “have more complex resistance mechanisms including special pumps that can remove antibacterial drugs from the cell before they can be effective,” Dr. Hevener said.

As a result, drug-resistant Gram-negative bacteria are making treatment of severe infections such as sepsis and pneumonia in health care settings difficult. 

Bloodstream infections with drug-resistant Klebsiella pneumoniae have a 40% mortality rate, Dr. Lewis said. And microbiome damage caused by antibiotics is also widespread and deadly, wiping out communities of helpful, protective gut bacteria. That contributes to over half of the C. difficile infections that affect 500,000 people and kill 30,000 a year in the United States. 

“Our arsenal of antibacterials that can be used to treat Gram-negative infections is dangerously low,” Dr. Hevener said. “Research will always be needed to develop new antibacterials with novel mechanisms of activity that can bypass bacterial resistance mechanisms.”

A version of this article appeared on Medscape.com.

A new antibiotic uses a never-before-seen mechanism to deliver a direct hit on tough-to-treat infections while leaving beneficial microbes alone. The strategy could lead to a new class of antibiotics that attack dangerous bacteria in a powerful new way, overcoming current drug resistance while sparing the gut microbiome.

“The biggest takeaway is the double-selective component,” said co-lead author Kristen A. Muñoz, PhD, who performed the research as a doctoral student at University of Illinois at Urbana-Champaign (UIUC). “We were able to develop a drug that not only targets problematic pathogens, but because it is selective for these pathogens only, we can spare the good bacteria and preserve the integrity of the microbiome.”

The drug goes after Gram-negative bacteria — pathogens responsible for debilitating and even fatal infections like gastroenteritis, urinary tract infections, pneumonia, sepsis, and cholera. The arsenal of antibiotics against them is old, with no new classes specifically targeting these bacteria coming on the market since 1968.

Many of these bugs have become resistant to one or more antibiotics, with deadly consequences. And antibiotics against them can also wipe out beneficial gut bacteria, allowing serious secondary infections to flare up.

In a study published in Nature, the drug lolamicin knocked out or reduced 130 strains of antibiotic-resistant Gram-negative bacteria in cell cultures. It also successfully treated drug-resistant bloodstream infections and pneumonia in mice while sparing their gut microbiome.

With their microbiomes intact, the mice then fought off secondary infection with Clostridioides difficile (a leading cause of opportunistic and sometimes fatal infections in US health care facilities), while mice treated with other compounds that damaged their microbiome succumbed.
 

How It Works

Like a well-built medieval castle, Gram-negative bacteria are encased in two protective walls, or membranes. Dr. Muñoz and her team at UIUC set out to breach this defense by finding compounds that hinder the “Lol system,” which ferries lipoproteins between them. 

From one compound they constructed lolamicin, which can stop Gram-negative pathogens — with little effect on Gram-negative beneficial bacteria and no effect on Gram-positive bacteria. 

“Gram-positive bacteria do not have an outer membrane, so they do not possess the Lol system,” Dr. Muñoz said. “When we compared the sequences of the Lol system in certain Gram-negative pathogens to Gram-negative commensal [beneficial] gut bacteria, we saw that the Lol systems were pretty different.”

Tossing a monkey wrench into the Lol system may be the study’s biggest contribution to future antibiotic development, said Kim Lewis, PhD, professor of Biology and director of Antimicrobial Discovery Center at Northeastern University, Boston, who has discovered several antibiotics now in preclinical research. One, darobactin, targets Gram-negative bugs without affecting the gut microbiome. Another, teixobactin, takes down Gram-positive bacteria without causing drug resistance. 

“Lolamicin hits a novel target. I would say that’s the most significant study finding,” said Dr. Lewis, who was not involved in the study. “That is rare. If you look at antibiotics introduced since 1968, they have been modifications of existing antibiotics or, rarely, new chemically but hitting the same proven targets. This one hits something properly new, and [that’s] what I found perhaps the most original and interesting.”

Kirk E. Hevener, PharmD, PhD, associate professor of Pharmaceutical Sciences at the University of Tennessee Health Science Center, Memphis, Tennessee, agreed. (Dr. Hevener also was not involved in the study.) “Lolamicin works by targeting a unique Gram-negative transport system. No currently approved antibacterials work in this way, meaning it potentially represents the first of a new class of antibacterials with narrow-spectrum Gram-negative activity and low gastrointestinal disturbance,” said Dr. Hevener, whose research looks at new antimicrobial drug targets.

The UIUC researchers noted that lolamicin has one drawback: Bacteria frequently developed resistance to it. But in future work, it could be tweaked, combined with other antibiotics, or used as a template for finding other Lol system attackers, they said.

“There is still a good amount of work cut out for us in terms of assessing the clinical translatability of lolamicin, but we are hopeful for the future of this drug,” Dr. Muñoz said.
 

Addressing a Dire Need

Bringing such a drug to market — from discovery to Food and Drug Administration approval — could take more than a decade, said Dr. Hevener. And new agents, especially for Gram-negative bugs, are sorely needed.

Not only do these bacteria shield themselves with a double membrane but they also “have more complex resistance mechanisms including special pumps that can remove antibacterial drugs from the cell before they can be effective,” Dr. Hevener said.

As a result, drug-resistant Gram-negative bacteria are making treatment of severe infections such as sepsis and pneumonia in health care settings difficult. 

Bloodstream infections with drug-resistant Klebsiella pneumoniae have a 40% mortality rate, Dr. Lewis said. And microbiome damage caused by antibiotics is also widespread and deadly, wiping out communities of helpful, protective gut bacteria. That contributes to over half of the C. difficile infections that affect 500,000 people and kill 30,000 a year in the United States. 

“Our arsenal of antibacterials that can be used to treat Gram-negative infections is dangerously low,” Dr. Hevener said. “Research will always be needed to develop new antibacterials with novel mechanisms of activity that can bypass bacterial resistance mechanisms.”

A version of this article appeared on Medscape.com.

A new antibiotic uses a never-before-seen mechanism to deliver a direct hit on tough-to-treat infections while leaving beneficial microbes alone. The strategy could lead to a new class of antibiotics that attack dangerous bacteria in a powerful new way, overcoming current drug resistance while sparing the gut microbiome.

“The biggest takeaway is the double-selective component,” said co-lead author Kristen A. Muñoz, PhD, who performed the research as a doctoral student at University of Illinois at Urbana-Champaign (UIUC). “We were able to develop a drug that not only targets problematic pathogens, but because it is selective for these pathogens only, we can spare the good bacteria and preserve the integrity of the microbiome.”

The drug goes after Gram-negative bacteria — pathogens responsible for debilitating and even fatal infections like gastroenteritis, urinary tract infections, pneumonia, sepsis, and cholera. The arsenal of antibiotics against them is old, with no new classes specifically targeting these bacteria coming on the market since 1968.

Many of these bugs have become resistant to one or more antibiotics, with deadly consequences. And antibiotics against them can also wipe out beneficial gut bacteria, allowing serious secondary infections to flare up.

In a study published in Nature, the drug lolamicin knocked out or reduced 130 strains of antibiotic-resistant Gram-negative bacteria in cell cultures. It also successfully treated drug-resistant bloodstream infections and pneumonia in mice while sparing their gut microbiome.

With their microbiomes intact, the mice then fought off secondary infection with Clostridioides difficile (a leading cause of opportunistic and sometimes fatal infections in US health care facilities), while mice treated with other compounds that damaged their microbiome succumbed.
 

How It Works

Like a well-built medieval castle, Gram-negative bacteria are encased in two protective walls, or membranes. Dr. Muñoz and her team at UIUC set out to breach this defense by finding compounds that hinder the “Lol system,” which ferries lipoproteins between them. 

From one compound they constructed lolamicin, which can stop Gram-negative pathogens — with little effect on Gram-negative beneficial bacteria and no effect on Gram-positive bacteria. 

“Gram-positive bacteria do not have an outer membrane, so they do not possess the Lol system,” Dr. Muñoz said. “When we compared the sequences of the Lol system in certain Gram-negative pathogens to Gram-negative commensal [beneficial] gut bacteria, we saw that the Lol systems were pretty different.”

Tossing a monkey wrench into the Lol system may be the study’s biggest contribution to future antibiotic development, said Kim Lewis, PhD, professor of Biology and director of Antimicrobial Discovery Center at Northeastern University, Boston, who has discovered several antibiotics now in preclinical research. One, darobactin, targets Gram-negative bugs without affecting the gut microbiome. Another, teixobactin, takes down Gram-positive bacteria without causing drug resistance. 

“Lolamicin hits a novel target. I would say that’s the most significant study finding,” said Dr. Lewis, who was not involved in the study. “That is rare. If you look at antibiotics introduced since 1968, they have been modifications of existing antibiotics or, rarely, new chemically but hitting the same proven targets. This one hits something properly new, and [that’s] what I found perhaps the most original and interesting.”

Kirk E. Hevener, PharmD, PhD, associate professor of Pharmaceutical Sciences at the University of Tennessee Health Science Center, Memphis, Tennessee, agreed. (Dr. Hevener also was not involved in the study.) “Lolamicin works by targeting a unique Gram-negative transport system. No currently approved antibacterials work in this way, meaning it potentially represents the first of a new class of antibacterials with narrow-spectrum Gram-negative activity and low gastrointestinal disturbance,” said Dr. Hevener, whose research looks at new antimicrobial drug targets.

The UIUC researchers noted that lolamicin has one drawback: Bacteria frequently developed resistance to it. But in future work, it could be tweaked, combined with other antibiotics, or used as a template for finding other Lol system attackers, they said.

“There is still a good amount of work cut out for us in terms of assessing the clinical translatability of lolamicin, but we are hopeful for the future of this drug,” Dr. Muñoz said.
 

Addressing a Dire Need

Bringing such a drug to market — from discovery to Food and Drug Administration approval — could take more than a decade, said Dr. Hevener. And new agents, especially for Gram-negative bugs, are sorely needed.

Not only do these bacteria shield themselves with a double membrane but they also “have more complex resistance mechanisms including special pumps that can remove antibacterial drugs from the cell before they can be effective,” Dr. Hevener said.

As a result, drug-resistant Gram-negative bacteria are making treatment of severe infections such as sepsis and pneumonia in health care settings difficult. 

Bloodstream infections with drug-resistant Klebsiella pneumoniae have a 40% mortality rate, Dr. Lewis said. And microbiome damage caused by antibiotics is also widespread and deadly, wiping out communities of helpful, protective gut bacteria. That contributes to over half of the C. difficile infections that affect 500,000 people and kill 30,000 a year in the United States. 

“Our arsenal of antibacterials that can be used to treat Gram-negative infections is dangerously low,” Dr. Hevener said. “Research will always be needed to develop new antibacterials with novel mechanisms of activity that can bypass bacterial resistance mechanisms.”

A version of this article appeared on Medscape.com.

An updated clinical approach to diagnosing urinary tract infections (UTIs) that considers five potential phenotype categories instead of the usual three could aid clinical management and better center patient needs, according to the authors of a new study in The Journal of Urology.

The current diagnostic paradigm includes UTI, asymptomatic bacteriuria (ASB), or not UTI, but the researchers believe these categories exclude for more ambiguous clinical cases, such as patients whose bacteria counts are low but who are symptomatic, or when nonspecific symptoms make it difficult to determine whether treatment with antibiotics is appropriate.

“Our findings suggest the need to reframe our conceptual model of UTI vs ASB to recognize clinical uncertainty and reflect the full spectrum of clinical presentations,” Sonali D. Advani, MBBS, MPH, an associate professor of medicine in infectious disease at Duke University School of Medicine, in Durham, North Carolina, and her colleagues wrote. “Recent data suggest that UTI may present as a bidirectional continuum from asymptomatic bladder colonization to a symptomatic bladder infection,” and some populations may lack the signs or symptoms specific to urinary tract or have chronic lower urinary tract symptoms (LUTS) that make it difficult to distinguish between ASB and UTI, they wrote.

Nitya E. Abraham, MD, an associate professor of urology at Albert Einstein College of Medicine and Montefiore Einstein in New York City, agreed the current paradigm has room for refinement.

“The current classification system doesn’t account for certain patients such as patients who have bothersome urinary symptoms, but urine testing comes back negative, or patients with positive urine testing, but who aren’t able to report the presence or absence of symptoms,” Dr. Abraham, who was not involved in the new research, told this news organization.

Boback Berookhim, MD, a urologist at Northwell Health in New Hyde Park, New York, who was also not involved in the research, said the goal with this study appears to be better identifying who will need antibiotics.

“I think this is more of a forward-looking study in terms of trying to identify patients who currently may not be treated or may be over treated and better identifying subsets,” Dr. Berookhim told this news organization.

However, he said the relevance of the work is far greater in hospitals than in outpatient settings.

“I think it’s much more relevant in inpatient environments where a patient is in hospital and whatever antibiotics are being written are going to be overseen and you’re going to see higher resistance patterns,” Dr. Berookhim said. “For the average doctor who’s seeing patients in the office and writing them prescriptions in the office, this doesn’t really affect them.”
 

Antibiotic Dilemma

A key issue in determining the best approach to UTI diagnosis is assessing the appropriateness of antibiotic treatment. Up to half of hospitalized patients have ASB, for which current practice guidelines advise against antibiotics, Dr. Advani and her colleagues noted. Yet many of these patients receive antibiotics regardless, and research has shown links between treatment and longer length of stay, antibiotic resistance, and infection with Clostridioides difficile.

The challenge comes with patients who do not fit easily into the existing categories. One includes patients who have positive urine cultures but whose symptoms, such as hypotension or fever, are not specific to the genitourinary tract.

While current guidelines advise against treating these patients with antibiotics, the patients are often older adults with cognitive impairment or delirium, and frontline physicians may err on the side of prescribing antibiotics because of their clinical uncertainty. That treatment can lead to tension with hospital antibiotic stewardship teams that recommend withholding antibiotics for those patients.

“These clinical scenarios highlight differences between the frontline clinicians’ and antibiotic stewardship teams’ definitions of ‘asymptomatic,’ highlighting the ambiguity of the term ‘asymptomatic bacteriuria,’” Dr. Advani and her colleagues wrote.

A fever, for example, could signal a viral or bacterial infection or result from a nonurinary source, Dr. Abraham said. “The antibiotic stewardship team likely prefers to observe the clinical course and wait for more data to demonstrate need for antibiotics,” she said. “Hence, there are conflicting priorities and confusion of when to treat with antibiotics for this common dilemma in patients presenting to the ER or urgent care.”

Meanwhile, other patients, particularly women, may present with urinary symptoms and pyuria but have lab results revealing a colony count below the 100,000 CFU/mL threshold that would indicate antibiotic treatment.

“Some of these women are likely suffering from a UTI and may not receive treatment if clinicians focus primarily on the urine culture results,” Dr. Abraham said. She pointed out the existence of other options than urine culture for better identifying UTI, such as urinary cell-free DNA or next-generation DNA testing of the urine. But she also said the 100,000 CFU/mL threshold should not be absolute.

“For example, I will treat patients for UTI with 10,000-50,000 CFU/mL if they also have UTI symptoms like blood in the urine, burning with urination, bladder pain, increased urgency or frequency, and the urinalysis shows a high white blood cell count,” Dr. Abraham said.

Dr. Abraham also noted a third group outside the scope of the new study: People with urinary symptoms who don’t undergo urine tests or who are treated empirically with antibiotics. “It is unclear whether those in this group truly have a UTI, but it is a common scenario that patients are unable to get urine tests and are treated with over-the-phone prescriptions to expedite treatment,” she said.
 

Get on the BUS

The researchers conducted a retrospective study across one academic medical center and four community hospitals in three states to assess the feasibility of using five categories of UTI diagnosis: The three existing ones plus LUTS/other urologic symptoms (OUS) and bacteriuria of unclear significance (BUS). These additional categories arose out of an hour-long discussion with a focus group of experts across several disciplines.

The analysis covered the charts of 3392 randomly selected encounters out of 220,531 total inpatient or emergency department encounters between January 2017 and December 2019 in which adults received a urinalysis and urine culture order within the same 24-hour period. The patients’ median age was 67 years, over half (59.6%) were women, and nearly a quarter (24.2%) had an underlying immunocompromising condition.

Most of the cultures were obtained from inpatients. Nearly a third (30.6%) were negative for culture, while 42.1% grew at least 100,000 CFU/mL of bacteria and 17% grew mixed flora.

Based on current criteria, 21.3% of the patients had a UTI, 20.8% had ASB, and 47.6% had no UTI. The remaining 10.3% had culture growth under 100,000 CFU/mL and, therefore, did not fit in any of these categories, “as there is no consistent guidance on whether to classify them as no UTI or ASB or contamination,” the authors wrote.

When the researchers applied the new criteria, more than half of the cases of ASB (68%) were reclassified as BUS, and 28.9% of the no-UTI cases were reclassified as LUTS/OUS.

In a sensitivity analysis that examined samples with bacteriuria below the 100,000 CFU/mL threshold, nearly half the unclassified cases (43.3%) were reassigned as a UTI, increasing the proportion of patients with a diagnosed UTI from 21.3% to 25.8% of the total population. Of the remaining patients who had originally been unclassified, 14.2% were newly defined as ASB, and 42.5% became BUS.

Dr. Abraham said the addition of the BUS and LUTS/OUS categories has the potential to improve and individualize patient care. Clinicians can consider nonantibiotic therapies for the patients who had LUTS/OUS while they look into possible causes, while the BUS cases enable frontline clinicians and antibiotic stewardship teams to “meet in the middle” by monitoring those patients more closely in case symptoms worsen, she said.

The authors highlighted three key takeaways from their study, starting with the fact that nearly two thirds of patients who underwent testing for a UTI did not have signs or symptoms localized to the urinary tract — the ones reclassified as BUS.

“Hence, reclassifying patients as BUS may provide an opportunity to acknowledge diagnostic uncertainty and need for additional monitoring than ASB patients so as to promote a nuanced and patient-centered approach to diagnosis and management,” the authors wrote.

Second, a third of patients initially classified as not having a UTI were reclassified into the new LUTS/OUS category because of their symptoms, such as a poor or intermittent stream, dribbling, hesitancy, frequency, urge incontinence, and nocturia. These patients would need further workup to determine the best approach to management.

Finally, the sensitivity analysis “suggested that lowering the bacterial threshold in some symptomatic patients may capture additional patients with UTI whose symptoms may be dismissed due to concern for contamination or attributed to LUTS rather than infection.” Given that the 100,000 CFU/mL threshold is based on a single study in 1956, the authors suggested more research may help define better CFU thresholds to improve clinical care.

Dr. Berookhim said the study authors took a reasonable and thorough approach in how they tried to consider the best way to update the current diagnostic classification schema.

“I think using this as a jumping off point to look deeper is worthwhile,” such as conducting randomized controlled trials to assess the use of new categories, he said. “Getting more granular than this, I think, would just muddy the waters and make it more difficult to make clinical decisions.”

The research was funded by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Advani reported consulting fees from Locus Biosciences, Sysmex America, GlaxoSmithKline, and bioMérieux. Dr. Abraham and Dr. Berookhim reported no relevant financial conflicts of interest.

A version of this article appeared on Medscape.com.

An updated clinical approach to diagnosing urinary tract infections (UTIs) that considers five potential phenotype categories instead of the usual three could aid clinical management and better center patient needs, according to the authors of a new study in The Journal of Urology.

The current diagnostic paradigm includes UTI, asymptomatic bacteriuria (ASB), or not UTI, but the researchers believe these categories exclude for more ambiguous clinical cases, such as patients whose bacteria counts are low but who are symptomatic, or when nonspecific symptoms make it difficult to determine whether treatment with antibiotics is appropriate.

“Our findings suggest the need to reframe our conceptual model of UTI vs ASB to recognize clinical uncertainty and reflect the full spectrum of clinical presentations,” Sonali D. Advani, MBBS, MPH, an associate professor of medicine in infectious disease at Duke University School of Medicine, in Durham, North Carolina, and her colleagues wrote. “Recent data suggest that UTI may present as a bidirectional continuum from asymptomatic bladder colonization to a symptomatic bladder infection,” and some populations may lack the signs or symptoms specific to urinary tract or have chronic lower urinary tract symptoms (LUTS) that make it difficult to distinguish between ASB and UTI, they wrote.

Nitya E. Abraham, MD, an associate professor of urology at Albert Einstein College of Medicine and Montefiore Einstein in New York City, agreed the current paradigm has room for refinement.

“The current classification system doesn’t account for certain patients such as patients who have bothersome urinary symptoms, but urine testing comes back negative, or patients with positive urine testing, but who aren’t able to report the presence or absence of symptoms,” Dr. Abraham, who was not involved in the new research, told this news organization.

Boback Berookhim, MD, a urologist at Northwell Health in New Hyde Park, New York, who was also not involved in the research, said the goal with this study appears to be better identifying who will need antibiotics.

“I think this is more of a forward-looking study in terms of trying to identify patients who currently may not be treated or may be over treated and better identifying subsets,” Dr. Berookhim told this news organization.

However, he said the relevance of the work is far greater in hospitals than in outpatient settings.

“I think it’s much more relevant in inpatient environments where a patient is in hospital and whatever antibiotics are being written are going to be overseen and you’re going to see higher resistance patterns,” Dr. Berookhim said. “For the average doctor who’s seeing patients in the office and writing them prescriptions in the office, this doesn’t really affect them.”
 

Antibiotic Dilemma

A key issue in determining the best approach to UTI diagnosis is assessing the appropriateness of antibiotic treatment. Up to half of hospitalized patients have ASB, for which current practice guidelines advise against antibiotics, Dr. Advani and her colleagues noted. Yet many of these patients receive antibiotics regardless, and research has shown links between treatment and longer length of stay, antibiotic resistance, and infection with Clostridioides difficile.

The challenge comes with patients who do not fit easily into the existing categories. One includes patients who have positive urine cultures but whose symptoms, such as hypotension or fever, are not specific to the genitourinary tract.

While current guidelines advise against treating these patients with antibiotics, the patients are often older adults with cognitive impairment or delirium, and frontline physicians may err on the side of prescribing antibiotics because of their clinical uncertainty. That treatment can lead to tension with hospital antibiotic stewardship teams that recommend withholding antibiotics for those patients.

“These clinical scenarios highlight differences between the frontline clinicians’ and antibiotic stewardship teams’ definitions of ‘asymptomatic,’ highlighting the ambiguity of the term ‘asymptomatic bacteriuria,’” Dr. Advani and her colleagues wrote.

A fever, for example, could signal a viral or bacterial infection or result from a nonurinary source, Dr. Abraham said. “The antibiotic stewardship team likely prefers to observe the clinical course and wait for more data to demonstrate need for antibiotics,” she said. “Hence, there are conflicting priorities and confusion of when to treat with antibiotics for this common dilemma in patients presenting to the ER or urgent care.”

Meanwhile, other patients, particularly women, may present with urinary symptoms and pyuria but have lab results revealing a colony count below the 100,000 CFU/mL threshold that would indicate antibiotic treatment.

“Some of these women are likely suffering from a UTI and may not receive treatment if clinicians focus primarily on the urine culture results,” Dr. Abraham said. She pointed out the existence of other options than urine culture for better identifying UTI, such as urinary cell-free DNA or next-generation DNA testing of the urine. But she also said the 100,000 CFU/mL threshold should not be absolute.

“For example, I will treat patients for UTI with 10,000-50,000 CFU/mL if they also have UTI symptoms like blood in the urine, burning with urination, bladder pain, increased urgency or frequency, and the urinalysis shows a high white blood cell count,” Dr. Abraham said.

Dr. Abraham also noted a third group outside the scope of the new study: People with urinary symptoms who don’t undergo urine tests or who are treated empirically with antibiotics. “It is unclear whether those in this group truly have a UTI, but it is a common scenario that patients are unable to get urine tests and are treated with over-the-phone prescriptions to expedite treatment,” she said.
 

Get on the BUS

The researchers conducted a retrospective study across one academic medical center and four community hospitals in three states to assess the feasibility of using five categories of UTI diagnosis: The three existing ones plus LUTS/other urologic symptoms (OUS) and bacteriuria of unclear significance (BUS). These additional categories arose out of an hour-long discussion with a focus group of experts across several disciplines.

The analysis covered the charts of 3392 randomly selected encounters out of 220,531 total inpatient or emergency department encounters between January 2017 and December 2019 in which adults received a urinalysis and urine culture order within the same 24-hour period. The patients’ median age was 67 years, over half (59.6%) were women, and nearly a quarter (24.2%) had an underlying immunocompromising condition.

Most of the cultures were obtained from inpatients. Nearly a third (30.6%) were negative for culture, while 42.1% grew at least 100,000 CFU/mL of bacteria and 17% grew mixed flora.

Based on current criteria, 21.3% of the patients had a UTI, 20.8% had ASB, and 47.6% had no UTI. The remaining 10.3% had culture growth under 100,000 CFU/mL and, therefore, did not fit in any of these categories, “as there is no consistent guidance on whether to classify them as no UTI or ASB or contamination,” the authors wrote.

When the researchers applied the new criteria, more than half of the cases of ASB (68%) were reclassified as BUS, and 28.9% of the no-UTI cases were reclassified as LUTS/OUS.

In a sensitivity analysis that examined samples with bacteriuria below the 100,000 CFU/mL threshold, nearly half the unclassified cases (43.3%) were reassigned as a UTI, increasing the proportion of patients with a diagnosed UTI from 21.3% to 25.8% of the total population. Of the remaining patients who had originally been unclassified, 14.2% were newly defined as ASB, and 42.5% became BUS.

Dr. Abraham said the addition of the BUS and LUTS/OUS categories has the potential to improve and individualize patient care. Clinicians can consider nonantibiotic therapies for the patients who had LUTS/OUS while they look into possible causes, while the BUS cases enable frontline clinicians and antibiotic stewardship teams to “meet in the middle” by monitoring those patients more closely in case symptoms worsen, she said.

The authors highlighted three key takeaways from their study, starting with the fact that nearly two thirds of patients who underwent testing for a UTI did not have signs or symptoms localized to the urinary tract — the ones reclassified as BUS.

“Hence, reclassifying patients as BUS may provide an opportunity to acknowledge diagnostic uncertainty and need for additional monitoring than ASB patients so as to promote a nuanced and patient-centered approach to diagnosis and management,” the authors wrote.

Second, a third of patients initially classified as not having a UTI were reclassified into the new LUTS/OUS category because of their symptoms, such as a poor or intermittent stream, dribbling, hesitancy, frequency, urge incontinence, and nocturia. These patients would need further workup to determine the best approach to management.

Finally, the sensitivity analysis “suggested that lowering the bacterial threshold in some symptomatic patients may capture additional patients with UTI whose symptoms may be dismissed due to concern for contamination or attributed to LUTS rather than infection.” Given that the 100,000 CFU/mL threshold is based on a single study in 1956, the authors suggested more research may help define better CFU thresholds to improve clinical care.

Dr. Berookhim said the study authors took a reasonable and thorough approach in how they tried to consider the best way to update the current diagnostic classification schema.

“I think using this as a jumping off point to look deeper is worthwhile,” such as conducting randomized controlled trials to assess the use of new categories, he said. “Getting more granular than this, I think, would just muddy the waters and make it more difficult to make clinical decisions.”

The research was funded by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Advani reported consulting fees from Locus Biosciences, Sysmex America, GlaxoSmithKline, and bioMérieux. Dr. Abraham and Dr. Berookhim reported no relevant financial conflicts of interest.

A version of this article appeared on Medscape.com.

An updated clinical approach to diagnosing urinary tract infections (UTIs) that considers five potential phenotype categories instead of the usual three could aid clinical management and better center patient needs, according to the authors of a new study in The Journal of Urology.

The current diagnostic paradigm includes UTI, asymptomatic bacteriuria (ASB), or not UTI, but the researchers believe these categories exclude for more ambiguous clinical cases, such as patients whose bacteria counts are low but who are symptomatic, or when nonspecific symptoms make it difficult to determine whether treatment with antibiotics is appropriate.

“Our findings suggest the need to reframe our conceptual model of UTI vs ASB to recognize clinical uncertainty and reflect the full spectrum of clinical presentations,” Sonali D. Advani, MBBS, MPH, an associate professor of medicine in infectious disease at Duke University School of Medicine, in Durham, North Carolina, and her colleagues wrote. “Recent data suggest that UTI may present as a bidirectional continuum from asymptomatic bladder colonization to a symptomatic bladder infection,” and some populations may lack the signs or symptoms specific to urinary tract or have chronic lower urinary tract symptoms (LUTS) that make it difficult to distinguish between ASB and UTI, they wrote.

Nitya E. Abraham, MD, an associate professor of urology at Albert Einstein College of Medicine and Montefiore Einstein in New York City, agreed the current paradigm has room for refinement.

“The current classification system doesn’t account for certain patients such as patients who have bothersome urinary symptoms, but urine testing comes back negative, or patients with positive urine testing, but who aren’t able to report the presence or absence of symptoms,” Dr. Abraham, who was not involved in the new research, told this news organization.

Boback Berookhim, MD, a urologist at Northwell Health in New Hyde Park, New York, who was also not involved in the research, said the goal with this study appears to be better identifying who will need antibiotics.

“I think this is more of a forward-looking study in terms of trying to identify patients who currently may not be treated or may be over treated and better identifying subsets,” Dr. Berookhim told this news organization.

However, he said the relevance of the work is far greater in hospitals than in outpatient settings.

“I think it’s much more relevant in inpatient environments where a patient is in hospital and whatever antibiotics are being written are going to be overseen and you’re going to see higher resistance patterns,” Dr. Berookhim said. “For the average doctor who’s seeing patients in the office and writing them prescriptions in the office, this doesn’t really affect them.”
 

Antibiotic Dilemma

A key issue in determining the best approach to UTI diagnosis is assessing the appropriateness of antibiotic treatment. Up to half of hospitalized patients have ASB, for which current practice guidelines advise against antibiotics, Dr. Advani and her colleagues noted. Yet many of these patients receive antibiotics regardless, and research has shown links between treatment and longer length of stay, antibiotic resistance, and infection with Clostridioides difficile.

The challenge comes with patients who do not fit easily into the existing categories. One includes patients who have positive urine cultures but whose symptoms, such as hypotension or fever, are not specific to the genitourinary tract.

While current guidelines advise against treating these patients with antibiotics, the patients are often older adults with cognitive impairment or delirium, and frontline physicians may err on the side of prescribing antibiotics because of their clinical uncertainty. That treatment can lead to tension with hospital antibiotic stewardship teams that recommend withholding antibiotics for those patients.

“These clinical scenarios highlight differences between the frontline clinicians’ and antibiotic stewardship teams’ definitions of ‘asymptomatic,’ highlighting the ambiguity of the term ‘asymptomatic bacteriuria,’” Dr. Advani and her colleagues wrote.

A fever, for example, could signal a viral or bacterial infection or result from a nonurinary source, Dr. Abraham said. “The antibiotic stewardship team likely prefers to observe the clinical course and wait for more data to demonstrate need for antibiotics,” she said. “Hence, there are conflicting priorities and confusion of when to treat with antibiotics for this common dilemma in patients presenting to the ER or urgent care.”

Meanwhile, other patients, particularly women, may present with urinary symptoms and pyuria but have lab results revealing a colony count below the 100,000 CFU/mL threshold that would indicate antibiotic treatment.

“Some of these women are likely suffering from a UTI and may not receive treatment if clinicians focus primarily on the urine culture results,” Dr. Abraham said. She pointed out the existence of other options than urine culture for better identifying UTI, such as urinary cell-free DNA or next-generation DNA testing of the urine. But she also said the 100,000 CFU/mL threshold should not be absolute.

“For example, I will treat patients for UTI with 10,000-50,000 CFU/mL if they also have UTI symptoms like blood in the urine, burning with urination, bladder pain, increased urgency or frequency, and the urinalysis shows a high white blood cell count,” Dr. Abraham said.

Dr. Abraham also noted a third group outside the scope of the new study: People with urinary symptoms who don’t undergo urine tests or who are treated empirically with antibiotics. “It is unclear whether those in this group truly have a UTI, but it is a common scenario that patients are unable to get urine tests and are treated with over-the-phone prescriptions to expedite treatment,” she said.
 

Get on the BUS

The researchers conducted a retrospective study across one academic medical center and four community hospitals in three states to assess the feasibility of using five categories of UTI diagnosis: The three existing ones plus LUTS/other urologic symptoms (OUS) and bacteriuria of unclear significance (BUS). These additional categories arose out of an hour-long discussion with a focus group of experts across several disciplines.

The analysis covered the charts of 3392 randomly selected encounters out of 220,531 total inpatient or emergency department encounters between January 2017 and December 2019 in which adults received a urinalysis and urine culture order within the same 24-hour period. The patients’ median age was 67 years, over half (59.6%) were women, and nearly a quarter (24.2%) had an underlying immunocompromising condition.

Most of the cultures were obtained from inpatients. Nearly a third (30.6%) were negative for culture, while 42.1% grew at least 100,000 CFU/mL of bacteria and 17% grew mixed flora.

Based on current criteria, 21.3% of the patients had a UTI, 20.8% had ASB, and 47.6% had no UTI. The remaining 10.3% had culture growth under 100,000 CFU/mL and, therefore, did not fit in any of these categories, “as there is no consistent guidance on whether to classify them as no UTI or ASB or contamination,” the authors wrote.

When the researchers applied the new criteria, more than half of the cases of ASB (68%) were reclassified as BUS, and 28.9% of the no-UTI cases were reclassified as LUTS/OUS.

In a sensitivity analysis that examined samples with bacteriuria below the 100,000 CFU/mL threshold, nearly half the unclassified cases (43.3%) were reassigned as a UTI, increasing the proportion of patients with a diagnosed UTI from 21.3% to 25.8% of the total population. Of the remaining patients who had originally been unclassified, 14.2% were newly defined as ASB, and 42.5% became BUS.

Dr. Abraham said the addition of the BUS and LUTS/OUS categories has the potential to improve and individualize patient care. Clinicians can consider nonantibiotic therapies for the patients who had LUTS/OUS while they look into possible causes, while the BUS cases enable frontline clinicians and antibiotic stewardship teams to “meet in the middle” by monitoring those patients more closely in case symptoms worsen, she said.

The authors highlighted three key takeaways from their study, starting with the fact that nearly two thirds of patients who underwent testing for a UTI did not have signs or symptoms localized to the urinary tract — the ones reclassified as BUS.

“Hence, reclassifying patients as BUS may provide an opportunity to acknowledge diagnostic uncertainty and need for additional monitoring than ASB patients so as to promote a nuanced and patient-centered approach to diagnosis and management,” the authors wrote.

Second, a third of patients initially classified as not having a UTI were reclassified into the new LUTS/OUS category because of their symptoms, such as a poor or intermittent stream, dribbling, hesitancy, frequency, urge incontinence, and nocturia. These patients would need further workup to determine the best approach to management.

Finally, the sensitivity analysis “suggested that lowering the bacterial threshold in some symptomatic patients may capture additional patients with UTI whose symptoms may be dismissed due to concern for contamination or attributed to LUTS rather than infection.” Given that the 100,000 CFU/mL threshold is based on a single study in 1956, the authors suggested more research may help define better CFU thresholds to improve clinical care.

Dr. Berookhim said the study authors took a reasonable and thorough approach in how they tried to consider the best way to update the current diagnostic classification schema.

“I think using this as a jumping off point to look deeper is worthwhile,” such as conducting randomized controlled trials to assess the use of new categories, he said. “Getting more granular than this, I think, would just muddy the waters and make it more difficult to make clinical decisions.”

The research was funded by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Advani reported consulting fees from Locus Biosciences, Sysmex America, GlaxoSmithKline, and bioMérieux. Dr. Abraham and Dr. Berookhim reported no relevant financial conflicts of interest.

A version of this article appeared on Medscape.com.