Infectious Diseases

BARCELONA, SPAIN — Streptococcus pneumoniae, the bacteria that causes pneumococcal disease, is sixfold more likely to colonize adults older than 60 years who have regular contact with children than those who do not, data from a community-based study showed.

However, there is “no clear evidence of adult-to-adult transmission,” and the researchers, led by Anne L. Wyllie, PhD, from the Yale School of Public Health, New Haven, Connecticut, noted that the study results suggest “the main benefit of adult pneumococcal conjugate vaccine (PCV) immunization is to directly protect adults who are exposed to children, who still carry and transmit some vaccine-type pneumococci despite successful pediatric national immunization programs.”

The data show that relatively high pneumococcus carriage rates are seen in people who have regular contact with children, who have had contact in the previous 2 weeks, and who have had contact for extended periods, Dr. Wyllie explained.

Preschoolers in particular were found to be most likely to transmit pneumococcus to older adults. “It is the 24- to 59-month-olds who are most associated with pneumococcal carriage, more than 1- to 2-year-olds,” she reported. However, transmission rates from children younger than 1 year are higher than those from children aged 1-2 years, she added.

The findings were presented at the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) 2024 global conference, formerly known as the ECCMID conference.
 

Originally Designed to Investigate Adult-to-Adult Transmission

The researchers wanted to understand the sources and dynamics of transmission, as well as the risk factors for pneumococcal disease in older adults, to help predict the effect of PCVs in people older than 60 years.

Although “we designed the study to specifically look at transmission between adults, in the end, we were presented with a very unique scenario” — restricted social mixing as a result of the COVID pandemic — during which “no community activities were happening,” Dr. Wyllie said. Because of this, the team was able to determine “the source of acquisition or transmission to the older adults was, very likely, coming from contact with children.”

Pneumococci are commonly found in respiratory tracts of healthy people. The US Centers for Disease Control and Prevention estimated that 20%-60% of school-aged children may be colonized compared with only 5%-10% of adults without children.

The longitudinal study was conducted among household pairs, such as married couples who were both aged at least 60 years and who did not have people younger than 60 years living in the household, in New Haven over two winter seasons: 2020-2021 and 2021-2022.

Self-collected saliva samples were assessed, and surveys on social behaviors and health were completed every 2 weeks for a 10-week period (with six study visits). The saliva sampling method was used because the researchers considered it to be more effective than samples from nasopharyngeal swabs. Quantitative polymerase chain reaction assays were used to test the saliva samples for the presence of pneumococcal DNA (pneumococcus genes piaB and lytA) and the diversity of pneumococcal strains (36 serotypes were targeted).
 

Strongly Suggestive of Transmission From Children to Older Adults

Of the 121 adults living in 61 households who were enrolled in the study, 62 adults participated in both seasons. Mean age was 70.9 years (range, 60-86 years), 51% of participants were women, and 85% were White.

Overall, 52 of 1088 (4.8%) samples tested positive for pneumococcus, and 27 of 121 (22.3%) adults were colonized on at least one sampling visit. Some were colonized at multiple timepoints, and two were colonized throughout the 10-week sampling period. Of the two participants who were colonized at five of six timepoints, one reported daily contact with children younger than 5 years and children aged 5-9 years in the two study seasons. This person was also positive at three of six sampling points during the first study season.

There were five instances in which both members of the household were carriers in the same season, although not necessarily at the same timepoint. Numbers were too small to determine whether transmission had occurred between the household pairs.

Contact with a 24- to 59-month-old child (older than 2 years but younger than 5 years) had the strongest association with elevated odds of carrying pneumococcus, the authors reported in their preprint, although the frequency and intensity of contact also mattered.

At any sampled time (point prevalence), pneumococcal carriage was substantially — just over sixfold — higher among older adults who had contact with children daily or every few days (10%) than among those who had no contact with children (1.6%).

In particular, contact between adults and children younger than 5 years and children aged 5-9 years was found to lead to elevated point prevalences of 13.8% and 14.1%, respectively. Pneumococcal carriage in children older than 10 years was lower, with a point prevalence of 8.3%.

The younger the child, the greater the point prevalence; point prevalences were 13.8% for samples from children aged 1 year and younger, 10.5% for samples from children aged 1-2 years, and 17.8% for children aged 2-5 years.

Carriage prevalence was higher in older adults who reported daily contact with children (15.7%) or contact every few days (14.0%) than in those who reported contact with children only once or twice a month (4.5%) or never (1.8%), they wrote.

“Older people who have a lot of contact with kids and are more susceptible to respiratory viruses can get a secondary infection from pneumococcus, especially during the cold and flu seasons. Vaccination can help to protect them or lessen severity of the illness,” Wyllie pointed out.

However, adult PCV immunization may not have a major impact on onward transmission to other adults, the authors wrote in their preprint.

This study supports prior work demonstrating that pneumococcal colonization is greater in households with children than in those without, said Stephen Pelton, MD, a pediatric infectious disease specialist from Boston University schools of medicine and public health. “The unique aspect is that Dr. Wyllie’s group has looked at individuals over age 60 and used the most sensitive methods currently available to detect pneumococcal carriage.”

“At the most recent ISPPD [International Society of Pneumonia and Pneumococcal Diseases conference], the role of adult-to-adult transmission in the community was discussed. This study confirms the critical role children play in community transmission of the pneumococcus,” Dr. Pelton noted.

Dr. Wyllie received consulting and/or advisory board fees from Pfizer, Merck, Diasorin, PPS Health, Primary Health, Co-Diagnostics, and Global Diagnostic Systems for work unrelated to this project and is the principal investigator on research grants from Pfizer, Merck, NIH RADx-UP, and SalivaDirect, Inc. to Yale University and from NIH RADx, Balvi.io, and Shield T3 to SalivaDirect, Inc. Dr. Pelton received honoraria from Merck, Pfizer, Sanofi, and GSK for participation in Pneumococcal Advisory Boards and DSMB (Sanofi). Boston Medical Center received grant funding for investigator-initiated research from Merck and Pfizer.
 

A version of this article appeared on Medscape.com.

BARCELONA, SPAIN — Streptococcus pneumoniae, the bacteria that causes pneumococcal disease, is sixfold more likely to colonize adults older than 60 years who have regular contact with children than those who do not, data from a community-based study showed.

However, there is “no clear evidence of adult-to-adult transmission,” and the researchers, led by Anne L. Wyllie, PhD, from the Yale School of Public Health, New Haven, Connecticut, noted that the study results suggest “the main benefit of adult pneumococcal conjugate vaccine (PCV) immunization is to directly protect adults who are exposed to children, who still carry and transmit some vaccine-type pneumococci despite successful pediatric national immunization programs.”

The data show that relatively high pneumococcus carriage rates are seen in people who have regular contact with children, who have had contact in the previous 2 weeks, and who have had contact for extended periods, Dr. Wyllie explained.

Preschoolers in particular were found to be most likely to transmit pneumococcus to older adults. “It is the 24- to 59-month-olds who are most associated with pneumococcal carriage, more than 1- to 2-year-olds,” she reported. However, transmission rates from children younger than 1 year are higher than those from children aged 1-2 years, she added.

The findings were presented at the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) 2024 global conference, formerly known as the ECCMID conference.
 

Originally Designed to Investigate Adult-to-Adult Transmission

The researchers wanted to understand the sources and dynamics of transmission, as well as the risk factors for pneumococcal disease in older adults, to help predict the effect of PCVs in people older than 60 years.

Although “we designed the study to specifically look at transmission between adults, in the end, we were presented with a very unique scenario” — restricted social mixing as a result of the COVID pandemic — during which “no community activities were happening,” Dr. Wyllie said. Because of this, the team was able to determine “the source of acquisition or transmission to the older adults was, very likely, coming from contact with children.”

Pneumococci are commonly found in respiratory tracts of healthy people. The US Centers for Disease Control and Prevention estimated that 20%-60% of school-aged children may be colonized compared with only 5%-10% of adults without children.

The longitudinal study was conducted among household pairs, such as married couples who were both aged at least 60 years and who did not have people younger than 60 years living in the household, in New Haven over two winter seasons: 2020-2021 and 2021-2022.

Self-collected saliva samples were assessed, and surveys on social behaviors and health were completed every 2 weeks for a 10-week period (with six study visits). The saliva sampling method was used because the researchers considered it to be more effective than samples from nasopharyngeal swabs. Quantitative polymerase chain reaction assays were used to test the saliva samples for the presence of pneumococcal DNA (pneumococcus genes piaB and lytA) and the diversity of pneumococcal strains (36 serotypes were targeted).
 

Strongly Suggestive of Transmission From Children to Older Adults

Of the 121 adults living in 61 households who were enrolled in the study, 62 adults participated in both seasons. Mean age was 70.9 years (range, 60-86 years), 51% of participants were women, and 85% were White.

Overall, 52 of 1088 (4.8%) samples tested positive for pneumococcus, and 27 of 121 (22.3%) adults were colonized on at least one sampling visit. Some were colonized at multiple timepoints, and two were colonized throughout the 10-week sampling period. Of the two participants who were colonized at five of six timepoints, one reported daily contact with children younger than 5 years and children aged 5-9 years in the two study seasons. This person was also positive at three of six sampling points during the first study season.

There were five instances in which both members of the household were carriers in the same season, although not necessarily at the same timepoint. Numbers were too small to determine whether transmission had occurred between the household pairs.

Contact with a 24- to 59-month-old child (older than 2 years but younger than 5 years) had the strongest association with elevated odds of carrying pneumococcus, the authors reported in their preprint, although the frequency and intensity of contact also mattered.

At any sampled time (point prevalence), pneumococcal carriage was substantially — just over sixfold — higher among older adults who had contact with children daily or every few days (10%) than among those who had no contact with children (1.6%).

In particular, contact between adults and children younger than 5 years and children aged 5-9 years was found to lead to elevated point prevalences of 13.8% and 14.1%, respectively. Pneumococcal carriage in children older than 10 years was lower, with a point prevalence of 8.3%.

The younger the child, the greater the point prevalence; point prevalences were 13.8% for samples from children aged 1 year and younger, 10.5% for samples from children aged 1-2 years, and 17.8% for children aged 2-5 years.

Carriage prevalence was higher in older adults who reported daily contact with children (15.7%) or contact every few days (14.0%) than in those who reported contact with children only once or twice a month (4.5%) or never (1.8%), they wrote.

“Older people who have a lot of contact with kids and are more susceptible to respiratory viruses can get a secondary infection from pneumococcus, especially during the cold and flu seasons. Vaccination can help to protect them or lessen severity of the illness,” Wyllie pointed out.

However, adult PCV immunization may not have a major impact on onward transmission to other adults, the authors wrote in their preprint.

This study supports prior work demonstrating that pneumococcal colonization is greater in households with children than in those without, said Stephen Pelton, MD, a pediatric infectious disease specialist from Boston University schools of medicine and public health. “The unique aspect is that Dr. Wyllie’s group has looked at individuals over age 60 and used the most sensitive methods currently available to detect pneumococcal carriage.”

“At the most recent ISPPD [International Society of Pneumonia and Pneumococcal Diseases conference], the role of adult-to-adult transmission in the community was discussed. This study confirms the critical role children play in community transmission of the pneumococcus,” Dr. Pelton noted.

Dr. Wyllie received consulting and/or advisory board fees from Pfizer, Merck, Diasorin, PPS Health, Primary Health, Co-Diagnostics, and Global Diagnostic Systems for work unrelated to this project and is the principal investigator on research grants from Pfizer, Merck, NIH RADx-UP, and SalivaDirect, Inc. to Yale University and from NIH RADx, Balvi.io, and Shield T3 to SalivaDirect, Inc. Dr. Pelton received honoraria from Merck, Pfizer, Sanofi, and GSK for participation in Pneumococcal Advisory Boards and DSMB (Sanofi). Boston Medical Center received grant funding for investigator-initiated research from Merck and Pfizer.
 

A version of this article appeared on Medscape.com.

BARCELONA, SPAIN — Streptococcus pneumoniae, the bacteria that causes pneumococcal disease, is sixfold more likely to colonize adults older than 60 years who have regular contact with children than those who do not, data from a community-based study showed.

However, there is “no clear evidence of adult-to-adult transmission,” and the researchers, led by Anne L. Wyllie, PhD, from the Yale School of Public Health, New Haven, Connecticut, noted that the study results suggest “the main benefit of adult pneumococcal conjugate vaccine (PCV) immunization is to directly protect adults who are exposed to children, who still carry and transmit some vaccine-type pneumococci despite successful pediatric national immunization programs.”

The data show that relatively high pneumococcus carriage rates are seen in people who have regular contact with children, who have had contact in the previous 2 weeks, and who have had contact for extended periods, Dr. Wyllie explained.

Preschoolers in particular were found to be most likely to transmit pneumococcus to older adults. “It is the 24- to 59-month-olds who are most associated with pneumococcal carriage, more than 1- to 2-year-olds,” she reported. However, transmission rates from children younger than 1 year are higher than those from children aged 1-2 years, she added.

The findings were presented at the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) 2024 global conference, formerly known as the ECCMID conference.
 

Originally Designed to Investigate Adult-to-Adult Transmission

The researchers wanted to understand the sources and dynamics of transmission, as well as the risk factors for pneumococcal disease in older adults, to help predict the effect of PCVs in people older than 60 years.

Although “we designed the study to specifically look at transmission between adults, in the end, we were presented with a very unique scenario” — restricted social mixing as a result of the COVID pandemic — during which “no community activities were happening,” Dr. Wyllie said. Because of this, the team was able to determine “the source of acquisition or transmission to the older adults was, very likely, coming from contact with children.”

Pneumococci are commonly found in respiratory tracts of healthy people. The US Centers for Disease Control and Prevention estimated that 20%-60% of school-aged children may be colonized compared with only 5%-10% of adults without children.

The longitudinal study was conducted among household pairs, such as married couples who were both aged at least 60 years and who did not have people younger than 60 years living in the household, in New Haven over two winter seasons: 2020-2021 and 2021-2022.

Self-collected saliva samples were assessed, and surveys on social behaviors and health were completed every 2 weeks for a 10-week period (with six study visits). The saliva sampling method was used because the researchers considered it to be more effective than samples from nasopharyngeal swabs. Quantitative polymerase chain reaction assays were used to test the saliva samples for the presence of pneumococcal DNA (pneumococcus genes piaB and lytA) and the diversity of pneumococcal strains (36 serotypes were targeted).
 

Strongly Suggestive of Transmission From Children to Older Adults

Of the 121 adults living in 61 households who were enrolled in the study, 62 adults participated in both seasons. Mean age was 70.9 years (range, 60-86 years), 51% of participants were women, and 85% were White.

Overall, 52 of 1088 (4.8%) samples tested positive for pneumococcus, and 27 of 121 (22.3%) adults were colonized on at least one sampling visit. Some were colonized at multiple timepoints, and two were colonized throughout the 10-week sampling period. Of the two participants who were colonized at five of six timepoints, one reported daily contact with children younger than 5 years and children aged 5-9 years in the two study seasons. This person was also positive at three of six sampling points during the first study season.

There were five instances in which both members of the household were carriers in the same season, although not necessarily at the same timepoint. Numbers were too small to determine whether transmission had occurred between the household pairs.

Contact with a 24- to 59-month-old child (older than 2 years but younger than 5 years) had the strongest association with elevated odds of carrying pneumococcus, the authors reported in their preprint, although the frequency and intensity of contact also mattered.

At any sampled time (point prevalence), pneumococcal carriage was substantially — just over sixfold — higher among older adults who had contact with children daily or every few days (10%) than among those who had no contact with children (1.6%).

In particular, contact between adults and children younger than 5 years and children aged 5-9 years was found to lead to elevated point prevalences of 13.8% and 14.1%, respectively. Pneumococcal carriage in children older than 10 years was lower, with a point prevalence of 8.3%.

The younger the child, the greater the point prevalence; point prevalences were 13.8% for samples from children aged 1 year and younger, 10.5% for samples from children aged 1-2 years, and 17.8% for children aged 2-5 years.

Carriage prevalence was higher in older adults who reported daily contact with children (15.7%) or contact every few days (14.0%) than in those who reported contact with children only once or twice a month (4.5%) or never (1.8%), they wrote.

“Older people who have a lot of contact with kids and are more susceptible to respiratory viruses can get a secondary infection from pneumococcus, especially during the cold and flu seasons. Vaccination can help to protect them or lessen severity of the illness,” Wyllie pointed out.

However, adult PCV immunization may not have a major impact on onward transmission to other adults, the authors wrote in their preprint.

This study supports prior work demonstrating that pneumococcal colonization is greater in households with children than in those without, said Stephen Pelton, MD, a pediatric infectious disease specialist from Boston University schools of medicine and public health. “The unique aspect is that Dr. Wyllie’s group has looked at individuals over age 60 and used the most sensitive methods currently available to detect pneumococcal carriage.”

“At the most recent ISPPD [International Society of Pneumonia and Pneumococcal Diseases conference], the role of adult-to-adult transmission in the community was discussed. This study confirms the critical role children play in community transmission of the pneumococcus,” Dr. Pelton noted.

Dr. Wyllie received consulting and/or advisory board fees from Pfizer, Merck, Diasorin, PPS Health, Primary Health, Co-Diagnostics, and Global Diagnostic Systems for work unrelated to this project and is the principal investigator on research grants from Pfizer, Merck, NIH RADx-UP, and SalivaDirect, Inc. to Yale University and from NIH RADx, Balvi.io, and Shield T3 to SalivaDirect, Inc. Dr. Pelton received honoraria from Merck, Pfizer, Sanofi, and GSK for participation in Pneumococcal Advisory Boards and DSMB (Sanofi). Boston Medical Center received grant funding for investigator-initiated research from Merck and Pfizer.
 

A version of this article appeared on Medscape.com.

When doctors and patients consider the appendix, it’s often with urgency. In cases of appendicitis, the clock could be ticking down to a life-threatening burst. Thus, despite recent research suggesting antibiotics could be an alternative therapy, appendectomy remains standard for uncomplicated appendicitis.

But what if removing the appendix could raise the risk for gastrointestinal (GI) diseases like irritable bowel syndrome and colorectal cancer? That’s what some emerging science suggests. And though the research is early and mixed, it’s enough to give some health professionals pause.

“If there’s no reason to remove the appendix, then it’s better to have one,” said Heather Smith, PhD, a comparative anatomist at Midwestern University, Glendale, Arizona. Preemptive removal is not supported by the evidence, she said.

To be fair, we’ve come a long way since 1928, when American physician Miles Breuer, MD, suggested that people with infected appendixes should be left to perish, so as to remove their inferior DNA from the gene pool (he called such people “uncivilized” and “candidates for extinction”). Charles Darwin, while less radical, believed the appendix was at best useless — a mere vestige of our ancestors switching diets from leaves to fruits.

What we know now is that the appendix isn’t just a troublesome piece of worthless flesh. Instead, it may act as a safe house for friendly gut bacteria and a training camp for the immune system. It also appears to play a role in several medical conditions, from ulcerative colitis and colorectal cancer to Parkinson’s disease and lupus. The roughly 300,000 Americans who undergo appendectomy each year should be made aware of this, some experts say. But the frustrating truth is, scientists are still trying to figure out in which cases having an appendix is protective and in which we may be better off without it.
 

A ‘Worm’ as Intestinal Protection

The appendix is a blind pouch (meaning its ending is closed off) that extends from the large intestine. Not all mammals have one; it’s been found in several species of primates and rodents, as well as in rabbits, wombats, and Florida manatees, among others (dogs and cats don’t have it). While a human appendix “looks like a little worm,” Dr. Smith said, these anatomical structures come in various sizes and shapes. Some are thick, as in a beaver, while others are long and spiraling, like a rabbit’s.

Comparative anatomy studies reveal that the appendix has evolved independently at least 29 times throughout mammalian evolution. This suggests that “it has some kind of an adaptive function,” Dr. Smith said. When French scientists analyzed data from 258 species of mammals, they discovered that those that possess an appendix live longer than those without one. A possible explanation, the researchers wrote, may lie with the appendix’s role in preventing diarrhea.

Their 2023 study supported this hypothesis. Based on veterinary records of 45 different species of primates housed in a French zoo, the scientists established that primates with appendixes are far less likely to suffer severe diarrhea than those that don’t possess this organ. The appendix, it appears, might be our tiny weapon against bowel troubles.

For immunologist William Parker, PhD, a visiting scholar at the University of North Carolina at Chapel Hill, these data are “about as good as we could hope for” in support of the idea that the appendix might protect mammals from GI problems. An experiment on humans would be unethical, Dr. Parker said. But observational studies offer clues.

One study showed that compared with people with an intact appendix, young adults with a history of appendectomy have more than double the risk of developing a serious infection with non-typhoidal Salmonella of the kind that would require hospitalization.
 

A ‘Safe House’ for Bacteria

Such studies add weight to a theory that Dr. Parker and his colleagues developed back in 2007: That the appendix acts as a “safe house” for beneficial gut bacteria.

Think of the colon as a wide pipe, Dr. Parker said, that may become contaminated with a pathogen such as Salmonella. Diarrhea follows, and the pipe gets repeatedly flushed, wiping everything clean, including your friendly gut microbiome. Luckily, “you’ve got this little offshoot of that pipe,” where the flow can’t really get in “because it’s so constricted,” Dr. Parker said. The friendly gut microbes can survive inside the appendix and repopulate the colon once diarrhea is over. Dr. Parker and his colleagues found that the human appendix contains a thick layer of beneficial bacteria. “They were right where we predicted they would be,” he said.

This safe house hypothesis could explain why the gut microbiome may be different in people who no longer have an appendix. In one small study, people who’d had an appendectomy had a less diverse microbiome, with a lower abundance of beneficial strains such as Butyricicoccus and Barnesiella, than did those with intact appendixes.

The appendix likely has a second function, too, Dr. Smith said: It may serve as a training camp for the immune system. “When there is an invading pathogen in the gut, it helps the GI system to mount the immune response,” she said. The human appendix is rich in special cells known as M cells. These act as scouts, detecting and capturing invasive bacteria and viruses and presenting them to the body’s defense team, such as the T lymphocytes.

If the appendix shelters beneficial bacteria and boosts immune response, that may explain its links to various diseases. According to an epidemiological study from Taiwan,patients who underwent an appendectomy have a 46% higher risk of developing irritable bowel syndrome (IBS) — a disease associated with a low abundance of Butyricicoccus bacteria. This is why, the study authors wrote, doctors should pay careful attention to people who’ve had their appendixes removed, monitoring them for potential symptoms of IBS.

The same database helped uncover other connections between appendectomy and disease. For one, there was type 2 diabetes: Within 3 years of the surgery, patients under 30 had double the risk of developing this disorder. Then there was lupus: While those who underwent appendectomy generally had higher risk for this autoimmune disease, women were particularly affected.
 

The Contentious Connections

The most heated scientific discussion surrounds the links between the appendix and conditions such as Parkinson’s disease, ulcerative colitis, and colorectal cancer. A small 2019 study showed, for example, that appendectomy may improve symptoms of certain forms of ulcerative colitis that don’t respond to standard medical treatments. A third of patients improved after their appendix was removed, and 17% fully recovered.

Why? According to Dr. Parker, appendectomy may work for ulcerative colitis because it’s “a way of suppressing the immune system, especially in the lower intestinal areas.” A 2023 meta-analysis found that people who’d had their appendix removed before being diagnosed with ulcerative colitis were less likely to need their colon removed later on.

Such a procedure may have a serious side effect, however: Colorectal cancer. French scientists discovered that removing the appendix may reduce the numbers of certain immune cells called CD3+ and CD8+ T cells, causing a weakened immune surveillance. As a result, tumor cells might escape detection.

Yet the links between appendix removal and cancer are far from clear. A recent meta-analysis found that while people with appendectomies generally had a higher risk for colorectal cancer, for Europeans, these effects were insignificant. In fact, removal of the appendix actually protected European women from this particular form of cancer. For Parker, such mixed results may stem from the fact that treatments and populations vary widely. The issue “may depend on complex social and medical factors,” Dr. Parker said.

Things also appear complicated with Parkinson’s disease — another condition linked to the appendix. A large epidemiological study showed that appendectomy is associated with a lower risk for Parkinson’s disease and a delayed age of Parkinson’s onset. It also found that a normal appendix contains α-synuclein, a protein that may accumulate in the brain and contribute to the development of Parkinson’s. “Although α-synuclein is toxic when in the brain, it appears to be quite normal when present in the appendix,” said Luis Vitetta, PhD, MD, a clinical epidemiologist at the University of Sydney, Camperdown, Australia. Yet, not all studies find that removing the appendix lowers the risk for Parkinson’s. In fact, some show the opposite results.
 

How Should Doctors View the Appendix?

Even with these mysteries and contradictions, Dr. Vitetta said, a healthy appendix in a healthy body appears to be protective. This is why, he said, when someone is diagnosed with appendicitis, careful assessment is essential before surgery is performed.

“Perhaps an antibiotic can actually help fix it,” he said. A 2020 study published in The New England Journal of Medicine showed that antibiotics may indeed be a good alternative to surgery for the treatment of appendicitis. “We don’t want necessarily to remove an appendix that could be beneficial,” Dr. Smith said.

The many links between the appendix and various diseases mean that doctors should be more vigilant when treating patients who’ve had this organ removed, Dr. Parker said. “When a patient loses an appendix, depending on their environment, there may be effects on infection and cancer. So they might need more regular checkups,” he said. This could include monitoring for IBS and colorectal cancer.

What’s more, Dr. Parker believes that research on the appendix puts even more emphasis on the need to protect the gut microbiome — such as taking probiotics with antibiotics. And while we are still a long way from understanding how exactly this worm-like structure affects various diseases, one thing appears quite certain: The appendix is not useless. “If Darwin had the information that we have, he would not have drawn these conclusions,” Dr. Parker said.
 

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

When doctors and patients consider the appendix, it’s often with urgency. In cases of appendicitis, the clock could be ticking down to a life-threatening burst. Thus, despite recent research suggesting antibiotics could be an alternative therapy, appendectomy remains standard for uncomplicated appendicitis.

But what if removing the appendix could raise the risk for gastrointestinal (GI) diseases like irritable bowel syndrome and colorectal cancer? That’s what some emerging science suggests. And though the research is early and mixed, it’s enough to give some health professionals pause.

“If there’s no reason to remove the appendix, then it’s better to have one,” said Heather Smith, PhD, a comparative anatomist at Midwestern University, Glendale, Arizona. Preemptive removal is not supported by the evidence, she said.

To be fair, we’ve come a long way since 1928, when American physician Miles Breuer, MD, suggested that people with infected appendixes should be left to perish, so as to remove their inferior DNA from the gene pool (he called such people “uncivilized” and “candidates for extinction”). Charles Darwin, while less radical, believed the appendix was at best useless — a mere vestige of our ancestors switching diets from leaves to fruits.

What we know now is that the appendix isn’t just a troublesome piece of worthless flesh. Instead, it may act as a safe house for friendly gut bacteria and a training camp for the immune system. It also appears to play a role in several medical conditions, from ulcerative colitis and colorectal cancer to Parkinson’s disease and lupus. The roughly 300,000 Americans who undergo appendectomy each year should be made aware of this, some experts say. But the frustrating truth is, scientists are still trying to figure out in which cases having an appendix is protective and in which we may be better off without it.
 

A ‘Worm’ as Intestinal Protection

The appendix is a blind pouch (meaning its ending is closed off) that extends from the large intestine. Not all mammals have one; it’s been found in several species of primates and rodents, as well as in rabbits, wombats, and Florida manatees, among others (dogs and cats don’t have it). While a human appendix “looks like a little worm,” Dr. Smith said, these anatomical structures come in various sizes and shapes. Some are thick, as in a beaver, while others are long and spiraling, like a rabbit’s.

Comparative anatomy studies reveal that the appendix has evolved independently at least 29 times throughout mammalian evolution. This suggests that “it has some kind of an adaptive function,” Dr. Smith said. When French scientists analyzed data from 258 species of mammals, they discovered that those that possess an appendix live longer than those without one. A possible explanation, the researchers wrote, may lie with the appendix’s role in preventing diarrhea.

Their 2023 study supported this hypothesis. Based on veterinary records of 45 different species of primates housed in a French zoo, the scientists established that primates with appendixes are far less likely to suffer severe diarrhea than those that don’t possess this organ. The appendix, it appears, might be our tiny weapon against bowel troubles.

For immunologist William Parker, PhD, a visiting scholar at the University of North Carolina at Chapel Hill, these data are “about as good as we could hope for” in support of the idea that the appendix might protect mammals from GI problems. An experiment on humans would be unethical, Dr. Parker said. But observational studies offer clues.

One study showed that compared with people with an intact appendix, young adults with a history of appendectomy have more than double the risk of developing a serious infection with non-typhoidal Salmonella of the kind that would require hospitalization.
 

A ‘Safe House’ for Bacteria

Such studies add weight to a theory that Dr. Parker and his colleagues developed back in 2007: That the appendix acts as a “safe house” for beneficial gut bacteria.

Think of the colon as a wide pipe, Dr. Parker said, that may become contaminated with a pathogen such as Salmonella. Diarrhea follows, and the pipe gets repeatedly flushed, wiping everything clean, including your friendly gut microbiome. Luckily, “you’ve got this little offshoot of that pipe,” where the flow can’t really get in “because it’s so constricted,” Dr. Parker said. The friendly gut microbes can survive inside the appendix and repopulate the colon once diarrhea is over. Dr. Parker and his colleagues found that the human appendix contains a thick layer of beneficial bacteria. “They were right where we predicted they would be,” he said.

This safe house hypothesis could explain why the gut microbiome may be different in people who no longer have an appendix. In one small study, people who’d had an appendectomy had a less diverse microbiome, with a lower abundance of beneficial strains such as Butyricicoccus and Barnesiella, than did those with intact appendixes.

The appendix likely has a second function, too, Dr. Smith said: It may serve as a training camp for the immune system. “When there is an invading pathogen in the gut, it helps the GI system to mount the immune response,” she said. The human appendix is rich in special cells known as M cells. These act as scouts, detecting and capturing invasive bacteria and viruses and presenting them to the body’s defense team, such as the T lymphocytes.

If the appendix shelters beneficial bacteria and boosts immune response, that may explain its links to various diseases. According to an epidemiological study from Taiwan,patients who underwent an appendectomy have a 46% higher risk of developing irritable bowel syndrome (IBS) — a disease associated with a low abundance of Butyricicoccus bacteria. This is why, the study authors wrote, doctors should pay careful attention to people who’ve had their appendixes removed, monitoring them for potential symptoms of IBS.

The same database helped uncover other connections between appendectomy and disease. For one, there was type 2 diabetes: Within 3 years of the surgery, patients under 30 had double the risk of developing this disorder. Then there was lupus: While those who underwent appendectomy generally had higher risk for this autoimmune disease, women were particularly affected.
 

The Contentious Connections

The most heated scientific discussion surrounds the links between the appendix and conditions such as Parkinson’s disease, ulcerative colitis, and colorectal cancer. A small 2019 study showed, for example, that appendectomy may improve symptoms of certain forms of ulcerative colitis that don’t respond to standard medical treatments. A third of patients improved after their appendix was removed, and 17% fully recovered.

Why? According to Dr. Parker, appendectomy may work for ulcerative colitis because it’s “a way of suppressing the immune system, especially in the lower intestinal areas.” A 2023 meta-analysis found that people who’d had their appendix removed before being diagnosed with ulcerative colitis were less likely to need their colon removed later on.

Such a procedure may have a serious side effect, however: Colorectal cancer. French scientists discovered that removing the appendix may reduce the numbers of certain immune cells called CD3+ and CD8+ T cells, causing a weakened immune surveillance. As a result, tumor cells might escape detection.

Yet the links between appendix removal and cancer are far from clear. A recent meta-analysis found that while people with appendectomies generally had a higher risk for colorectal cancer, for Europeans, these effects were insignificant. In fact, removal of the appendix actually protected European women from this particular form of cancer. For Parker, such mixed results may stem from the fact that treatments and populations vary widely. The issue “may depend on complex social and medical factors,” Dr. Parker said.

Things also appear complicated with Parkinson’s disease — another condition linked to the appendix. A large epidemiological study showed that appendectomy is associated with a lower risk for Parkinson’s disease and a delayed age of Parkinson’s onset. It also found that a normal appendix contains α-synuclein, a protein that may accumulate in the brain and contribute to the development of Parkinson’s. “Although α-synuclein is toxic when in the brain, it appears to be quite normal when present in the appendix,” said Luis Vitetta, PhD, MD, a clinical epidemiologist at the University of Sydney, Camperdown, Australia. Yet, not all studies find that removing the appendix lowers the risk for Parkinson’s. In fact, some show the opposite results.
 

How Should Doctors View the Appendix?

Even with these mysteries and contradictions, Dr. Vitetta said, a healthy appendix in a healthy body appears to be protective. This is why, he said, when someone is diagnosed with appendicitis, careful assessment is essential before surgery is performed.

“Perhaps an antibiotic can actually help fix it,” he said. A 2020 study published in The New England Journal of Medicine showed that antibiotics may indeed be a good alternative to surgery for the treatment of appendicitis. “We don’t want necessarily to remove an appendix that could be beneficial,” Dr. Smith said.

The many links between the appendix and various diseases mean that doctors should be more vigilant when treating patients who’ve had this organ removed, Dr. Parker said. “When a patient loses an appendix, depending on their environment, there may be effects on infection and cancer. So they might need more regular checkups,” he said. This could include monitoring for IBS and colorectal cancer.

What’s more, Dr. Parker believes that research on the appendix puts even more emphasis on the need to protect the gut microbiome — such as taking probiotics with antibiotics. And while we are still a long way from understanding how exactly this worm-like structure affects various diseases, one thing appears quite certain: The appendix is not useless. “If Darwin had the information that we have, he would not have drawn these conclusions,” Dr. Parker said.
 

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

When doctors and patients consider the appendix, it’s often with urgency. In cases of appendicitis, the clock could be ticking down to a life-threatening burst. Thus, despite recent research suggesting antibiotics could be an alternative therapy, appendectomy remains standard for uncomplicated appendicitis.

But what if removing the appendix could raise the risk for gastrointestinal (GI) diseases like irritable bowel syndrome and colorectal cancer? That’s what some emerging science suggests. And though the research is early and mixed, it’s enough to give some health professionals pause.

“If there’s no reason to remove the appendix, then it’s better to have one,” said Heather Smith, PhD, a comparative anatomist at Midwestern University, Glendale, Arizona. Preemptive removal is not supported by the evidence, she said.

To be fair, we’ve come a long way since 1928, when American physician Miles Breuer, MD, suggested that people with infected appendixes should be left to perish, so as to remove their inferior DNA from the gene pool (he called such people “uncivilized” and “candidates for extinction”). Charles Darwin, while less radical, believed the appendix was at best useless — a mere vestige of our ancestors switching diets from leaves to fruits.

What we know now is that the appendix isn’t just a troublesome piece of worthless flesh. Instead, it may act as a safe house for friendly gut bacteria and a training camp for the immune system. It also appears to play a role in several medical conditions, from ulcerative colitis and colorectal cancer to Parkinson’s disease and lupus. The roughly 300,000 Americans who undergo appendectomy each year should be made aware of this, some experts say. But the frustrating truth is, scientists are still trying to figure out in which cases having an appendix is protective and in which we may be better off without it.
 

A ‘Worm’ as Intestinal Protection

The appendix is a blind pouch (meaning its ending is closed off) that extends from the large intestine. Not all mammals have one; it’s been found in several species of primates and rodents, as well as in rabbits, wombats, and Florida manatees, among others (dogs and cats don’t have it). While a human appendix “looks like a little worm,” Dr. Smith said, these anatomical structures come in various sizes and shapes. Some are thick, as in a beaver, while others are long and spiraling, like a rabbit’s.

Comparative anatomy studies reveal that the appendix has evolved independently at least 29 times throughout mammalian evolution. This suggests that “it has some kind of an adaptive function,” Dr. Smith said. When French scientists analyzed data from 258 species of mammals, they discovered that those that possess an appendix live longer than those without one. A possible explanation, the researchers wrote, may lie with the appendix’s role in preventing diarrhea.

Their 2023 study supported this hypothesis. Based on veterinary records of 45 different species of primates housed in a French zoo, the scientists established that primates with appendixes are far less likely to suffer severe diarrhea than those that don’t possess this organ. The appendix, it appears, might be our tiny weapon against bowel troubles.

For immunologist William Parker, PhD, a visiting scholar at the University of North Carolina at Chapel Hill, these data are “about as good as we could hope for” in support of the idea that the appendix might protect mammals from GI problems. An experiment on humans would be unethical, Dr. Parker said. But observational studies offer clues.

One study showed that compared with people with an intact appendix, young adults with a history of appendectomy have more than double the risk of developing a serious infection with non-typhoidal Salmonella of the kind that would require hospitalization.
 

A ‘Safe House’ for Bacteria

Such studies add weight to a theory that Dr. Parker and his colleagues developed back in 2007: That the appendix acts as a “safe house” for beneficial gut bacteria.

Think of the colon as a wide pipe, Dr. Parker said, that may become contaminated with a pathogen such as Salmonella. Diarrhea follows, and the pipe gets repeatedly flushed, wiping everything clean, including your friendly gut microbiome. Luckily, “you’ve got this little offshoot of that pipe,” where the flow can’t really get in “because it’s so constricted,” Dr. Parker said. The friendly gut microbes can survive inside the appendix and repopulate the colon once diarrhea is over. Dr. Parker and his colleagues found that the human appendix contains a thick layer of beneficial bacteria. “They were right where we predicted they would be,” he said.

This safe house hypothesis could explain why the gut microbiome may be different in people who no longer have an appendix. In one small study, people who’d had an appendectomy had a less diverse microbiome, with a lower abundance of beneficial strains such as Butyricicoccus and Barnesiella, than did those with intact appendixes.

The appendix likely has a second function, too, Dr. Smith said: It may serve as a training camp for the immune system. “When there is an invading pathogen in the gut, it helps the GI system to mount the immune response,” she said. The human appendix is rich in special cells known as M cells. These act as scouts, detecting and capturing invasive bacteria and viruses and presenting them to the body’s defense team, such as the T lymphocytes.

If the appendix shelters beneficial bacteria and boosts immune response, that may explain its links to various diseases. According to an epidemiological study from Taiwan,patients who underwent an appendectomy have a 46% higher risk of developing irritable bowel syndrome (IBS) — a disease associated with a low abundance of Butyricicoccus bacteria. This is why, the study authors wrote, doctors should pay careful attention to people who’ve had their appendixes removed, monitoring them for potential symptoms of IBS.

The same database helped uncover other connections between appendectomy and disease. For one, there was type 2 diabetes: Within 3 years of the surgery, patients under 30 had double the risk of developing this disorder. Then there was lupus: While those who underwent appendectomy generally had higher risk for this autoimmune disease, women were particularly affected.
 

The Contentious Connections

The most heated scientific discussion surrounds the links between the appendix and conditions such as Parkinson’s disease, ulcerative colitis, and colorectal cancer. A small 2019 study showed, for example, that appendectomy may improve symptoms of certain forms of ulcerative colitis that don’t respond to standard medical treatments. A third of patients improved after their appendix was removed, and 17% fully recovered.

Why? According to Dr. Parker, appendectomy may work for ulcerative colitis because it’s “a way of suppressing the immune system, especially in the lower intestinal areas.” A 2023 meta-analysis found that people who’d had their appendix removed before being diagnosed with ulcerative colitis were less likely to need their colon removed later on.

Such a procedure may have a serious side effect, however: Colorectal cancer. French scientists discovered that removing the appendix may reduce the numbers of certain immune cells called CD3+ and CD8+ T cells, causing a weakened immune surveillance. As a result, tumor cells might escape detection.

Yet the links between appendix removal and cancer are far from clear. A recent meta-analysis found that while people with appendectomies generally had a higher risk for colorectal cancer, for Europeans, these effects were insignificant. In fact, removal of the appendix actually protected European women from this particular form of cancer. For Parker, such mixed results may stem from the fact that treatments and populations vary widely. The issue “may depend on complex social and medical factors,” Dr. Parker said.

Things also appear complicated with Parkinson’s disease — another condition linked to the appendix. A large epidemiological study showed that appendectomy is associated with a lower risk for Parkinson’s disease and a delayed age of Parkinson’s onset. It also found that a normal appendix contains α-synuclein, a protein that may accumulate in the brain and contribute to the development of Parkinson’s. “Although α-synuclein is toxic when in the brain, it appears to be quite normal when present in the appendix,” said Luis Vitetta, PhD, MD, a clinical epidemiologist at the University of Sydney, Camperdown, Australia. Yet, not all studies find that removing the appendix lowers the risk for Parkinson’s. In fact, some show the opposite results.
 

How Should Doctors View the Appendix?

Even with these mysteries and contradictions, Dr. Vitetta said, a healthy appendix in a healthy body appears to be protective. This is why, he said, when someone is diagnosed with appendicitis, careful assessment is essential before surgery is performed.

“Perhaps an antibiotic can actually help fix it,” he said. A 2020 study published in The New England Journal of Medicine showed that antibiotics may indeed be a good alternative to surgery for the treatment of appendicitis. “We don’t want necessarily to remove an appendix that could be beneficial,” Dr. Smith said.

The many links between the appendix and various diseases mean that doctors should be more vigilant when treating patients who’ve had this organ removed, Dr. Parker said. “When a patient loses an appendix, depending on their environment, there may be effects on infection and cancer. So they might need more regular checkups,” he said. This could include monitoring for IBS and colorectal cancer.

What’s more, Dr. Parker believes that research on the appendix puts even more emphasis on the need to protect the gut microbiome — such as taking probiotics with antibiotics. And while we are still a long way from understanding how exactly this worm-like structure affects various diseases, one thing appears quite certain: The appendix is not useless. “If Darwin had the information that we have, he would not have drawn these conclusions,” Dr. Parker said.
 

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.

The US Food and Drug Administration (FDA) approved mRESVIA (mRNA-1345, Moderna), a vaccine for respiratory syncytial virus (RSV).

The mRNA vaccine is approved for adults aged 60 years or older to prevent lower respiratory tract disease caused by RSV. It is the third vaccine to be approved for RSV in the past year after Arexvy from GSK and Abrysvo by Pfizer.

“The FDA approval of our second product, mRESVIA, builds on the strength and versatility of our mRNA platform,” Stéphane Bancel, chief executive officer of Moderna, said in a news release. “mRESVIA protects older adults from the severe outcomes of RSV infection. This approval is also the first time an mRNA vaccine has been approved for a disease other than COVID-19.”

mRESVIA is a single-dose vaccine available in prefilled syringes, which the company says are designed to maximize ease of administration, saving vaccinators’ time, and reducing the risk for administrative errors.

The approval is based on the positive results from the phase 3 ConquerRSV clinical trial, published in The New England Journal of Medicine in December 2023. The study, conducted in approximately 37,000 adults aged 60 years or older in 22 countries, found a vaccine efficacy against RSV lower respiratory tract disease of 83.7% after a median 3.7 months of follow-up.

An additional longer-term analysis showed continued protection over 8.6 months median follow-up. No serious safety concerns were identified. The most reported adverse reactions were injection site pain, fatigue, headache, myalgia, and arthralgia.

Moderna has also filed for approval in multiple markets around the world, and says it expects mRESVIA to be available in the United States in time for the 2024-2025 respiratory virus season.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) approved mRESVIA (mRNA-1345, Moderna), a vaccine for respiratory syncytial virus (RSV).

The mRNA vaccine is approved for adults aged 60 years or older to prevent lower respiratory tract disease caused by RSV. It is the third vaccine to be approved for RSV in the past year after Arexvy from GSK and Abrysvo by Pfizer.

“The FDA approval of our second product, mRESVIA, builds on the strength and versatility of our mRNA platform,” Stéphane Bancel, chief executive officer of Moderna, said in a news release. “mRESVIA protects older adults from the severe outcomes of RSV infection. This approval is also the first time an mRNA vaccine has been approved for a disease other than COVID-19.”

mRESVIA is a single-dose vaccine available in prefilled syringes, which the company says are designed to maximize ease of administration, saving vaccinators’ time, and reducing the risk for administrative errors.

The approval is based on the positive results from the phase 3 ConquerRSV clinical trial, published in The New England Journal of Medicine in December 2023. The study, conducted in approximately 37,000 adults aged 60 years or older in 22 countries, found a vaccine efficacy against RSV lower respiratory tract disease of 83.7% after a median 3.7 months of follow-up.

An additional longer-term analysis showed continued protection over 8.6 months median follow-up. No serious safety concerns were identified. The most reported adverse reactions were injection site pain, fatigue, headache, myalgia, and arthralgia.

Moderna has also filed for approval in multiple markets around the world, and says it expects mRESVIA to be available in the United States in time for the 2024-2025 respiratory virus season.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) approved mRESVIA (mRNA-1345, Moderna), a vaccine for respiratory syncytial virus (RSV).

The mRNA vaccine is approved for adults aged 60 years or older to prevent lower respiratory tract disease caused by RSV. It is the third vaccine to be approved for RSV in the past year after Arexvy from GSK and Abrysvo by Pfizer.

“The FDA approval of our second product, mRESVIA, builds on the strength and versatility of our mRNA platform,” Stéphane Bancel, chief executive officer of Moderna, said in a news release. “mRESVIA protects older adults from the severe outcomes of RSV infection. This approval is also the first time an mRNA vaccine has been approved for a disease other than COVID-19.”

mRESVIA is a single-dose vaccine available in prefilled syringes, which the company says are designed to maximize ease of administration, saving vaccinators’ time, and reducing the risk for administrative errors.

The approval is based on the positive results from the phase 3 ConquerRSV clinical trial, published in The New England Journal of Medicine in December 2023. The study, conducted in approximately 37,000 adults aged 60 years or older in 22 countries, found a vaccine efficacy against RSV lower respiratory tract disease of 83.7% after a median 3.7 months of follow-up.

An additional longer-term analysis showed continued protection over 8.6 months median follow-up. No serious safety concerns were identified. The most reported adverse reactions were injection site pain, fatigue, headache, myalgia, and arthralgia.

Moderna has also filed for approval in multiple markets around the world, and says it expects mRESVIA to be available in the United States in time for the 2024-2025 respiratory virus season.

A version of this article appeared on Medscape.com.

Many adults are complacent about vaccinations, believing that annual COVID and flu shots aside, they had all the immunizations they need as children and teens. But adults need vaccines as well, especially if they have missed earlier doses. And older and health-compromised adults, in particular, can benefit from newer vaccines that were not part of the childhood schedule.

“The question is whether adults had the vaccinations they need in the first place,” Sandra Adamson Fryhofer, MD, an internist in Atlanta and the American Medical Association’s liaison to the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention, said in an interview. “Many do not even have reliable records of vaccination.”

Mary Jane Starke

Primary care physicians are ideally positioned to get adult patients to update their vaccination status on older vaccines and obtain newer ones as needed. “ACIP recommendations for adult vaccines are getting longer and more complicated and the way they’re administered is more complex, too, in that they’re not all given in the primary care office but sometimes in pharmacies,” Dr. Fryhofer said.

Not all adult patients want to update their vaccinations. “Vaccine hesitancy among many adults is accelerated by the several new vaccines that have been recommended in recent years,” Lauren Block, MD, MPH, an internist at Northwell Health and assistant professor in the Institute of Health System Science at the Feinstein Institutes for Medical Research in metropolitan New York City, said in an interview.

Physicians are rightly concerned about the lagging rates of adult vaccination, Dr. Block said. “Given the prevalence of conditions like pneumonia and shingles and the morbidity associated with them, healthcare providers should take every opportunity to discuss vaccination with patients, from well visits to hospital visits,” Dr. Block added. 

Feinstein Institute for Medical Research

She pointed to several obstacles to broader uptake, including product shortages, financial barriers, and, increasingly, the negative vocal messaging from media outlets and social media.
 

Current Recommendations

The main vaccines recommended for adults, besides flu and COVID shots, are for respiratory syncytial virus (RVS); shingles; pneumococcal disease; measles, mumps, and rubella (MMR); and tetanus, diphtheria, and pertussis (Tdap). Less commonly, booster vaccines for MM, and hepatitis are recommended when titers are proven to be low.

ACIP’s updated 2024 Adult Immunization Schedule can be downloaded from the website of the CDC.

The newest additions to the schedule include RSV vaccines, the mpox vaccine (Jynneos), a new MenACWY-MenB combo vaccine (Penbraya), and the new 2023-2024 formulation of updated COVID vaccines (both mRNA and protein-based adjuvanted versions).
 

1. Respiratory Syncytial Virus Vaccines

There are two licensed RSV vaccines, Arexvy and Abrysvo. The CDC schedule recommends a single-dose RSV vaccine for adults age 60 years and older, especially those at high risk of contracting the virus — but after shared decision-making based on a discussion of the risk-harm balance since this vaccine carries a small increased chance of developing the neurological symptoms of Guillain-Barré syndrome.

Chronic health conditions associated with a higher risk of severe RVS include cardiopulmonary disease, diabetes, and kidney, liver, and hematologic disorders, as well as compromised immunity, older age, and frailty.
 

2. Shingles Vaccines

This painful disease carries the potential complication of postherpetic neuralgia (PHN), which leads to long-term nerve pain in 10%-18% of patients, especially those over age 40. ACIP recommends two doses of the recombinant zoster vaccine (Shingrix) for individuals 50 years and older. Those 19 years and older with weakened immune systems due to disease or medical treatments should get two doses of the recombinant vaccine, as they have a higher risk of getting shingles and its complications, including neurological problems and skin and eye infections.

3 Pneumococcal Vaccines

There are three approved pneumococcal vaccines: PCV15 (Vaxneuvance), PCV20 (Prevnar20), and PPSV23 (Pneumovax23).

“The pneumococcal vaccine schedule is the most complicated one as higher-valent products continue to become available,” Dr. Fryhofer said.

The two types are pneumococcal conjugate vaccines (PCVs, specifically PCV15 and PCV20) and the pneumococcal polysaccharide vaccine (PPSV23). “While PPSV23 covers 23 strains, it doesn’t give the long-term immunity of the conjugate vaccine,” said Dr. Fryhofer. “A patient may have completed their vaccination with the polysaccharide vaccine but 5 years out may no longer be protected. So we offer the option of getting a dose of PCV20 to round out the protection and confer greater immune memory.”

The ACIP schedule recommends immunization against the Streptococcus pneumoniae pathogen for all older and all at-risk adults. Routine administration of PCV15 or PCV20 is advised for those 65 years or older who have never received any pneumococcal conjugate vaccine or whose previous vaccination history is unknown. If PCV15 is used, it should be followed by PPSV23. Those 65 years or older should get PPSV23 even if they already had one or more doses of pneumococcal vaccine before turning 65.

Further vaccination is recommended for younger at-risk adults aged 19-64 years who have received both PCV13 and PPSV23 but have incomplete vaccination status. These individuals are advised to complete their pneumococcal series by receiving either a single dose of PCV20 at an interval of at least 5 years after the last pneumococcal vaccine dose or more than one dose of PPSV23.

See Pneumococcal Vaccination: Summary of Who and When to Vaccinate for CDC guidance on vaccination options for adults who have previously received a pneumococcal conjugate vaccine. Or, to sort out quickly who gets what and when based on their age, concurrent conditions, and vaccination history, the CDC offers a type-in app called the PneumoRecs VaxAdvisor.
 

4. Measles, Mumps, and Rubella, and Varicella Vaccines

The two approved MMR vaccines are M-M-R II and PRIORIX. A third vaccine, ProQuad, adds varicella.

Adults lacking presumptive evidence of immunity should get at least one dose of the MMR combination vaccine.

Those born before 1957 are deemed to be immune, Dr. Fryhofer noted.

Two doses are recommended for adults entering high-risk settings for measles or mumps transmission such as healthcare personnel, students away at college, and international travelers. The two doses should be separated by at least 28 days. It’s no secret that measles, though preventable, is making a comeback, with 146 reported cases (48 in adults) across 21 states as of May 31 — most linked to international travel.

Women who plan to get pregnant should be vaccinated before but not during each pregnancy. (The vaccine is safe during lactation.) And those of childbearing age with no presumptive evidence of immunity are advised to get at least one dose of the MMR vaccine.
 

5. Tetanus, Diphtheria, and Pertussis Vaccine

Adults with no previous Tdap vaccination should receive a single dose of Adacel or Boostrix followed by a booster every 10 years. Boostrix is recommended for adults over 64 years.

During every pregnancy, women should have a single dose of Tdap, preferably in gestational weeks 27 through 36.

As to the immediate postpartum period, Tdap is recommended only for mothers who did not receive it during their current pregnancy and never received a prior dose. If a woman did not receive Tdap during her current pregnancy but did receive a prior dose of Tdap, she does not need Tdap postpartum.
 

The Challenges

According to Dr. Fryhofer, widespread disinformation about the risks of immunization against vaccine-preventable diseases has brought us to a flashpoint. “It’s now more important than ever to keep telling patients that vaccination is one of the most effective tools for preventing individual illness and protecting public health.”

She recommends that doctors follow the National Institutes of Health’s AIMS method to broach the subject of adult vaccination and increase participation in an inquiring, reassuring, and low-pressure way. Standing for Announce, Inquire, Mirror, and Secure, AIMS structures a nonjudgmental, patient-friendly conversation around immunization to elicit and acknowledge the reasons for hesitancy while explaining the safety and efficacy of vaccines.

Dr. Fryhofer frequently uses AIMS to bring inoculation-averse patients around. “Keep the conversation open with reluctant patients but leave them where they are. They need to see you as a reliable source and nonjudgmental source of information,” she said.

Dr. Block recommends outlining the diseases that have been eliminated through vaccines, from polio to measles, as well as the dangers of vaccine refusal, as indicated by recent outbreaks of vaccine-preventable diseases in areas with low immunization rates. “This approach highlights the opportunity we all have to get vaccinated to protect ourselves and our communities,”  she said.

In Dr. Fryhofer’s view, the situation is urgent and doctors need to be proactive. “We’re now at a public-health tipping point where we may see a sliding back and a reversing of many years of progress.”

Dr. Fryhofer and Dr. Block disclosed no competing interests relevant to their comments.

Many adults are complacent about vaccinations, believing that annual COVID and flu shots aside, they had all the immunizations they need as children and teens. But adults need vaccines as well, especially if they have missed earlier doses. And older and health-compromised adults, in particular, can benefit from newer vaccines that were not part of the childhood schedule.

“The question is whether adults had the vaccinations they need in the first place,” Sandra Adamson Fryhofer, MD, an internist in Atlanta and the American Medical Association’s liaison to the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention, said in an interview. “Many do not even have reliable records of vaccination.”

Mary Jane Starke

Primary care physicians are ideally positioned to get adult patients to update their vaccination status on older vaccines and obtain newer ones as needed. “ACIP recommendations for adult vaccines are getting longer and more complicated and the way they’re administered is more complex, too, in that they’re not all given in the primary care office but sometimes in pharmacies,” Dr. Fryhofer said.

Not all adult patients want to update their vaccinations. “Vaccine hesitancy among many adults is accelerated by the several new vaccines that have been recommended in recent years,” Lauren Block, MD, MPH, an internist at Northwell Health and assistant professor in the Institute of Health System Science at the Feinstein Institutes for Medical Research in metropolitan New York City, said in an interview.

Physicians are rightly concerned about the lagging rates of adult vaccination, Dr. Block said. “Given the prevalence of conditions like pneumonia and shingles and the morbidity associated with them, healthcare providers should take every opportunity to discuss vaccination with patients, from well visits to hospital visits,” Dr. Block added. 

Feinstein Institute for Medical Research

She pointed to several obstacles to broader uptake, including product shortages, financial barriers, and, increasingly, the negative vocal messaging from media outlets and social media.
 

Current Recommendations

The main vaccines recommended for adults, besides flu and COVID shots, are for respiratory syncytial virus (RVS); shingles; pneumococcal disease; measles, mumps, and rubella (MMR); and tetanus, diphtheria, and pertussis (Tdap). Less commonly, booster vaccines for MM, and hepatitis are recommended when titers are proven to be low.

ACIP’s updated 2024 Adult Immunization Schedule can be downloaded from the website of the CDC.

The newest additions to the schedule include RSV vaccines, the mpox vaccine (Jynneos), a new MenACWY-MenB combo vaccine (Penbraya), and the new 2023-2024 formulation of updated COVID vaccines (both mRNA and protein-based adjuvanted versions).
 

1. Respiratory Syncytial Virus Vaccines

There are two licensed RSV vaccines, Arexvy and Abrysvo. The CDC schedule recommends a single-dose RSV vaccine for adults age 60 years and older, especially those at high risk of contracting the virus — but after shared decision-making based on a discussion of the risk-harm balance since this vaccine carries a small increased chance of developing the neurological symptoms of Guillain-Barré syndrome.

Chronic health conditions associated with a higher risk of severe RVS include cardiopulmonary disease, diabetes, and kidney, liver, and hematologic disorders, as well as compromised immunity, older age, and frailty.
 

2. Shingles Vaccines

This painful disease carries the potential complication of postherpetic neuralgia (PHN), which leads to long-term nerve pain in 10%-18% of patients, especially those over age 40. ACIP recommends two doses of the recombinant zoster vaccine (Shingrix) for individuals 50 years and older. Those 19 years and older with weakened immune systems due to disease or medical treatments should get two doses of the recombinant vaccine, as they have a higher risk of getting shingles and its complications, including neurological problems and skin and eye infections.

3 Pneumococcal Vaccines

There are three approved pneumococcal vaccines: PCV15 (Vaxneuvance), PCV20 (Prevnar20), and PPSV23 (Pneumovax23).

“The pneumococcal vaccine schedule is the most complicated one as higher-valent products continue to become available,” Dr. Fryhofer said.

The two types are pneumococcal conjugate vaccines (PCVs, specifically PCV15 and PCV20) and the pneumococcal polysaccharide vaccine (PPSV23). “While PPSV23 covers 23 strains, it doesn’t give the long-term immunity of the conjugate vaccine,” said Dr. Fryhofer. “A patient may have completed their vaccination with the polysaccharide vaccine but 5 years out may no longer be protected. So we offer the option of getting a dose of PCV20 to round out the protection and confer greater immune memory.”

The ACIP schedule recommends immunization against the Streptococcus pneumoniae pathogen for all older and all at-risk adults. Routine administration of PCV15 or PCV20 is advised for those 65 years or older who have never received any pneumococcal conjugate vaccine or whose previous vaccination history is unknown. If PCV15 is used, it should be followed by PPSV23. Those 65 years or older should get PPSV23 even if they already had one or more doses of pneumococcal vaccine before turning 65.

Further vaccination is recommended for younger at-risk adults aged 19-64 years who have received both PCV13 and PPSV23 but have incomplete vaccination status. These individuals are advised to complete their pneumococcal series by receiving either a single dose of PCV20 at an interval of at least 5 years after the last pneumococcal vaccine dose or more than one dose of PPSV23.

See Pneumococcal Vaccination: Summary of Who and When to Vaccinate for CDC guidance on vaccination options for adults who have previously received a pneumococcal conjugate vaccine. Or, to sort out quickly who gets what and when based on their age, concurrent conditions, and vaccination history, the CDC offers a type-in app called the PneumoRecs VaxAdvisor.
 

4. Measles, Mumps, and Rubella, and Varicella Vaccines

The two approved MMR vaccines are M-M-R II and PRIORIX. A third vaccine, ProQuad, adds varicella.

Adults lacking presumptive evidence of immunity should get at least one dose of the MMR combination vaccine.

Those born before 1957 are deemed to be immune, Dr. Fryhofer noted.

Two doses are recommended for adults entering high-risk settings for measles or mumps transmission such as healthcare personnel, students away at college, and international travelers. The two doses should be separated by at least 28 days. It’s no secret that measles, though preventable, is making a comeback, with 146 reported cases (48 in adults) across 21 states as of May 31 — most linked to international travel.

Women who plan to get pregnant should be vaccinated before but not during each pregnancy. (The vaccine is safe during lactation.) And those of childbearing age with no presumptive evidence of immunity are advised to get at least one dose of the MMR vaccine.
 

5. Tetanus, Diphtheria, and Pertussis Vaccine

Adults with no previous Tdap vaccination should receive a single dose of Adacel or Boostrix followed by a booster every 10 years. Boostrix is recommended for adults over 64 years.

During every pregnancy, women should have a single dose of Tdap, preferably in gestational weeks 27 through 36.

As to the immediate postpartum period, Tdap is recommended only for mothers who did not receive it during their current pregnancy and never received a prior dose. If a woman did not receive Tdap during her current pregnancy but did receive a prior dose of Tdap, she does not need Tdap postpartum.
 

The Challenges

According to Dr. Fryhofer, widespread disinformation about the risks of immunization against vaccine-preventable diseases has brought us to a flashpoint. “It’s now more important than ever to keep telling patients that vaccination is one of the most effective tools for preventing individual illness and protecting public health.”

She recommends that doctors follow the National Institutes of Health’s AIMS method to broach the subject of adult vaccination and increase participation in an inquiring, reassuring, and low-pressure way. Standing for Announce, Inquire, Mirror, and Secure, AIMS structures a nonjudgmental, patient-friendly conversation around immunization to elicit and acknowledge the reasons for hesitancy while explaining the safety and efficacy of vaccines.

Dr. Fryhofer frequently uses AIMS to bring inoculation-averse patients around. “Keep the conversation open with reluctant patients but leave them where they are. They need to see you as a reliable source and nonjudgmental source of information,” she said.

Dr. Block recommends outlining the diseases that have been eliminated through vaccines, from polio to measles, as well as the dangers of vaccine refusal, as indicated by recent outbreaks of vaccine-preventable diseases in areas with low immunization rates. “This approach highlights the opportunity we all have to get vaccinated to protect ourselves and our communities,”  she said.

In Dr. Fryhofer’s view, the situation is urgent and doctors need to be proactive. “We’re now at a public-health tipping point where we may see a sliding back and a reversing of many years of progress.”

Dr. Fryhofer and Dr. Block disclosed no competing interests relevant to their comments.

Many adults are complacent about vaccinations, believing that annual COVID and flu shots aside, they had all the immunizations they need as children and teens. But adults need vaccines as well, especially if they have missed earlier doses. And older and health-compromised adults, in particular, can benefit from newer vaccines that were not part of the childhood schedule.

“The question is whether adults had the vaccinations they need in the first place,” Sandra Adamson Fryhofer, MD, an internist in Atlanta and the American Medical Association’s liaison to the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention, said in an interview. “Many do not even have reliable records of vaccination.”

Mary Jane Starke

Primary care physicians are ideally positioned to get adult patients to update their vaccination status on older vaccines and obtain newer ones as needed. “ACIP recommendations for adult vaccines are getting longer and more complicated and the way they’re administered is more complex, too, in that they’re not all given in the primary care office but sometimes in pharmacies,” Dr. Fryhofer said.

Not all adult patients want to update their vaccinations. “Vaccine hesitancy among many adults is accelerated by the several new vaccines that have been recommended in recent years,” Lauren Block, MD, MPH, an internist at Northwell Health and assistant professor in the Institute of Health System Science at the Feinstein Institutes for Medical Research in metropolitan New York City, said in an interview.

Physicians are rightly concerned about the lagging rates of adult vaccination, Dr. Block said. “Given the prevalence of conditions like pneumonia and shingles and the morbidity associated with them, healthcare providers should take every opportunity to discuss vaccination with patients, from well visits to hospital visits,” Dr. Block added. 

Feinstein Institute for Medical Research

She pointed to several obstacles to broader uptake, including product shortages, financial barriers, and, increasingly, the negative vocal messaging from media outlets and social media.
 

Current Recommendations

The main vaccines recommended for adults, besides flu and COVID shots, are for respiratory syncytial virus (RVS); shingles; pneumococcal disease; measles, mumps, and rubella (MMR); and tetanus, diphtheria, and pertussis (Tdap). Less commonly, booster vaccines for MM, and hepatitis are recommended when titers are proven to be low.

ACIP’s updated 2024 Adult Immunization Schedule can be downloaded from the website of the CDC.

The newest additions to the schedule include RSV vaccines, the mpox vaccine (Jynneos), a new MenACWY-MenB combo vaccine (Penbraya), and the new 2023-2024 formulation of updated COVID vaccines (both mRNA and protein-based adjuvanted versions).
 

1. Respiratory Syncytial Virus Vaccines

There are two licensed RSV vaccines, Arexvy and Abrysvo. The CDC schedule recommends a single-dose RSV vaccine for adults age 60 years and older, especially those at high risk of contracting the virus — but after shared decision-making based on a discussion of the risk-harm balance since this vaccine carries a small increased chance of developing the neurological symptoms of Guillain-Barré syndrome.

Chronic health conditions associated with a higher risk of severe RVS include cardiopulmonary disease, diabetes, and kidney, liver, and hematologic disorders, as well as compromised immunity, older age, and frailty.
 

2. Shingles Vaccines

This painful disease carries the potential complication of postherpetic neuralgia (PHN), which leads to long-term nerve pain in 10%-18% of patients, especially those over age 40. ACIP recommends two doses of the recombinant zoster vaccine (Shingrix) for individuals 50 years and older. Those 19 years and older with weakened immune systems due to disease or medical treatments should get two doses of the recombinant vaccine, as they have a higher risk of getting shingles and its complications, including neurological problems and skin and eye infections.

3 Pneumococcal Vaccines

There are three approved pneumococcal vaccines: PCV15 (Vaxneuvance), PCV20 (Prevnar20), and PPSV23 (Pneumovax23).

“The pneumococcal vaccine schedule is the most complicated one as higher-valent products continue to become available,” Dr. Fryhofer said.

The two types are pneumococcal conjugate vaccines (PCVs, specifically PCV15 and PCV20) and the pneumococcal polysaccharide vaccine (PPSV23). “While PPSV23 covers 23 strains, it doesn’t give the long-term immunity of the conjugate vaccine,” said Dr. Fryhofer. “A patient may have completed their vaccination with the polysaccharide vaccine but 5 years out may no longer be protected. So we offer the option of getting a dose of PCV20 to round out the protection and confer greater immune memory.”

The ACIP schedule recommends immunization against the Streptococcus pneumoniae pathogen for all older and all at-risk adults. Routine administration of PCV15 or PCV20 is advised for those 65 years or older who have never received any pneumococcal conjugate vaccine or whose previous vaccination history is unknown. If PCV15 is used, it should be followed by PPSV23. Those 65 years or older should get PPSV23 even if they already had one or more doses of pneumococcal vaccine before turning 65.

Further vaccination is recommended for younger at-risk adults aged 19-64 years who have received both PCV13 and PPSV23 but have incomplete vaccination status. These individuals are advised to complete their pneumococcal series by receiving either a single dose of PCV20 at an interval of at least 5 years after the last pneumococcal vaccine dose or more than one dose of PPSV23.

See Pneumococcal Vaccination: Summary of Who and When to Vaccinate for CDC guidance on vaccination options for adults who have previously received a pneumococcal conjugate vaccine. Or, to sort out quickly who gets what and when based on their age, concurrent conditions, and vaccination history, the CDC offers a type-in app called the PneumoRecs VaxAdvisor.
 

4. Measles, Mumps, and Rubella, and Varicella Vaccines

The two approved MMR vaccines are M-M-R II and PRIORIX. A third vaccine, ProQuad, adds varicella.

Adults lacking presumptive evidence of immunity should get at least one dose of the MMR combination vaccine.

Those born before 1957 are deemed to be immune, Dr. Fryhofer noted.

Two doses are recommended for adults entering high-risk settings for measles or mumps transmission such as healthcare personnel, students away at college, and international travelers. The two doses should be separated by at least 28 days. It’s no secret that measles, though preventable, is making a comeback, with 146 reported cases (48 in adults) across 21 states as of May 31 — most linked to international travel.

Women who plan to get pregnant should be vaccinated before but not during each pregnancy. (The vaccine is safe during lactation.) And those of childbearing age with no presumptive evidence of immunity are advised to get at least one dose of the MMR vaccine.
 

5. Tetanus, Diphtheria, and Pertussis Vaccine

Adults with no previous Tdap vaccination should receive a single dose of Adacel or Boostrix followed by a booster every 10 years. Boostrix is recommended for adults over 64 years.

During every pregnancy, women should have a single dose of Tdap, preferably in gestational weeks 27 through 36.

As to the immediate postpartum period, Tdap is recommended only for mothers who did not receive it during their current pregnancy and never received a prior dose. If a woman did not receive Tdap during her current pregnancy but did receive a prior dose of Tdap, she does not need Tdap postpartum.
 

The Challenges

According to Dr. Fryhofer, widespread disinformation about the risks of immunization against vaccine-preventable diseases has brought us to a flashpoint. “It’s now more important than ever to keep telling patients that vaccination is one of the most effective tools for preventing individual illness and protecting public health.”

She recommends that doctors follow the National Institutes of Health’s AIMS method to broach the subject of adult vaccination and increase participation in an inquiring, reassuring, and low-pressure way. Standing for Announce, Inquire, Mirror, and Secure, AIMS structures a nonjudgmental, patient-friendly conversation around immunization to elicit and acknowledge the reasons for hesitancy while explaining the safety and efficacy of vaccines.

Dr. Fryhofer frequently uses AIMS to bring inoculation-averse patients around. “Keep the conversation open with reluctant patients but leave them where they are. They need to see you as a reliable source and nonjudgmental source of information,” she said.

Dr. Block recommends outlining the diseases that have been eliminated through vaccines, from polio to measles, as well as the dangers of vaccine refusal, as indicated by recent outbreaks of vaccine-preventable diseases in areas with low immunization rates. “This approach highlights the opportunity we all have to get vaccinated to protect ourselves and our communities,”  she said.

In Dr. Fryhofer’s view, the situation is urgent and doctors need to be proactive. “We’re now at a public-health tipping point where we may see a sliding back and a reversing of many years of progress.”

Dr. Fryhofer and Dr. Block disclosed no competing interests relevant to their comments.

BOSTON — New Endocrine Society guidelines call for limiting vitamin D supplementation beyond the daily recommended intake to specific risk groups and advises against routine 25-hydroxyvitamin D [25(OH)D] testing in healthy individuals. 

The evidence-based document was presented on June 3, 2024, at the Endocrine Society annual meeting, and simultaneously published in The Journal of Clinical Endocrinology and Metabolism. It advises that people who may benefit from vitamin D supplementation include: 

• Children aged 1-18 years to prevent rickets and to potentially lower the risk for respiratory tract infections
• Pregnant people to lower the risk for maternal and fetal or neonatal complications
• Adults older than 75 years to lower the risk for mortality
• Adults with prediabetes to lower the risk for type 2 diabetes

In those groups, the recommendation is for daily (rather than intermittent) empiric vitamin D supplementation of more than what was recommended in 2011 by the National Academy of Medicine (NAM), which was then called the Institute of Medicine (IOM): 600 IU/d for those aged 1-70 years and 800 IU/d for those older than 70 years. The document acknowledges that the optimal dose for these populations isn’t known, but it provides the dose ranges that were used in the trials cited as evidence for the recommendations. 

In contrast, the document advises against more vitamin D than the recommended daily intake for most healthier adults younger than 75 years and recommends against testing for blood vitamin D levels in the general population, including those with obesity or darker complexions. 

Guideline author Anastassios G. Pittas, MD, professor of medicine at Tufts University School of Medicine, Boston, told this news organization, “this guideline refers to people who are otherwise healthy, and there’s no clear indication for vitamin D, such as people with already established osteoporosis. This guideline is not relevant to them.”

Dr. Pittas also noted, “there’s no single question and single answer about the role of vitamin D in health and disease, which is what people often want to know. There are many questions, and we cannot answer all of them.”

Panel Chair Marie B. Demay, MD, professor of medicine at Harvard Medical School, Boston, told this news organization that indeed the panel was limited by lack of randomized clinical trial evidence to answer many important questions. “There is a paucity of data regarding definition of optimal levels and optimal intake of vitamin D for preventing specific diseases ... What we really need are large scale clinical trials and biomarkers so we can predict disease outcome before it happens.”

Overall, Dr. Demay said, “The recommendations are that populations adhere to the [NAM/IOM] dietary recommended intakes, and there are certain populations that will likely benefit from levels of intake above [those].” 

Asked to comment, session moderator Clifford J. Rosen, MD, director of Clinical and Translational Research and senior scientist at Maine Medical Center Research Institute, Scarborough, Maine, noted that screening for vitamin D is quite common in clinical practice, but the recommendation against doing so makes sense. 

“When clinicians measure vitamin D, then they’re forced to make a decision what to do about it. That’s where questions about the levels come in. And that’s a big problem. So what the panel’s saying is, don’t screen ... This really gets to the heart of the issue, because we have no data that there’s anything about screening that allows us to improve quality of life ... Screening is probably not worthwhile in any age group.”

Dr. Rosen, who was an author on the 2011 NAM/IOM dietary reference intakes, said that since then, new data have come out regarding the role of vitamin D in mortality in people older than 75 years, benefit in children with regard to respiratory illness, and the potential benefit of vitamin D in pregnancy. “Otherwise, I think we’re going over a lot of the same stuff that we’ve talked about since I was on the IOM panel 15 years ago ... But I think the level of evidence and rigor with which they did it is really impressive.”

However, Simeon I. Taylor, MD, professor of medicine at the University of Maryland, Baltimore, expressed disappointment that the document was limited to healthy people. “Although acknowledging challenges in managing vitamin D status in patients with several diseases, [such as] chronic kidney disease or inflammatory bowel disease, the new guidelines do not provide sufficient guidance for practicing physicians about how to manage these complex patients.”

In addition, Dr. Taylor said that the guidelines “do not explicitly consider the literature suggesting that alternative testing strategies may provide more relevant insights into vitamin D status. Just as variation in levels of thyroid-binding globulin have convinced endocrinologists not to rely on measurement of total thyroxine; interindividual variation in levels of vitamin D binding protein must be accounted for to interpret measurements of total levels of 25(OH)D. It would have been useful to explicitly consider the possible value of measuring vitamin D binding protein-independent indices of vitamin D status.”

Dr. Taylor also raised the same point as an audience member did during the Q&A period regarding patients with osteoporosis or osteopenia. “The value and utility of the new guidelines would be greatly strengthened by providing guidance for how to approach this important and very large group of individuals.”

Dr. Taylor did say that the document has “several strengths, including the fact that they acknowledge the major limitations of the quality of relevant evidence derived from clinical trials.” 

In an accompanying commentary, the guideline authors delve into the issues of skin pigmentation and race as they pertain to vitamin D metabolism, writing: 

The panel discovered that no randomized clinical trials have directly assessed vitamin D related patient-important outcomes based on participants’ skin pigmentation, although race and ethnicity often served as presumed proxies for skin pigmentation in the literature. In their deliberations, guideline panel members and selected Endocrine Society leaders underscored the critical need to distinguish between skin pigmentation as a biological variable and race and ethnicity as socially determined constructs. This differentiation is vital to maximize scientific rigor and, thus, the validity of resulting recommendations.

Dr. Pittas and Dr. Demay have no disclosures relevant to this clinical practice guideline. Dr. Rosen has no disclosures. Dr. Taylor serves as a consultant for Ionis Pharmaceuticals.
 

A version of this article appeared on Medscape.com.

BOSTON — New Endocrine Society guidelines call for limiting vitamin D supplementation beyond the daily recommended intake to specific risk groups and advises against routine 25-hydroxyvitamin D [25(OH)D] testing in healthy individuals. 

The evidence-based document was presented on June 3, 2024, at the Endocrine Society annual meeting, and simultaneously published in The Journal of Clinical Endocrinology and Metabolism. It advises that people who may benefit from vitamin D supplementation include: 

• Children aged 1-18 years to prevent rickets and to potentially lower the risk for respiratory tract infections
• Pregnant people to lower the risk for maternal and fetal or neonatal complications
• Adults older than 75 years to lower the risk for mortality
• Adults with prediabetes to lower the risk for type 2 diabetes

In those groups, the recommendation is for daily (rather than intermittent) empiric vitamin D supplementation of more than what was recommended in 2011 by the National Academy of Medicine (NAM), which was then called the Institute of Medicine (IOM): 600 IU/d for those aged 1-70 years and 800 IU/d for those older than 70 years. The document acknowledges that the optimal dose for these populations isn’t known, but it provides the dose ranges that were used in the trials cited as evidence for the recommendations. 

In contrast, the document advises against more vitamin D than the recommended daily intake for most healthier adults younger than 75 years and recommends against testing for blood vitamin D levels in the general population, including those with obesity or darker complexions. 

Guideline author Anastassios G. Pittas, MD, professor of medicine at Tufts University School of Medicine, Boston, told this news organization, “this guideline refers to people who are otherwise healthy, and there’s no clear indication for vitamin D, such as people with already established osteoporosis. This guideline is not relevant to them.”

Dr. Pittas also noted, “there’s no single question and single answer about the role of vitamin D in health and disease, which is what people often want to know. There are many questions, and we cannot answer all of them.”

Panel Chair Marie B. Demay, MD, professor of medicine at Harvard Medical School, Boston, told this news organization that indeed the panel was limited by lack of randomized clinical trial evidence to answer many important questions. “There is a paucity of data regarding definition of optimal levels and optimal intake of vitamin D for preventing specific diseases ... What we really need are large scale clinical trials and biomarkers so we can predict disease outcome before it happens.”

Overall, Dr. Demay said, “The recommendations are that populations adhere to the [NAM/IOM] dietary recommended intakes, and there are certain populations that will likely benefit from levels of intake above [those].” 

Asked to comment, session moderator Clifford J. Rosen, MD, director of Clinical and Translational Research and senior scientist at Maine Medical Center Research Institute, Scarborough, Maine, noted that screening for vitamin D is quite common in clinical practice, but the recommendation against doing so makes sense. 

“When clinicians measure vitamin D, then they’re forced to make a decision what to do about it. That’s where questions about the levels come in. And that’s a big problem. So what the panel’s saying is, don’t screen ... This really gets to the heart of the issue, because we have no data that there’s anything about screening that allows us to improve quality of life ... Screening is probably not worthwhile in any age group.”

Dr. Rosen, who was an author on the 2011 NAM/IOM dietary reference intakes, said that since then, new data have come out regarding the role of vitamin D in mortality in people older than 75 years, benefit in children with regard to respiratory illness, and the potential benefit of vitamin D in pregnancy. “Otherwise, I think we’re going over a lot of the same stuff that we’ve talked about since I was on the IOM panel 15 years ago ... But I think the level of evidence and rigor with which they did it is really impressive.”

However, Simeon I. Taylor, MD, professor of medicine at the University of Maryland, Baltimore, expressed disappointment that the document was limited to healthy people. “Although acknowledging challenges in managing vitamin D status in patients with several diseases, [such as] chronic kidney disease or inflammatory bowel disease, the new guidelines do not provide sufficient guidance for practicing physicians about how to manage these complex patients.”

In addition, Dr. Taylor said that the guidelines “do not explicitly consider the literature suggesting that alternative testing strategies may provide more relevant insights into vitamin D status. Just as variation in levels of thyroid-binding globulin have convinced endocrinologists not to rely on measurement of total thyroxine; interindividual variation in levels of vitamin D binding protein must be accounted for to interpret measurements of total levels of 25(OH)D. It would have been useful to explicitly consider the possible value of measuring vitamin D binding protein-independent indices of vitamin D status.”

Dr. Taylor also raised the same point as an audience member did during the Q&A period regarding patients with osteoporosis or osteopenia. “The value and utility of the new guidelines would be greatly strengthened by providing guidance for how to approach this important and very large group of individuals.”

Dr. Taylor did say that the document has “several strengths, including the fact that they acknowledge the major limitations of the quality of relevant evidence derived from clinical trials.” 

In an accompanying commentary, the guideline authors delve into the issues of skin pigmentation and race as they pertain to vitamin D metabolism, writing: 

The panel discovered that no randomized clinical trials have directly assessed vitamin D related patient-important outcomes based on participants’ skin pigmentation, although race and ethnicity often served as presumed proxies for skin pigmentation in the literature. In their deliberations, guideline panel members and selected Endocrine Society leaders underscored the critical need to distinguish between skin pigmentation as a biological variable and race and ethnicity as socially determined constructs. This differentiation is vital to maximize scientific rigor and, thus, the validity of resulting recommendations.

Dr. Pittas and Dr. Demay have no disclosures relevant to this clinical practice guideline. Dr. Rosen has no disclosures. Dr. Taylor serves as a consultant for Ionis Pharmaceuticals.
 

A version of this article appeared on Medscape.com.

BOSTON — New Endocrine Society guidelines call for limiting vitamin D supplementation beyond the daily recommended intake to specific risk groups and advises against routine 25-hydroxyvitamin D [25(OH)D] testing in healthy individuals. 

The evidence-based document was presented on June 3, 2024, at the Endocrine Society annual meeting, and simultaneously published in The Journal of Clinical Endocrinology and Metabolism. It advises that people who may benefit from vitamin D supplementation include: 

• Children aged 1-18 years to prevent rickets and to potentially lower the risk for respiratory tract infections
• Pregnant people to lower the risk for maternal and fetal or neonatal complications
• Adults older than 75 years to lower the risk for mortality
• Adults with prediabetes to lower the risk for type 2 diabetes

In those groups, the recommendation is for daily (rather than intermittent) empiric vitamin D supplementation of more than what was recommended in 2011 by the National Academy of Medicine (NAM), which was then called the Institute of Medicine (IOM): 600 IU/d for those aged 1-70 years and 800 IU/d for those older than 70 years. The document acknowledges that the optimal dose for these populations isn’t known, but it provides the dose ranges that were used in the trials cited as evidence for the recommendations. 

In contrast, the document advises against more vitamin D than the recommended daily intake for most healthier adults younger than 75 years and recommends against testing for blood vitamin D levels in the general population, including those with obesity or darker complexions. 

Guideline author Anastassios G. Pittas, MD, professor of medicine at Tufts University School of Medicine, Boston, told this news organization, “this guideline refers to people who are otherwise healthy, and there’s no clear indication for vitamin D, such as people with already established osteoporosis. This guideline is not relevant to them.”

Dr. Pittas also noted, “there’s no single question and single answer about the role of vitamin D in health and disease, which is what people often want to know. There are many questions, and we cannot answer all of them.”

Panel Chair Marie B. Demay, MD, professor of medicine at Harvard Medical School, Boston, told this news organization that indeed the panel was limited by lack of randomized clinical trial evidence to answer many important questions. “There is a paucity of data regarding definition of optimal levels and optimal intake of vitamin D for preventing specific diseases ... What we really need are large scale clinical trials and biomarkers so we can predict disease outcome before it happens.”

Overall, Dr. Demay said, “The recommendations are that populations adhere to the [NAM/IOM] dietary recommended intakes, and there are certain populations that will likely benefit from levels of intake above [those].” 

Asked to comment, session moderator Clifford J. Rosen, MD, director of Clinical and Translational Research and senior scientist at Maine Medical Center Research Institute, Scarborough, Maine, noted that screening for vitamin D is quite common in clinical practice, but the recommendation against doing so makes sense. 

“When clinicians measure vitamin D, then they’re forced to make a decision what to do about it. That’s where questions about the levels come in. And that’s a big problem. So what the panel’s saying is, don’t screen ... This really gets to the heart of the issue, because we have no data that there’s anything about screening that allows us to improve quality of life ... Screening is probably not worthwhile in any age group.”

Dr. Rosen, who was an author on the 2011 NAM/IOM dietary reference intakes, said that since then, new data have come out regarding the role of vitamin D in mortality in people older than 75 years, benefit in children with regard to respiratory illness, and the potential benefit of vitamin D in pregnancy. “Otherwise, I think we’re going over a lot of the same stuff that we’ve talked about since I was on the IOM panel 15 years ago ... But I think the level of evidence and rigor with which they did it is really impressive.”

However, Simeon I. Taylor, MD, professor of medicine at the University of Maryland, Baltimore, expressed disappointment that the document was limited to healthy people. “Although acknowledging challenges in managing vitamin D status in patients with several diseases, [such as] chronic kidney disease or inflammatory bowel disease, the new guidelines do not provide sufficient guidance for practicing physicians about how to manage these complex patients.”

In addition, Dr. Taylor said that the guidelines “do not explicitly consider the literature suggesting that alternative testing strategies may provide more relevant insights into vitamin D status. Just as variation in levels of thyroid-binding globulin have convinced endocrinologists not to rely on measurement of total thyroxine; interindividual variation in levels of vitamin D binding protein must be accounted for to interpret measurements of total levels of 25(OH)D. It would have been useful to explicitly consider the possible value of measuring vitamin D binding protein-independent indices of vitamin D status.”

Dr. Taylor also raised the same point as an audience member did during the Q&A period regarding patients with osteoporosis or osteopenia. “The value and utility of the new guidelines would be greatly strengthened by providing guidance for how to approach this important and very large group of individuals.”

Dr. Taylor did say that the document has “several strengths, including the fact that they acknowledge the major limitations of the quality of relevant evidence derived from clinical trials.” 

In an accompanying commentary, the guideline authors delve into the issues of skin pigmentation and race as they pertain to vitamin D metabolism, writing: 

The panel discovered that no randomized clinical trials have directly assessed vitamin D related patient-important outcomes based on participants’ skin pigmentation, although race and ethnicity often served as presumed proxies for skin pigmentation in the literature. In their deliberations, guideline panel members and selected Endocrine Society leaders underscored the critical need to distinguish between skin pigmentation as a biological variable and race and ethnicity as socially determined constructs. This differentiation is vital to maximize scientific rigor and, thus, the validity of resulting recommendations.

Dr. Pittas and Dr. Demay have no disclosures relevant to this clinical practice guideline. Dr. Rosen has no disclosures. Dr. Taylor serves as a consultant for Ionis Pharmaceuticals.
 

A version of this article appeared on Medscape.com.

Between 2011 and 2019, chronic cutaneous wounds accounted for about one third of all health care visits for cutaneous wounds, and the most common diagnoses were open wounds of the thumb without nail damage. However, fewer than 8% of chronic wounds were managed by dermatologists during this time.

Those are among key findings from an analysis of National Ambulatory Medical Care Survey (NAMCS) data between 2011 and 2019 presented as a late-breaking abstract at the annual meeting of the Society for Investigative Dermatology. “Cutaneous wounds were estimated to account for 28.1 to 96.1 billion dollars in US health care costs in 2014,” one of the study authors, Rithi Chandy, MD, MS, a research fellow at the Center for Dermatology Research at Wake Forest University School of Medicine, Winston-Salem, North Carolina, said in an interview following the meeting. “By examining national trends in patient visits and treatment, we may be able to better inform health care utilization for cutaneous wounds.”

A version of this article appeared on Medscape.com .

Between 2011 and 2019, chronic cutaneous wounds accounted for about one third of all health care visits for cutaneous wounds, and the most common diagnoses were open wounds of the thumb without nail damage. However, fewer than 8% of chronic wounds were managed by dermatologists during this time.

Those are among key findings from an analysis of National Ambulatory Medical Care Survey (NAMCS) data between 2011 and 2019 presented as a late-breaking abstract at the annual meeting of the Society for Investigative Dermatology. “Cutaneous wounds were estimated to account for 28.1 to 96.1 billion dollars in US health care costs in 2014,” one of the study authors, Rithi Chandy, MD, MS, a research fellow at the Center for Dermatology Research at Wake Forest University School of Medicine, Winston-Salem, North Carolina, said in an interview following the meeting. “By examining national trends in patient visits and treatment, we may be able to better inform health care utilization for cutaneous wounds.”

A version of this article appeared on Medscape.com .

Between 2011 and 2019, chronic cutaneous wounds accounted for about one third of all health care visits for cutaneous wounds, and the most common diagnoses were open wounds of the thumb without nail damage. However, fewer than 8% of chronic wounds were managed by dermatologists during this time.

Those are among key findings from an analysis of National Ambulatory Medical Care Survey (NAMCS) data between 2011 and 2019 presented as a late-breaking abstract at the annual meeting of the Society for Investigative Dermatology. “Cutaneous wounds were estimated to account for 28.1 to 96.1 billion dollars in US health care costs in 2014,” one of the study authors, Rithi Chandy, MD, MS, a research fellow at the Center for Dermatology Research at Wake Forest University School of Medicine, Winston-Salem, North Carolina, said in an interview following the meeting. “By examining national trends in patient visits and treatment, we may be able to better inform health care utilization for cutaneous wounds.”

A version of this article appeared on Medscape.com .

What if there were tests that could tell you whether the following drugs were a good match for your patients: Antidepressants, statins, painkillers, anticlotting medicines, chemotherapy agents, HIV treatments, organ transplant antirejection drugs, proton pump inhibitors for heartburn, and more?

That’s quite a list. And that’s pharmacogenetics, testing patients for genetic differences that affect how well a given drug will work for them and what kind of side effects to expect.

“About 9 out of 10 people will have a genetic difference in their DNA that can impact how they respond to common medications,” said Emily J. Cicali, PharmD, a clinical associate at the University of Florida College of Pharmacy, Gainesville.

Dr. Cicali is the clinical director of UF Health’s MyRx, a virtual program that gives Florida and New Jersey residents access to pharmacogenetic (PGx) tests plus expert interpretation by the health system’s pharmacists. Genetic factors are thought to contribute to about 25% or more of inappropriate drug responses or adverse events, said Kristin Wiisanen, PharmD, dean of the College of Pharmacy at Rosalind Franklin University of Medicine and Science in North Chicago.

“Pharmacogenetics helps consumers avoid drugs that may not work well for them or could cause serious adverse events. It’s personalized medicine,” Dr. Cicali said.

Through a cheek swab or blood sample, the MyRx program — and a growing number of health system programs, doctors’ offices, and home tests available across the United States — gives consumers a window on inherited gene variants that can affect how their body activates, metabolizes, and clears away medications from a long list of widely used drugs.

Why PGx Tests Can Have a Big Impact

These tests work by looking for genes that control drug metabolism.

“You have several different drug-metabolizing enzymes in your liver,” Dr. Cicali explained. “Pharmacogenetic tests look for gene variants that encode for these enzymes. If you’re an ultrarapid metabolizer, you have more of the enzymes that metabolize certain drugs, and there could be a risk the drug won’t work well because it doesn’t stay in the body long enough. On the other end of the spectrum, poor metabolizers have low levels of enzymes that affect certain drugs, so the drugs hang around longer and cause side effects.”

While pharmacogenetics is still considered an emerging science, it’s becoming more mainstream as test prices drop, insurance coverage expands, and an explosion of new research boosts understanding of gene-drug interactions, Dr. Wiisanen said.

Politicians are trying to extend its reach, too. The Right Drug Dose Now Act of 2024, introduced in Congress in late March, aims to accelerate the use of PGx by boosting public awareness and by inserting PGx test results into consumers’ electronic health records. (Though a similar bill died in a US House subcommittee in 2023.)

“The use of pharmacogenetic data to guide prescribing is growing rapidly,” Dr. Wiisanen said. “It’s becoming a routine part of drug therapy for many medications.”

What the Research Shows

When researchers sequenced the DNA of more than 10,000 Mayo Clinic patients, they made a discovery that might surprise many Americans: Gene variants that affect the effectiveness and safety of widely used drugs are not rare glitches. More than 99% of study participants had at least one. And 79% had three or more.

The Mayo-Baylor RIGHT 10K Study — one of the largest PGx studies ever conducted in the United States — looked at 77 gene variants, most involved with drug metabolism in the liver. Researchers focused closely on 13 with extensively studied, gene-based prescribing recommendations for 21 drugs including antidepressants, statins, pain killers, anticlotting medications for heart conditions, HIV treatments, chemotherapy agents, and antirejection drugs for organ transplants.

When researchers added participants’ genetic data to their electronic health records, they also sent semi-urgent alerts, which are alerts with the potential for severe harm, to the clinicians of 61 study volunteers. Over half changed patients’ drugs or doses.

The changes made a difference. One participant taking the pain drug tramadol turned out to be a poor metabolizer and was having dizzy spells because blood levels of the drug stayed high for long periods. Stopping tramadol stopped the dizziness. A participant taking escitalopram plus bupropion for major depression found out that the combo was likely ineffective because they metabolized escitalopram rapidly. A switch to a higher dose of bupropion alone put their depression into full remission.

“So many factors play into how you respond to medications,” said Mayo Clinic pharmacogenomics pharmacist Jessica Wright, PharmD, BCACP, one of the study authors. “Genetics is one of those pieces. Pharmacogenetic testing can reveal things that clinicians may not have been aware of or could help explain a patient’s exaggerated side effect.”

Pharmacogenetics is also called pharmacogenomics. The terms are often used interchangeably, even among PGx pharmacists, though the first refers to how individual genes influence drug response and the second to the effects of multiple genes, said Kelly E. Caudle, PharmD, PhD, an associate member of the Department of Pharmacy and Pharmaceutical Sciences at St. Jude Children’s Research Hospital in Memphis, Tennessee. Dr. Caudle is also co-principal investigator and director of the National Institutes of Health (NIH)-funded Clinical Pharmacogenetics Implementation Consortium (CPIC). The group creates, publishes, and posts evidence-based clinical practice guidelines for drugs with well-researched PGx influences.

By any name, PGx may help explain, predict, and sidestep unpredictable responses to a variety of drugs:

• In a 2023 multicenter study of 6944 people from seven European countries in The Lancet, those given customized drug treatments based on a 12-gene PGx panel had 30% fewer side effects than those who didn’t get this personalized prescribing. People in the study were being treated for cancer, heart disease, and mental health issues, among other conditions.
• In a 2023  from China’s Tongji University, Shanghai, of 650 survivors of strokes and transient ischemic attacks, those whose antiplatelet drugs (such as clopidogrel) were customized based on PGx testing had a lower risk for stroke and other vascular events in the next 90 days. The study was published in Frontiers in Pharmacology.
• In a University of Pennsylvania  of 1944 adults with major depression, published in the Journal of the American Medical Association, those whose antidepressants were guided by PGx test results were 28% more likely to go into remission during the first 24 weeks of treatment than those in a control group. But by 24 weeks, equal numbers were in remission. A 2023 Chinese  of 11 depression studies, published in BMC Psychiatry, came to a similar conclusion: PGx-guided antidepressant prescriptions may help people feel better quicker, perhaps by avoiding some of the usual trial-and-error of different depression drugs.

PGx checks are already strongly recommended or considered routine before some medications are prescribed. These include abacavir (Ziagen), an antiviral treatment for HIV that can have severe side effects in people with one gene variant.

The US Food and Drug Administration (FDA) recommends genetic testing for people with colon cancer before starting the drug irinotecan (Camptosar), which can cause severe diarrhea and raise infection risk in people with a gene variant that slows the drug’s elimination from the body.

Genetic testing is also recommended by the FDA for people with acute lymphoblastic leukemia before receiving the chemotherapy drug mercaptopurine (Purinethol) because a gene variant that affects drug processing can trigger serious side effects and raise the risk for infection at standard dosages.

“One of the key benefits of pharmacogenomic testing is in preventing adverse drug reactions,” Dr. Wiisanen said. “Testing of the thiopurine methyltransferase enzyme to guide dosing with 6-mercaptopurine or azathioprine can help prevent myelosuppression, a serious adverse drug reaction caused by lower production of blood cells in bone marrow.”

When, Why, and How to Test

“A family doctor should consider a PGx test if a patient is planning on taking a medication for which there is a CPIC guideline with a dosing recommendation,” said Teri Klein, PhD, professor of biomedical data science at Stanford University in California, and principal investigator at PharmGKB, an online resource funded by the NIH that provides information for healthcare practitioners, researchers, and consumers about PGx. Affiliated with CPIC, it’s based at Stanford University.

You might also consider it for patients already on a drug who are “not responding or experiencing side effects,” Dr. Caudle said.

Here’s how four PGx experts suggest consumers and physicians approach this option.

Find a Test

More than a dozen PGx tests are on the market — some only a provider can order, others a consumer can order after a review by their provider or by a provider from the testing company. Some of the tests (using saliva) may be administered at home, while blood tests are done in a doctor’s office or laboratory. Companies that offer the tests include ARUP Laboratories, Genomind, Labcorp, Mayo Clinic Laboratories, Myriad Neuroscience, Precision Sciences Inc., Tempus, and OneOme, but there are many others online. (Keep in mind that many laboratories offer “lab-developed tests” — created for use in a single laboratory — but these can be harder to verify. “The FDA regulates pharmacogenomic testing in laboratories,” Dr. Wiisanen said, “but many of the regulatory parameters are still being defined.”)

Because PGx is so new, there is no official list of recommended tests. So you’ll have to do a little homework. You can check that the laboratory is accredited by searching for it in the NIH Genetic Testing Laboratory Registry database. Beyond that, you’ll have to consult other evidence-based resources to confirm that the drug you’re interested in has research-backed data about specific gene variants (alleles) that affect metabolism as well as research-based clinical guidelines for using PGx results to make prescribing decisions.

The CPIC’s guidelines include dosing and alternate drug recommendations for more than 100 antidepressants, chemotherapy drugs, the antiplatelet and anticlotting drugs clopidogrel and warfarin, local anesthetics, antivirals and antibacterials, pain killers and anti-inflammatory drugs, and some cholesterol-lowering statins such as lovastatin and fluvastatin.

For help figuring out if a test looks for the right gene variants, Dr. Caudle and Dr. Wright recommended checking with the Association for Molecular Pathology’s website. The group published a brief list of best practices for pharmacogenomic testing in 2019. And it keeps a list of gene variants (alleles) that should be included in tests. Clinical guidelines from the CPIC and other groups, available on PharmGKB’s website, also list gene variants that affect the metabolism of the drug.

Consider Cost

The price tag for a test is typically several hundred dollars — but it can run as high as $1000-$2500. And health insurance doesn’t always pick up the tab.

In a 2023 University of Florida study of more than 1000 insurance claims for PGx testing, the number reimbursed varied from 72% for a pain diagnosis to 52% for cardiology to 46% for psychiatry.

Medicare covers some PGx testing when a consumer and their providers meet certain criteria, including whether a drug being considered has a significant gene-drug interaction. California’s Medi-Cal health insurance program covers PGx as do Medicaid programs in some states, including Arkansas and Rhode Island. You can find state-by-state coverage information on the Genetics Policy Hub’s website.

Understand the Results

As more insurers cover PGx, Dr. Klein and Dr. Wiisanen say the field will grow and more providers will use it to inform prescribing. But some health systems aren’t waiting.

In addition to UF Health’s MyRx, PGx is part of personalized medicine programs at the University of Pennsylvania in Philadelphia, Endeavor Health in Chicago, the Mayo Clinic, the University of California, San Francisco, Sanford Health in Sioux Falls, South Dakota, and St. Jude Children’s Research Hospital in Memphis, Tennessee.

Beyond testing, they offer a very useful service: A consult with a pharmacogenetics pharmacist to review the results and explain what they mean for a consumer’s current and future medications.

Physicians and curious consumers can also consult CPIC’s guidelines, which give recommendations about how to interpret the results of a PGx test, said Dr. Klein, a co-principal investigator at CPIC. CPIC has a grading system for both the evidence that supports the recommendation (high, moderate, or weak) and the recommendation itself (strong, moderate, or optional).

Currently, labeling for 456 prescription drugs sold in the United States includes some type of PGx information, according to the FDA’s Table of Pharmacogenomic Biomarkers in Drug Labeling and an annotated guide from PharmGKB.

Just 108 drug labels currently tell doctors and patients what to do with the information — such as requiring or suggesting testing or offering prescribing recommendations, according to PharmGKB. In contrast, PharmGKB’s online resources include evidence-based clinical guidelines for 201 drugs from CPIC and from professional PGx societies in the Netherlands, Canada, France, and elsewhere.

Consumers and physicians can also look for a pharmacist with pharmacogenetics training in their area or through a nearby medical center to learn more, Dr. Wright suggested. And while consumers can test without working with their own physician, the experts advise against it. Don’t stop or change the dose of medications you already take on your own, they say . And do work with your primary care practitioner or specialist to get tested and understand how the results fit into the bigger picture of how your body responds to your medications.

A version of this article appeared on Medscape.com.

What if there were tests that could tell you whether the following drugs were a good match for your patients: Antidepressants, statins, painkillers, anticlotting medicines, chemotherapy agents, HIV treatments, organ transplant antirejection drugs, proton pump inhibitors for heartburn, and more?

That’s quite a list. And that’s pharmacogenetics, testing patients for genetic differences that affect how well a given drug will work for them and what kind of side effects to expect.

“About 9 out of 10 people will have a genetic difference in their DNA that can impact how they respond to common medications,” said Emily J. Cicali, PharmD, a clinical associate at the University of Florida College of Pharmacy, Gainesville.

Dr. Cicali is the clinical director of UF Health’s MyRx, a virtual program that gives Florida and New Jersey residents access to pharmacogenetic (PGx) tests plus expert interpretation by the health system’s pharmacists. Genetic factors are thought to contribute to about 25% or more of inappropriate drug responses or adverse events, said Kristin Wiisanen, PharmD, dean of the College of Pharmacy at Rosalind Franklin University of Medicine and Science in North Chicago.

“Pharmacogenetics helps consumers avoid drugs that may not work well for them or could cause serious adverse events. It’s personalized medicine,” Dr. Cicali said.

Through a cheek swab or blood sample, the MyRx program — and a growing number of health system programs, doctors’ offices, and home tests available across the United States — gives consumers a window on inherited gene variants that can affect how their body activates, metabolizes, and clears away medications from a long list of widely used drugs.

Why PGx Tests Can Have a Big Impact

These tests work by looking for genes that control drug metabolism.

“You have several different drug-metabolizing enzymes in your liver,” Dr. Cicali explained. “Pharmacogenetic tests look for gene variants that encode for these enzymes. If you’re an ultrarapid metabolizer, you have more of the enzymes that metabolize certain drugs, and there could be a risk the drug won’t work well because it doesn’t stay in the body long enough. On the other end of the spectrum, poor metabolizers have low levels of enzymes that affect certain drugs, so the drugs hang around longer and cause side effects.”

While pharmacogenetics is still considered an emerging science, it’s becoming more mainstream as test prices drop, insurance coverage expands, and an explosion of new research boosts understanding of gene-drug interactions, Dr. Wiisanen said.

Politicians are trying to extend its reach, too. The Right Drug Dose Now Act of 2024, introduced in Congress in late March, aims to accelerate the use of PGx by boosting public awareness and by inserting PGx test results into consumers’ electronic health records. (Though a similar bill died in a US House subcommittee in 2023.)

“The use of pharmacogenetic data to guide prescribing is growing rapidly,” Dr. Wiisanen said. “It’s becoming a routine part of drug therapy for many medications.”

What the Research Shows

When researchers sequenced the DNA of more than 10,000 Mayo Clinic patients, they made a discovery that might surprise many Americans: Gene variants that affect the effectiveness and safety of widely used drugs are not rare glitches. More than 99% of study participants had at least one. And 79% had three or more.

The Mayo-Baylor RIGHT 10K Study — one of the largest PGx studies ever conducted in the United States — looked at 77 gene variants, most involved with drug metabolism in the liver. Researchers focused closely on 13 with extensively studied, gene-based prescribing recommendations for 21 drugs including antidepressants, statins, pain killers, anticlotting medications for heart conditions, HIV treatments, chemotherapy agents, and antirejection drugs for organ transplants.

When researchers added participants’ genetic data to their electronic health records, they also sent semi-urgent alerts, which are alerts with the potential for severe harm, to the clinicians of 61 study volunteers. Over half changed patients’ drugs or doses.

The changes made a difference. One participant taking the pain drug tramadol turned out to be a poor metabolizer and was having dizzy spells because blood levels of the drug stayed high for long periods. Stopping tramadol stopped the dizziness. A participant taking escitalopram plus bupropion for major depression found out that the combo was likely ineffective because they metabolized escitalopram rapidly. A switch to a higher dose of bupropion alone put their depression into full remission.

“So many factors play into how you respond to medications,” said Mayo Clinic pharmacogenomics pharmacist Jessica Wright, PharmD, BCACP, one of the study authors. “Genetics is one of those pieces. Pharmacogenetic testing can reveal things that clinicians may not have been aware of or could help explain a patient’s exaggerated side effect.”

Pharmacogenetics is also called pharmacogenomics. The terms are often used interchangeably, even among PGx pharmacists, though the first refers to how individual genes influence drug response and the second to the effects of multiple genes, said Kelly E. Caudle, PharmD, PhD, an associate member of the Department of Pharmacy and Pharmaceutical Sciences at St. Jude Children’s Research Hospital in Memphis, Tennessee. Dr. Caudle is also co-principal investigator and director of the National Institutes of Health (NIH)-funded Clinical Pharmacogenetics Implementation Consortium (CPIC). The group creates, publishes, and posts evidence-based clinical practice guidelines for drugs with well-researched PGx influences.

By any name, PGx may help explain, predict, and sidestep unpredictable responses to a variety of drugs:

• In a 2023 multicenter study of 6944 people from seven European countries in The Lancet, those given customized drug treatments based on a 12-gene PGx panel had 30% fewer side effects than those who didn’t get this personalized prescribing. People in the study were being treated for cancer, heart disease, and mental health issues, among other conditions.
• In a 2023  from China’s Tongji University, Shanghai, of 650 survivors of strokes and transient ischemic attacks, those whose antiplatelet drugs (such as clopidogrel) were customized based on PGx testing had a lower risk for stroke and other vascular events in the next 90 days. The study was published in Frontiers in Pharmacology.
• In a University of Pennsylvania  of 1944 adults with major depression, published in the Journal of the American Medical Association, those whose antidepressants were guided by PGx test results were 28% more likely to go into remission during the first 24 weeks of treatment than those in a control group. But by 24 weeks, equal numbers were in remission. A 2023 Chinese  of 11 depression studies, published in BMC Psychiatry, came to a similar conclusion: PGx-guided antidepressant prescriptions may help people feel better quicker, perhaps by avoiding some of the usual trial-and-error of different depression drugs.

PGx checks are already strongly recommended or considered routine before some medications are prescribed. These include abacavir (Ziagen), an antiviral treatment for HIV that can have severe side effects in people with one gene variant.

The US Food and Drug Administration (FDA) recommends genetic testing for people with colon cancer before starting the drug irinotecan (Camptosar), which can cause severe diarrhea and raise infection risk in people with a gene variant that slows the drug’s elimination from the body.

Genetic testing is also recommended by the FDA for people with acute lymphoblastic leukemia before receiving the chemotherapy drug mercaptopurine (Purinethol) because a gene variant that affects drug processing can trigger serious side effects and raise the risk for infection at standard dosages.

“One of the key benefits of pharmacogenomic testing is in preventing adverse drug reactions,” Dr. Wiisanen said. “Testing of the thiopurine methyltransferase enzyme to guide dosing with 6-mercaptopurine or azathioprine can help prevent myelosuppression, a serious adverse drug reaction caused by lower production of blood cells in bone marrow.”

When, Why, and How to Test

“A family doctor should consider a PGx test if a patient is planning on taking a medication for which there is a CPIC guideline with a dosing recommendation,” said Teri Klein, PhD, professor of biomedical data science at Stanford University in California, and principal investigator at PharmGKB, an online resource funded by the NIH that provides information for healthcare practitioners, researchers, and consumers about PGx. Affiliated with CPIC, it’s based at Stanford University.

You might also consider it for patients already on a drug who are “not responding or experiencing side effects,” Dr. Caudle said.

Here’s how four PGx experts suggest consumers and physicians approach this option.

Find a Test

More than a dozen PGx tests are on the market — some only a provider can order, others a consumer can order after a review by their provider or by a provider from the testing company. Some of the tests (using saliva) may be administered at home, while blood tests are done in a doctor’s office or laboratory. Companies that offer the tests include ARUP Laboratories, Genomind, Labcorp, Mayo Clinic Laboratories, Myriad Neuroscience, Precision Sciences Inc., Tempus, and OneOme, but there are many others online. (Keep in mind that many laboratories offer “lab-developed tests” — created for use in a single laboratory — but these can be harder to verify. “The FDA regulates pharmacogenomic testing in laboratories,” Dr. Wiisanen said, “but many of the regulatory parameters are still being defined.”)

Because PGx is so new, there is no official list of recommended tests. So you’ll have to do a little homework. You can check that the laboratory is accredited by searching for it in the NIH Genetic Testing Laboratory Registry database. Beyond that, you’ll have to consult other evidence-based resources to confirm that the drug you’re interested in has research-backed data about specific gene variants (alleles) that affect metabolism as well as research-based clinical guidelines for using PGx results to make prescribing decisions.

The CPIC’s guidelines include dosing and alternate drug recommendations for more than 100 antidepressants, chemotherapy drugs, the antiplatelet and anticlotting drugs clopidogrel and warfarin, local anesthetics, antivirals and antibacterials, pain killers and anti-inflammatory drugs, and some cholesterol-lowering statins such as lovastatin and fluvastatin.

For help figuring out if a test looks for the right gene variants, Dr. Caudle and Dr. Wright recommended checking with the Association for Molecular Pathology’s website. The group published a brief list of best practices for pharmacogenomic testing in 2019. And it keeps a list of gene variants (alleles) that should be included in tests. Clinical guidelines from the CPIC and other groups, available on PharmGKB’s website, also list gene variants that affect the metabolism of the drug.

Consider Cost

The price tag for a test is typically several hundred dollars — but it can run as high as $1000-$2500. And health insurance doesn’t always pick up the tab.

In a 2023 University of Florida study of more than 1000 insurance claims for PGx testing, the number reimbursed varied from 72% for a pain diagnosis to 52% for cardiology to 46% for psychiatry.

Medicare covers some PGx testing when a consumer and their providers meet certain criteria, including whether a drug being considered has a significant gene-drug interaction. California’s Medi-Cal health insurance program covers PGx as do Medicaid programs in some states, including Arkansas and Rhode Island. You can find state-by-state coverage information on the Genetics Policy Hub’s website.

Understand the Results

As more insurers cover PGx, Dr. Klein and Dr. Wiisanen say the field will grow and more providers will use it to inform prescribing. But some health systems aren’t waiting.

In addition to UF Health’s MyRx, PGx is part of personalized medicine programs at the University of Pennsylvania in Philadelphia, Endeavor Health in Chicago, the Mayo Clinic, the University of California, San Francisco, Sanford Health in Sioux Falls, South Dakota, and St. Jude Children’s Research Hospital in Memphis, Tennessee.

Beyond testing, they offer a very useful service: A consult with a pharmacogenetics pharmacist to review the results and explain what they mean for a consumer’s current and future medications.

Physicians and curious consumers can also consult CPIC’s guidelines, which give recommendations about how to interpret the results of a PGx test, said Dr. Klein, a co-principal investigator at CPIC. CPIC has a grading system for both the evidence that supports the recommendation (high, moderate, or weak) and the recommendation itself (strong, moderate, or optional).

Currently, labeling for 456 prescription drugs sold in the United States includes some type of PGx information, according to the FDA’s Table of Pharmacogenomic Biomarkers in Drug Labeling and an annotated guide from PharmGKB.

Just 108 drug labels currently tell doctors and patients what to do with the information — such as requiring or suggesting testing or offering prescribing recommendations, according to PharmGKB. In contrast, PharmGKB’s online resources include evidence-based clinical guidelines for 201 drugs from CPIC and from professional PGx societies in the Netherlands, Canada, France, and elsewhere.

Consumers and physicians can also look for a pharmacist with pharmacogenetics training in their area or through a nearby medical center to learn more, Dr. Wright suggested. And while consumers can test without working with their own physician, the experts advise against it. Don’t stop or change the dose of medications you already take on your own, they say . And do work with your primary care practitioner or specialist to get tested and understand how the results fit into the bigger picture of how your body responds to your medications.

A version of this article appeared on Medscape.com.

What if there were tests that could tell you whether the following drugs were a good match for your patients: Antidepressants, statins, painkillers, anticlotting medicines, chemotherapy agents, HIV treatments, organ transplant antirejection drugs, proton pump inhibitors for heartburn, and more?

That’s quite a list. And that’s pharmacogenetics, testing patients for genetic differences that affect how well a given drug will work for them and what kind of side effects to expect.

“About 9 out of 10 people will have a genetic difference in their DNA that can impact how they respond to common medications,” said Emily J. Cicali, PharmD, a clinical associate at the University of Florida College of Pharmacy, Gainesville.

Dr. Cicali is the clinical director of UF Health’s MyRx, a virtual program that gives Florida and New Jersey residents access to pharmacogenetic (PGx) tests plus expert interpretation by the health system’s pharmacists. Genetic factors are thought to contribute to about 25% or more of inappropriate drug responses or adverse events, said Kristin Wiisanen, PharmD, dean of the College of Pharmacy at Rosalind Franklin University of Medicine and Science in North Chicago.

“Pharmacogenetics helps consumers avoid drugs that may not work well for them or could cause serious adverse events. It’s personalized medicine,” Dr. Cicali said.

Through a cheek swab or blood sample, the MyRx program — and a growing number of health system programs, doctors’ offices, and home tests available across the United States — gives consumers a window on inherited gene variants that can affect how their body activates, metabolizes, and clears away medications from a long list of widely used drugs.

Why PGx Tests Can Have a Big Impact

These tests work by looking for genes that control drug metabolism.

“You have several different drug-metabolizing enzymes in your liver,” Dr. Cicali explained. “Pharmacogenetic tests look for gene variants that encode for these enzymes. If you’re an ultrarapid metabolizer, you have more of the enzymes that metabolize certain drugs, and there could be a risk the drug won’t work well because it doesn’t stay in the body long enough. On the other end of the spectrum, poor metabolizers have low levels of enzymes that affect certain drugs, so the drugs hang around longer and cause side effects.”

While pharmacogenetics is still considered an emerging science, it’s becoming more mainstream as test prices drop, insurance coverage expands, and an explosion of new research boosts understanding of gene-drug interactions, Dr. Wiisanen said.

Politicians are trying to extend its reach, too. The Right Drug Dose Now Act of 2024, introduced in Congress in late March, aims to accelerate the use of PGx by boosting public awareness and by inserting PGx test results into consumers’ electronic health records. (Though a similar bill died in a US House subcommittee in 2023.)

“The use of pharmacogenetic data to guide prescribing is growing rapidly,” Dr. Wiisanen said. “It’s becoming a routine part of drug therapy for many medications.”

What the Research Shows

When researchers sequenced the DNA of more than 10,000 Mayo Clinic patients, they made a discovery that might surprise many Americans: Gene variants that affect the effectiveness and safety of widely used drugs are not rare glitches. More than 99% of study participants had at least one. And 79% had three or more.

The Mayo-Baylor RIGHT 10K Study — one of the largest PGx studies ever conducted in the United States — looked at 77 gene variants, most involved with drug metabolism in the liver. Researchers focused closely on 13 with extensively studied, gene-based prescribing recommendations for 21 drugs including antidepressants, statins, pain killers, anticlotting medications for heart conditions, HIV treatments, chemotherapy agents, and antirejection drugs for organ transplants.

When researchers added participants’ genetic data to their electronic health records, they also sent semi-urgent alerts, which are alerts with the potential for severe harm, to the clinicians of 61 study volunteers. Over half changed patients’ drugs or doses.

The changes made a difference. One participant taking the pain drug tramadol turned out to be a poor metabolizer and was having dizzy spells because blood levels of the drug stayed high for long periods. Stopping tramadol stopped the dizziness. A participant taking escitalopram plus bupropion for major depression found out that the combo was likely ineffective because they metabolized escitalopram rapidly. A switch to a higher dose of bupropion alone put their depression into full remission.

“So many factors play into how you respond to medications,” said Mayo Clinic pharmacogenomics pharmacist Jessica Wright, PharmD, BCACP, one of the study authors. “Genetics is one of those pieces. Pharmacogenetic testing can reveal things that clinicians may not have been aware of or could help explain a patient’s exaggerated side effect.”

Pharmacogenetics is also called pharmacogenomics. The terms are often used interchangeably, even among PGx pharmacists, though the first refers to how individual genes influence drug response and the second to the effects of multiple genes, said Kelly E. Caudle, PharmD, PhD, an associate member of the Department of Pharmacy and Pharmaceutical Sciences at St. Jude Children’s Research Hospital in Memphis, Tennessee. Dr. Caudle is also co-principal investigator and director of the National Institutes of Health (NIH)-funded Clinical Pharmacogenetics Implementation Consortium (CPIC). The group creates, publishes, and posts evidence-based clinical practice guidelines for drugs with well-researched PGx influences.

By any name, PGx may help explain, predict, and sidestep unpredictable responses to a variety of drugs:

• In a 2023 multicenter study of 6944 people from seven European countries in The Lancet, those given customized drug treatments based on a 12-gene PGx panel had 30% fewer side effects than those who didn’t get this personalized prescribing. People in the study were being treated for cancer, heart disease, and mental health issues, among other conditions.
• In a 2023  from China’s Tongji University, Shanghai, of 650 survivors of strokes and transient ischemic attacks, those whose antiplatelet drugs (such as clopidogrel) were customized based on PGx testing had a lower risk for stroke and other vascular events in the next 90 days. The study was published in Frontiers in Pharmacology.
• In a University of Pennsylvania  of 1944 adults with major depression, published in the Journal of the American Medical Association, those whose antidepressants were guided by PGx test results were 28% more likely to go into remission during the first 24 weeks of treatment than those in a control group. But by 24 weeks, equal numbers were in remission. A 2023 Chinese  of 11 depression studies, published in BMC Psychiatry, came to a similar conclusion: PGx-guided antidepressant prescriptions may help people feel better quicker, perhaps by avoiding some of the usual trial-and-error of different depression drugs.

PGx checks are already strongly recommended or considered routine before some medications are prescribed. These include abacavir (Ziagen), an antiviral treatment for HIV that can have severe side effects in people with one gene variant.

The US Food and Drug Administration (FDA) recommends genetic testing for people with colon cancer before starting the drug irinotecan (Camptosar), which can cause severe diarrhea and raise infection risk in people with a gene variant that slows the drug’s elimination from the body.

Genetic testing is also recommended by the FDA for people with acute lymphoblastic leukemia before receiving the chemotherapy drug mercaptopurine (Purinethol) because a gene variant that affects drug processing can trigger serious side effects and raise the risk for infection at standard dosages.

“One of the key benefits of pharmacogenomic testing is in preventing adverse drug reactions,” Dr. Wiisanen said. “Testing of the thiopurine methyltransferase enzyme to guide dosing with 6-mercaptopurine or azathioprine can help prevent myelosuppression, a serious adverse drug reaction caused by lower production of blood cells in bone marrow.”

When, Why, and How to Test

“A family doctor should consider a PGx test if a patient is planning on taking a medication for which there is a CPIC guideline with a dosing recommendation,” said Teri Klein, PhD, professor of biomedical data science at Stanford University in California, and principal investigator at PharmGKB, an online resource funded by the NIH that provides information for healthcare practitioners, researchers, and consumers about PGx. Affiliated with CPIC, it’s based at Stanford University.

You might also consider it for patients already on a drug who are “not responding or experiencing side effects,” Dr. Caudle said.

Here’s how four PGx experts suggest consumers and physicians approach this option.

Find a Test

More than a dozen PGx tests are on the market — some only a provider can order, others a consumer can order after a review by their provider or by a provider from the testing company. Some of the tests (using saliva) may be administered at home, while blood tests are done in a doctor’s office or laboratory. Companies that offer the tests include ARUP Laboratories, Genomind, Labcorp, Mayo Clinic Laboratories, Myriad Neuroscience, Precision Sciences Inc., Tempus, and OneOme, but there are many others online. (Keep in mind that many laboratories offer “lab-developed tests” — created for use in a single laboratory — but these can be harder to verify. “The FDA regulates pharmacogenomic testing in laboratories,” Dr. Wiisanen said, “but many of the regulatory parameters are still being defined.”)

Because PGx is so new, there is no official list of recommended tests. So you’ll have to do a little homework. You can check that the laboratory is accredited by searching for it in the NIH Genetic Testing Laboratory Registry database. Beyond that, you’ll have to consult other evidence-based resources to confirm that the drug you’re interested in has research-backed data about specific gene variants (alleles) that affect metabolism as well as research-based clinical guidelines for using PGx results to make prescribing decisions.

The CPIC’s guidelines include dosing and alternate drug recommendations for more than 100 antidepressants, chemotherapy drugs, the antiplatelet and anticlotting drugs clopidogrel and warfarin, local anesthetics, antivirals and antibacterials, pain killers and anti-inflammatory drugs, and some cholesterol-lowering statins such as lovastatin and fluvastatin.

For help figuring out if a test looks for the right gene variants, Dr. Caudle and Dr. Wright recommended checking with the Association for Molecular Pathology’s website. The group published a brief list of best practices for pharmacogenomic testing in 2019. And it keeps a list of gene variants (alleles) that should be included in tests. Clinical guidelines from the CPIC and other groups, available on PharmGKB’s website, also list gene variants that affect the metabolism of the drug.

Consider Cost

The price tag for a test is typically several hundred dollars — but it can run as high as $1000-$2500. And health insurance doesn’t always pick up the tab.

In a 2023 University of Florida study of more than 1000 insurance claims for PGx testing, the number reimbursed varied from 72% for a pain diagnosis to 52% for cardiology to 46% for psychiatry.

Medicare covers some PGx testing when a consumer and their providers meet certain criteria, including whether a drug being considered has a significant gene-drug interaction. California’s Medi-Cal health insurance program covers PGx as do Medicaid programs in some states, including Arkansas and Rhode Island. You can find state-by-state coverage information on the Genetics Policy Hub’s website.

Understand the Results

As more insurers cover PGx, Dr. Klein and Dr. Wiisanen say the field will grow and more providers will use it to inform prescribing. But some health systems aren’t waiting.

In addition to UF Health’s MyRx, PGx is part of personalized medicine programs at the University of Pennsylvania in Philadelphia, Endeavor Health in Chicago, the Mayo Clinic, the University of California, San Francisco, Sanford Health in Sioux Falls, South Dakota, and St. Jude Children’s Research Hospital in Memphis, Tennessee.

Beyond testing, they offer a very useful service: A consult with a pharmacogenetics pharmacist to review the results and explain what they mean for a consumer’s current and future medications.

Physicians and curious consumers can also consult CPIC’s guidelines, which give recommendations about how to interpret the results of a PGx test, said Dr. Klein, a co-principal investigator at CPIC. CPIC has a grading system for both the evidence that supports the recommendation (high, moderate, or weak) and the recommendation itself (strong, moderate, or optional).

Currently, labeling for 456 prescription drugs sold in the United States includes some type of PGx information, according to the FDA’s Table of Pharmacogenomic Biomarkers in Drug Labeling and an annotated guide from PharmGKB.

Just 108 drug labels currently tell doctors and patients what to do with the information — such as requiring or suggesting testing or offering prescribing recommendations, according to PharmGKB. In contrast, PharmGKB’s online resources include evidence-based clinical guidelines for 201 drugs from CPIC and from professional PGx societies in the Netherlands, Canada, France, and elsewhere.

Consumers and physicians can also look for a pharmacist with pharmacogenetics training in their area or through a nearby medical center to learn more, Dr. Wright suggested. And while consumers can test without working with their own physician, the experts advise against it. Don’t stop or change the dose of medications you already take on your own, they say . And do work with your primary care practitioner or specialist to get tested and understand how the results fit into the bigger picture of how your body responds to your medications.

A version of this article appeared on Medscape.com.

The principle of resilience and survival is crucial for medically significant fungi. These microorganisms are far from creating the postapocalyptic scenario depicted in TV series like The Last of Us, and much work is necessary to learn more about them. Accurate statistics on fungal infections, accompanied by clinical histories, simple laboratory tests, new antifungals, and a necessary One Health approach are lacking. 

The entomopathogenic fungus Ophiocordyceps unilateralis was made notorious by the TV series, but for now, it only manages to control the brains of some ants at will. Luckily, there are no signs that fungi affecting humans are inclined to create zombies.

What is clear is that the world belongs to the kingdom of fungi and that fungi are everywhere. There are already close to 150,000 described species, but millions remain to be discovered. They abound in decomposing organic matter, soil, or animal excrement, including that of bats and pigeons. Some fungi have even managed to find a home in hospitals. Lastly, we must not forget those that establish themselves in the human microbiome.

Given such diversity, it is legitimate to ask whether any of them could be capable of generating new pandemics. Could the forgotten Cryptococcus neoformans, Aspergillus fumigatus, or Histoplasma species, among others, trigger new health emergencies on the scale of the one generated by SARS-CoV-2?

We cannot forget that a coronavirus has already confirmed that reality can surpass fiction. However, Edith Sánchez Paredes, a biologist, doctor in biomedical sciences, and specialist in medical mycology, provided a reassuring response to Medscape Spanish Edition on this point.

“That would be very difficult to see because the way fungal infections are acquired is not from person to person, in most cases,” said Dr. Sánchez Paredes, from the Mycology Unit of the Faculty of Medicine at the National Autonomous University of Mexico.

Close to 300 species have already been classified as pathogenic in humans. Although the numbers are not precise and are increasing, it is estimated that around 1,500,000 people worldwide die each year of systemic fungal infections.

“However, it is important to emphasize that establishment of an infection depends not only on the causal agent. A crucial factor is the host, in this case, the human. Generally, these types of infections will develop in individuals with some deficiency in their immune system. The more deficient the immune response, the more likely a fungal infection may occur,” stated Dr. Sánchez Paredes.

The possibility of a pandemic like the one experienced with SARS-CoV-2 in the short term is remote, but the threat posed by fungal infections persists.

In 2022, the World Health Organization (WHO) defined a priority list of pathogenic fungi, with the aim of guiding actions to control them. It is mentioned there that invasive fungal diseases are on the rise worldwide, particularly in immunocompromised populations.

“Despite the growing concern, fungal infections receive very little attention and resources, leading to a paucity of quality data on fungal disease distribution and antifungal resistance patterns. Consequently, it is impossible to estimate their exact burden,” as stated in the document.

In line with this, an article published in Mycoses in 2022 concluded that fungal infections are neglected diseases in Latin America. Among other difficulties, deficiencies in access to tests such as polymerase chain reaction or serum detection of beta-1,3-D-glucan have been reported there.

In terms of treatments, most countries encounter problems with access to liposomal amphotericin B and new azoles, such as posaconazole and isavuconazole.

“Unfortunately, in Latin America, we suffer from a poor infrastructure for diagnosing fungal infections; likewise, we have limited access to antifungals available in the global market. What’s more, we lack reliable data on the epidemiology of fungal infections in the region, so many times governments are unaware of the true extent of the problem,” said Rogelio de Jesús Treviño Rangel, PhD, a medical microbiologist and expert in clinical mycology, professor, and researcher at the Faculty of Medicine of the Autonomous University of Nuevo León in Mexico.
 

Need for More Medical Mycology Training

Dr. Fernando Messina is a medical mycologist with the Mycology Unit of the Francisco Javier Muñiz Infectious Diseases Hospital in Buenos Aires, Argentina. He has noted an increase in the number of cases of cryptococcosis, histoplasmosis, and aspergillosis in his daily practice.

“Particularly, pulmonary aspergillosis is steadily increasing. This is because many patients have structural lung alterations that favor the appearance of this mycosis. This is related to the increase in cases of tuberculosis and the rise in life expectancy of patients with chronic obstructive pulmonary disease or other pulmonary or systemic diseases,” Dr. Messina stated.

For Dr. Messina, the main obstacle in current clinical practice is the low level of awareness among nonspecialist physicians regarding the presence of systemic fungal infections, and because these infections are more common than realized, it is vital to consider fungal etiology before starting empirical antibiotic therapy.

“Health professionals usually do not think about mycoses because mycology occupies a very small space in medical education at universities. As the Venezuelan mycologist Gioconda Cunto de San Blas once said, ‘Mycology is the Cinderella of microbiology.’ To change this, we need to give more space to mycoses in undergraduate and postgraduate studies,” Dr. Messina asserted.

He added, “The main challenge is to train professionals with an emphasis on the clinical interpretation of cases. Current medicine has a strong trend toward molecular biology and the use of rapid diagnostic methods, without considering the clinical symptoms or the patient’s history. Determinations are very useful, but it is necessary to interpret the results.”

Dr. Messina sees it as unlikely in the short term for a pandemic to be caused by fungi, but if it were to occur, he believes it would happen in healthcare systems in regions that are not prepared in terms of infrastructure. However, as seen in the health emergency resulting from SARS-CoV-2, he thinks the impact would be mitigated by the performance of healthcare professionals.

“In general, we have the ability to adapt to any adverse situation or change — although it is clear that we need more doctors, biochemists, and microbiologists trained in mycology,” emphasized Dr. Messina.

More than 40 interns pass through Muñiz Hospital each year. They are doctors and biochemists from Argentina, other countries in the region, or even Europe, seeking to enhance their training in mycology. Regarding fungal infection laboratory work, the interest lies in learning to use traditional techniques and innovative molecular methods.

“Rapid diagnostic methods, especially the detection of circulating antigens, have marked a change in the prognosis of deep mycosis in immunocompromised hosts. The possibility of screening and monitoring in this group of patients is very important and has a great benefit,” said Gabriela Santiso, PhD, a biochemist and head of the Mycology Unit of the Francisco Javier Muñiz Infectious Diseases Hospital.

According to Dr. Santiso, the current landscape includes the ability to identify genus and species, which can help in understanding resistance to antifungals. Furthermore, conducting sensitivity tests to these drugs, using standardized commercial methods, also provides timely information for treatment.

But Dr. Santiso warns that Latin America is a vast region with great disparity in human and technological resources. Although most countries in the region have networks facilitating access to timely diagnosis, resources are generally more available in major urban centers.

This often clashes with the epidemiology of most fungal infections. “Let’s not forget that many fungal pathologies affect low-income people who have difficulties accessing health centers, which sometimes turns them into chronic diseases that are hard to treat,” Dr. Santiso pointed out.

In mycology laboratories, the biggest cost is incurred by new diagnostic tests, such as those allowing molecular identification. Conventional methods are not usually expensive, but they require time and effort to train human resources to handle them.

Because new methodologies are not always available or easily accessible throughout the region, Dr. Santiso recommended not neglecting traditional mycological techniques. “Molecular methods, rapid diagnostic methods, and conventional mycology techniques are complementary and not mutually exclusive tests. Continuous training and updating are needed in this area,” she emphasized.
 

Why Are Resistant Fungal Infections Becoming Increasingly Common?

The first barrier for fungi to cause infection in humans is body temperature; most of them cannot withstand 37 °C. However, they also struggle to evade the immune response that is activated when they try to enter the body. 

“We are normally exposed to many of these fungi, almost all the time, but if our immune system is adequate, it may not go beyond a mild infection, in most cases subclinical, which will resolve quickly,” Dr. Sánchez Paredes stated.

However, according to Dr. Sánchez Paredes, if the immune response is weak, “the fungus will have no trouble establishing itself in our organs. Some are even part of our microbiota, such as Candida albicans, which in the face of an imbalance or immunocompromise, can lead to serious infections.”

It is clear that the population at risk for immunosuppression has increased. According to the WHO, this is due to the high prevalence of such diseases as tuberculosis, cancer, and HIV infection, among others.

But the WHO also believes that the increase in fungal infections is related to greater population access to critical care units, invasive procedures, chemotherapy, or immunotherapy treatments.

Furthermore, factors related to the fungus itself and the environment play a role. “These organisms have enzymes, proteins, and other molecules that allow them to survive in the environment in which they normally inhabit. When they face a new and stressful one, they must express other molecules that will allow them to survive. All of this helps them evade elements of the immune system, antifungals, and, of course, body temperature,” according to Dr. Sánchez Paredes.

It is possible that climate change is also behind the noticeable increase in fungal infections and that this crisis may have an even greater impact in the future. The temperature of the environment has increased, and fungi will have to adapt to the planet’s temperature, to the point where body temperature may no longer be a significant barrier for them.

Environmental changes would also be responsible for modifications in the distribution of endemic mycoses, and it is believed that fungi will more frequently find new ecological niches, be able to survive in other environments, and alter distribution zones.

This is what is happening between Mexico and the United States with coccidioidomycosis, or valley fever. “We will begin to see cases of some mycoses where they were not normally seen, so we will have to conduct more studies to confirm that the fungus is inhabiting these new areas or is simply appearing in new sites owing to migration and the great mobility of populations,” Dr. Sánchez Paredes said.

Finally, exposure to environmental factors would partly be responsible for the increasing resistance to first-line antifungals observed in these microorganisms. This seems to be the case with A. fumigatus when exposed to azoles used as fungicides in agriculture.
 

One Health in Fungal Infections

The increasing resistance to antifungals is a clear testament that human, animal, and environmental health are interconnected. This is why a multidisciplinary approach that adopts the perspective of One Health is necessary for its management.

“The use of fungicides in agriculture, structurally similar to the azoles used in clinics, generates resistance in Aspergillus fumigatus found in the environment. These fungi in humans can be associated with infections that do not respond to first-line treatment,” explained Carlos Arturo Álvarez, an infectious diseases physician and professor at the Faculty of Medicine at the National University of Colombia.

According to Dr. Álvarez, the approach to control them should not only focus on the search for diagnostic methods that allow early detection of antifungal resistance or research on new antifungal treatments. He believes that progress must also be made with strategies that allow for the proper use of antifungals in agriculture.

“Unfortunately, the One Health approach is not yet well implemented in the region, and in my view, there is a lack of articulation in the different sectors. That is, there is a need for true coordination between government offices of agriculture, animal and human health, academia, and international organizations. This is not happening yet, and I believe we are in the initial stage of visibility,” Dr. Álvarez opined.

Veterinary public health is another pillar of the aforementioned approach. For various reasons, animals experience a higher frequency of fungal infections. A few carry and transmit true zoonoses that affect human health, but most often, animals act only as sentinels indicating a potential source of transmission.

Carolina Segundo Zaragoza, PhD, has worked in veterinary mycology for 30 years. She currently heads the veterinary mycology laboratory at the Animal Production Teaching, Research, and Extension Center in Altiplano, under the Faculty of Veterinary Medicine and Animal Husbandry at the National Autonomous University of Mexico. Because she has frequent contact with specialists in human mycology, during her professional career she has received several patient consultations, most of which were for cutaneous mycoses.

“They detect some dermatomycosis and realize that the common factor is owning a companion animal or a production animal with which the patient has contact. Both animals and humans present the same type of lesions, and then comes the question: Who infected whom? I remind them that the main source of infection is the soil and that animals should not be blamed in the first instance,” Dr. Segundo Zaragoza clarified.

She is currently collaborating on a research project analyzing the presence of Coccidioides immitis in the soil. This pathogen is responsible for coccidioidomycosis in dogs and humans, and she sees with satisfaction how these types of initiatives, which include some components of the One Health vision, are becoming more common in Mexico.

“Fortunately, human mycologists are increasingly providing more space for the dissemination of veterinary mycology. So I have had the opportunity to be invited to different forums on medical mycology to present the clinical cases we can have in animals and talk about the research projects we carry out. I have more and more opportunities to conduct joint research with human mycologists and veterinary doctors,” she said.

Dr. Segundo Zaragoza believes that to better implement the One Health vision, standardizing the criteria for detecting, diagnosing, and treating mycoses is necessary. She considers that teamwork will be key to achieving the common goal of safeguarding the well-being and health of humans and animals.
 

Alarms Sound for Candida auris

The WHO included the yeast Candida auris in its group of pathogens with critical priority, and since 2009, it has raised alarm owing to the ease with which it grows in hospitals. In that setting, C auris is known for its high transmissibility, its ability to cause outbreaks, and the high mortality rate from disseminated infections.

“It has been a concern for the mycological community because it shows resistance to most antifungals used clinically, mainly azoles, but also for causing epidemic outbreaks,” emphasized Dr. Sánchez Paredes.

Its mode of transmission is not very clear, but it has been documented to be present on the skin and persist in hospital materials and furniture. It causes nosocomial infections in critically ill patients, such as those in intensive care, and those with cancer or who have received a transplant.

Risk factors for its development include renal insufficiency, hospital stays of more than 15 days, mechanical ventilation, central lines, use of parenteral nutrition, and presence of sepsis.

As for other mycoses, there are no precise studies reporting global incidence rates, but the trend indicates an increase in the detection of outbreaks in various countries lately — something that began to be visible during the COVID-19 pandemic.

In Mexico, Dr. Treviño Rangel and colleagues from Nuevo León reported the first case of candidemia caused by this agent. It occurred in May 2020 and involved a 58-year-old woman with a history of severe endometriosis and multiple complications in the gastrointestinal tract. The patient’s condition improved favorably thanks to antifungal therapy with caspofungin and liposomal amphotericin B.

However, 3 months after that episode, the group reported an outbreak of C. auris at the same hospital in 12 critically ill patients co-infected with SARS-CoV-2. All were on mechanical ventilation, had peripherally inserted central catheters and urinary catheters, and had a prolonged hospital stay (20-70 days). The mortality in patients with candidemia in this cohort was 83.3%.
 

Open Ending

As seen in some science fiction series, fungal infections in the region still have an open ending, and Global Action For Fungal Infections (GAFFI) has estimated that with better diagnostics and treatments, deaths caused by fungi could decrease to less than 750,000 per year worldwide.

But if everything continues as is, some aspects of what is to come may resemble the dystopia depicted in The Last of Us. No zombies, but emerging and reemerging fungi in a chaotic distribution, and resistant to all established treatments.

“The risk factors of patients and their immune status, combined with the behavior of mycoses, bring a complicated scenario. But therapeutic failure resulting from multidrug resistance to antifungals could make it catastrophic,” Dr. Sánchez Paredes summarized.

At the moment, there are only four families of drugs capable of counteracting fungal infections — and as mentioned, some are already scarce in Latin America’s hospital pharmacies.

“Historically, fungal infections have been given less importance than those caused by viruses or bacteria. Even in some developed countries, the true extent of morbidity and mortality they present is unknown. This results in less investment in the development of new antifungal molecules because knowledge is lacking about the incidence and prevalence of these diseases,” Dr. Treviño Rangel pointed out.

He added that the main limitation for the development of new drugs is economic. “Unfortunately, not many pharmaceutical companies are willing to invest in the development of new antifungals, and there are no government programs specifically promoting and supporting research into new therapeutic options against these neglected diseases,” he asserted.

Development of vaccines to prevent fungal infections faces the same barriers. Although, according to Dr. Treviño Rangel, the difficulties are compounded by the great similarity between fungal cells and human cells. This makes it possible for harmful cross-reactivity to occur. In addition, because most severe fungal infections occur in individuals with immunosuppression, a vaccine would need to trigger an adequate immune response despite this issue.

Meanwhile, fungi quietly continue to do what they do best: resist and survive. For millions of years, they have mutated and adapted to new environments. Some theories even blame them for the extinction of dinosaurs and the subsequent rise of mammals. They exist on the edge of life and death, decomposing and creating. There is consensus that at the moment, it does not seem feasible for them to generate a pandemic like the one due to SARS-CoV-2, given their transmission mechanism. But who is willing to rule out that this may not happen in the long or medium term?

Dr. Sánchez Paredes, Dr. Treviño Rangel, Dr. Messina, Dr. Santiso, Dr. Álvarez, and Dr. Segundo Zaragoza have declared no relevant financial conflicts of interest. 
 

This story was translated from Medscape Spanish Edition 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.

The principle of resilience and survival is crucial for medically significant fungi. These microorganisms are far from creating the postapocalyptic scenario depicted in TV series like The Last of Us, and much work is necessary to learn more about them. Accurate statistics on fungal infections, accompanied by clinical histories, simple laboratory tests, new antifungals, and a necessary One Health approach are lacking. 

The entomopathogenic fungus Ophiocordyceps unilateralis was made notorious by the TV series, but for now, it only manages to control the brains of some ants at will. Luckily, there are no signs that fungi affecting humans are inclined to create zombies.

What is clear is that the world belongs to the kingdom of fungi and that fungi are everywhere. There are already close to 150,000 described species, but millions remain to be discovered. They abound in decomposing organic matter, soil, or animal excrement, including that of bats and pigeons. Some fungi have even managed to find a home in hospitals. Lastly, we must not forget those that establish themselves in the human microbiome.

Given such diversity, it is legitimate to ask whether any of them could be capable of generating new pandemics. Could the forgotten Cryptococcus neoformans, Aspergillus fumigatus, or Histoplasma species, among others, trigger new health emergencies on the scale of the one generated by SARS-CoV-2?

We cannot forget that a coronavirus has already confirmed that reality can surpass fiction. However, Edith Sánchez Paredes, a biologist, doctor in biomedical sciences, and specialist in medical mycology, provided a reassuring response to Medscape Spanish Edition on this point.

“That would be very difficult to see because the way fungal infections are acquired is not from person to person, in most cases,” said Dr. Sánchez Paredes, from the Mycology Unit of the Faculty of Medicine at the National Autonomous University of Mexico.

Close to 300 species have already been classified as pathogenic in humans. Although the numbers are not precise and are increasing, it is estimated that around 1,500,000 people worldwide die each year of systemic fungal infections.

“However, it is important to emphasize that establishment of an infection depends not only on the causal agent. A crucial factor is the host, in this case, the human. Generally, these types of infections will develop in individuals with some deficiency in their immune system. The more deficient the immune response, the more likely a fungal infection may occur,” stated Dr. Sánchez Paredes.

The possibility of a pandemic like the one experienced with SARS-CoV-2 in the short term is remote, but the threat posed by fungal infections persists.

In 2022, the World Health Organization (WHO) defined a priority list of pathogenic fungi, with the aim of guiding actions to control them. It is mentioned there that invasive fungal diseases are on the rise worldwide, particularly in immunocompromised populations.

“Despite the growing concern, fungal infections receive very little attention and resources, leading to a paucity of quality data on fungal disease distribution and antifungal resistance patterns. Consequently, it is impossible to estimate their exact burden,” as stated in the document.

In line with this, an article published in Mycoses in 2022 concluded that fungal infections are neglected diseases in Latin America. Among other difficulties, deficiencies in access to tests such as polymerase chain reaction or serum detection of beta-1,3-D-glucan have been reported there.

In terms of treatments, most countries encounter problems with access to liposomal amphotericin B and new azoles, such as posaconazole and isavuconazole.

“Unfortunately, in Latin America, we suffer from a poor infrastructure for diagnosing fungal infections; likewise, we have limited access to antifungals available in the global market. What’s more, we lack reliable data on the epidemiology of fungal infections in the region, so many times governments are unaware of the true extent of the problem,” said Rogelio de Jesús Treviño Rangel, PhD, a medical microbiologist and expert in clinical mycology, professor, and researcher at the Faculty of Medicine of the Autonomous University of Nuevo León in Mexico.
 

Need for More Medical Mycology Training

Dr. Fernando Messina is a medical mycologist with the Mycology Unit of the Francisco Javier Muñiz Infectious Diseases Hospital in Buenos Aires, Argentina. He has noted an increase in the number of cases of cryptococcosis, histoplasmosis, and aspergillosis in his daily practice.

“Particularly, pulmonary aspergillosis is steadily increasing. This is because many patients have structural lung alterations that favor the appearance of this mycosis. This is related to the increase in cases of tuberculosis and the rise in life expectancy of patients with chronic obstructive pulmonary disease or other pulmonary or systemic diseases,” Dr. Messina stated.

For Dr. Messina, the main obstacle in current clinical practice is the low level of awareness among nonspecialist physicians regarding the presence of systemic fungal infections, and because these infections are more common than realized, it is vital to consider fungal etiology before starting empirical antibiotic therapy.

“Health professionals usually do not think about mycoses because mycology occupies a very small space in medical education at universities. As the Venezuelan mycologist Gioconda Cunto de San Blas once said, ‘Mycology is the Cinderella of microbiology.’ To change this, we need to give more space to mycoses in undergraduate and postgraduate studies,” Dr. Messina asserted.

He added, “The main challenge is to train professionals with an emphasis on the clinical interpretation of cases. Current medicine has a strong trend toward molecular biology and the use of rapid diagnostic methods, without considering the clinical symptoms or the patient’s history. Determinations are very useful, but it is necessary to interpret the results.”

Dr. Messina sees it as unlikely in the short term for a pandemic to be caused by fungi, but if it were to occur, he believes it would happen in healthcare systems in regions that are not prepared in terms of infrastructure. However, as seen in the health emergency resulting from SARS-CoV-2, he thinks the impact would be mitigated by the performance of healthcare professionals.

“In general, we have the ability to adapt to any adverse situation or change — although it is clear that we need more doctors, biochemists, and microbiologists trained in mycology,” emphasized Dr. Messina.

More than 40 interns pass through Muñiz Hospital each year. They are doctors and biochemists from Argentina, other countries in the region, or even Europe, seeking to enhance their training in mycology. Regarding fungal infection laboratory work, the interest lies in learning to use traditional techniques and innovative molecular methods.

“Rapid diagnostic methods, especially the detection of circulating antigens, have marked a change in the prognosis of deep mycosis in immunocompromised hosts. The possibility of screening and monitoring in this group of patients is very important and has a great benefit,” said Gabriela Santiso, PhD, a biochemist and head of the Mycology Unit of the Francisco Javier Muñiz Infectious Diseases Hospital.

According to Dr. Santiso, the current landscape includes the ability to identify genus and species, which can help in understanding resistance to antifungals. Furthermore, conducting sensitivity tests to these drugs, using standardized commercial methods, also provides timely information for treatment.

But Dr. Santiso warns that Latin America is a vast region with great disparity in human and technological resources. Although most countries in the region have networks facilitating access to timely diagnosis, resources are generally more available in major urban centers.

This often clashes with the epidemiology of most fungal infections. “Let’s not forget that many fungal pathologies affect low-income people who have difficulties accessing health centers, which sometimes turns them into chronic diseases that are hard to treat,” Dr. Santiso pointed out.

In mycology laboratories, the biggest cost is incurred by new diagnostic tests, such as those allowing molecular identification. Conventional methods are not usually expensive, but they require time and effort to train human resources to handle them.

Because new methodologies are not always available or easily accessible throughout the region, Dr. Santiso recommended not neglecting traditional mycological techniques. “Molecular methods, rapid diagnostic methods, and conventional mycology techniques are complementary and not mutually exclusive tests. Continuous training and updating are needed in this area,” she emphasized.
 

Why Are Resistant Fungal Infections Becoming Increasingly Common?

The first barrier for fungi to cause infection in humans is body temperature; most of them cannot withstand 37 °C. However, they also struggle to evade the immune response that is activated when they try to enter the body. 

“We are normally exposed to many of these fungi, almost all the time, but if our immune system is adequate, it may not go beyond a mild infection, in most cases subclinical, which will resolve quickly,” Dr. Sánchez Paredes stated.

However, according to Dr. Sánchez Paredes, if the immune response is weak, “the fungus will have no trouble establishing itself in our organs. Some are even part of our microbiota, such as Candida albicans, which in the face of an imbalance or immunocompromise, can lead to serious infections.”

It is clear that the population at risk for immunosuppression has increased. According to the WHO, this is due to the high prevalence of such diseases as tuberculosis, cancer, and HIV infection, among others.

But the WHO also believes that the increase in fungal infections is related to greater population access to critical care units, invasive procedures, chemotherapy, or immunotherapy treatments.

Furthermore, factors related to the fungus itself and the environment play a role. “These organisms have enzymes, proteins, and other molecules that allow them to survive in the environment in which they normally inhabit. When they face a new and stressful one, they must express other molecules that will allow them to survive. All of this helps them evade elements of the immune system, antifungals, and, of course, body temperature,” according to Dr. Sánchez Paredes.

It is possible that climate change is also behind the noticeable increase in fungal infections and that this crisis may have an even greater impact in the future. The temperature of the environment has increased, and fungi will have to adapt to the planet’s temperature, to the point where body temperature may no longer be a significant barrier for them.

Environmental changes would also be responsible for modifications in the distribution of endemic mycoses, and it is believed that fungi will more frequently find new ecological niches, be able to survive in other environments, and alter distribution zones.

This is what is happening between Mexico and the United States with coccidioidomycosis, or valley fever. “We will begin to see cases of some mycoses where they were not normally seen, so we will have to conduct more studies to confirm that the fungus is inhabiting these new areas or is simply appearing in new sites owing to migration and the great mobility of populations,” Dr. Sánchez Paredes said.

Finally, exposure to environmental factors would partly be responsible for the increasing resistance to first-line antifungals observed in these microorganisms. This seems to be the case with A. fumigatus when exposed to azoles used as fungicides in agriculture.
 

One Health in Fungal Infections

The increasing resistance to antifungals is a clear testament that human, animal, and environmental health are interconnected. This is why a multidisciplinary approach that adopts the perspective of One Health is necessary for its management.

“The use of fungicides in agriculture, structurally similar to the azoles used in clinics, generates resistance in Aspergillus fumigatus found in the environment. These fungi in humans can be associated with infections that do not respond to first-line treatment,” explained Carlos Arturo Álvarez, an infectious diseases physician and professor at the Faculty of Medicine at the National University of Colombia.

According to Dr. Álvarez, the approach to control them should not only focus on the search for diagnostic methods that allow early detection of antifungal resistance or research on new antifungal treatments. He believes that progress must also be made with strategies that allow for the proper use of antifungals in agriculture.

“Unfortunately, the One Health approach is not yet well implemented in the region, and in my view, there is a lack of articulation in the different sectors. That is, there is a need for true coordination between government offices of agriculture, animal and human health, academia, and international organizations. This is not happening yet, and I believe we are in the initial stage of visibility,” Dr. Álvarez opined.

Veterinary public health is another pillar of the aforementioned approach. For various reasons, animals experience a higher frequency of fungal infections. A few carry and transmit true zoonoses that affect human health, but most often, animals act only as sentinels indicating a potential source of transmission.

Carolina Segundo Zaragoza, PhD, has worked in veterinary mycology for 30 years. She currently heads the veterinary mycology laboratory at the Animal Production Teaching, Research, and Extension Center in Altiplano, under the Faculty of Veterinary Medicine and Animal Husbandry at the National Autonomous University of Mexico. Because she has frequent contact with specialists in human mycology, during her professional career she has received several patient consultations, most of which were for cutaneous mycoses.

“They detect some dermatomycosis and realize that the common factor is owning a companion animal or a production animal with which the patient has contact. Both animals and humans present the same type of lesions, and then comes the question: Who infected whom? I remind them that the main source of infection is the soil and that animals should not be blamed in the first instance,” Dr. Segundo Zaragoza clarified.

She is currently collaborating on a research project analyzing the presence of Coccidioides immitis in the soil. This pathogen is responsible for coccidioidomycosis in dogs and humans, and she sees with satisfaction how these types of initiatives, which include some components of the One Health vision, are becoming more common in Mexico.

“Fortunately, human mycologists are increasingly providing more space for the dissemination of veterinary mycology. So I have had the opportunity to be invited to different forums on medical mycology to present the clinical cases we can have in animals and talk about the research projects we carry out. I have more and more opportunities to conduct joint research with human mycologists and veterinary doctors,” she said.

Dr. Segundo Zaragoza believes that to better implement the One Health vision, standardizing the criteria for detecting, diagnosing, and treating mycoses is necessary. She considers that teamwork will be key to achieving the common goal of safeguarding the well-being and health of humans and animals.
 

Alarms Sound for Candida auris

The WHO included the yeast Candida auris in its group of pathogens with critical priority, and since 2009, it has raised alarm owing to the ease with which it grows in hospitals. In that setting, C auris is known for its high transmissibility, its ability to cause outbreaks, and the high mortality rate from disseminated infections.

“It has been a concern for the mycological community because it shows resistance to most antifungals used clinically, mainly azoles, but also for causing epidemic outbreaks,” emphasized Dr. Sánchez Paredes.

Its mode of transmission is not very clear, but it has been documented to be present on the skin and persist in hospital materials and furniture. It causes nosocomial infections in critically ill patients, such as those in intensive care, and those with cancer or who have received a transplant.

Risk factors for its development include renal insufficiency, hospital stays of more than 15 days, mechanical ventilation, central lines, use of parenteral nutrition, and presence of sepsis.

As for other mycoses, there are no precise studies reporting global incidence rates, but the trend indicates an increase in the detection of outbreaks in various countries lately — something that began to be visible during the COVID-19 pandemic.

In Mexico, Dr. Treviño Rangel and colleagues from Nuevo León reported the first case of candidemia caused by this agent. It occurred in May 2020 and involved a 58-year-old woman with a history of severe endometriosis and multiple complications in the gastrointestinal tract. The patient’s condition improved favorably thanks to antifungal therapy with caspofungin and liposomal amphotericin B.

However, 3 months after that episode, the group reported an outbreak of C. auris at the same hospital in 12 critically ill patients co-infected with SARS-CoV-2. All were on mechanical ventilation, had peripherally inserted central catheters and urinary catheters, and had a prolonged hospital stay (20-70 days). The mortality in patients with candidemia in this cohort was 83.3%.
 

Open Ending

As seen in some science fiction series, fungal infections in the region still have an open ending, and Global Action For Fungal Infections (GAFFI) has estimated that with better diagnostics and treatments, deaths caused by fungi could decrease to less than 750,000 per year worldwide.

But if everything continues as is, some aspects of what is to come may resemble the dystopia depicted in The Last of Us. No zombies, but emerging and reemerging fungi in a chaotic distribution, and resistant to all established treatments.

“The risk factors of patients and their immune status, combined with the behavior of mycoses, bring a complicated scenario. But therapeutic failure resulting from multidrug resistance to antifungals could make it catastrophic,” Dr. Sánchez Paredes summarized.

At the moment, there are only four families of drugs capable of counteracting fungal infections — and as mentioned, some are already scarce in Latin America’s hospital pharmacies.

“Historically, fungal infections have been given less importance than those caused by viruses or bacteria. Even in some developed countries, the true extent of morbidity and mortality they present is unknown. This results in less investment in the development of new antifungal molecules because knowledge is lacking about the incidence and prevalence of these diseases,” Dr. Treviño Rangel pointed out.

He added that the main limitation for the development of new drugs is economic. “Unfortunately, not many pharmaceutical companies are willing to invest in the development of new antifungals, and there are no government programs specifically promoting and supporting research into new therapeutic options against these neglected diseases,” he asserted.

Development of vaccines to prevent fungal infections faces the same barriers. Although, according to Dr. Treviño Rangel, the difficulties are compounded by the great similarity between fungal cells and human cells. This makes it possible for harmful cross-reactivity to occur. In addition, because most severe fungal infections occur in individuals with immunosuppression, a vaccine would need to trigger an adequate immune response despite this issue.

Meanwhile, fungi quietly continue to do what they do best: resist and survive. For millions of years, they have mutated and adapted to new environments. Some theories even blame them for the extinction of dinosaurs and the subsequent rise of mammals. They exist on the edge of life and death, decomposing and creating. There is consensus that at the moment, it does not seem feasible for them to generate a pandemic like the one due to SARS-CoV-2, given their transmission mechanism. But who is willing to rule out that this may not happen in the long or medium term?

Dr. Sánchez Paredes, Dr. Treviño Rangel, Dr. Messina, Dr. Santiso, Dr. Álvarez, and Dr. Segundo Zaragoza have declared no relevant financial conflicts of interest. 
 

This story was translated from Medscape Spanish Edition 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.

The principle of resilience and survival is crucial for medically significant fungi. These microorganisms are far from creating the postapocalyptic scenario depicted in TV series like The Last of Us, and much work is necessary to learn more about them. Accurate statistics on fungal infections, accompanied by clinical histories, simple laboratory tests, new antifungals, and a necessary One Health approach are lacking. 

The entomopathogenic fungus Ophiocordyceps unilateralis was made notorious by the TV series, but for now, it only manages to control the brains of some ants at will. Luckily, there are no signs that fungi affecting humans are inclined to create zombies.

What is clear is that the world belongs to the kingdom of fungi and that fungi are everywhere. There are already close to 150,000 described species, but millions remain to be discovered. They abound in decomposing organic matter, soil, or animal excrement, including that of bats and pigeons. Some fungi have even managed to find a home in hospitals. Lastly, we must not forget those that establish themselves in the human microbiome.

Given such diversity, it is legitimate to ask whether any of them could be capable of generating new pandemics. Could the forgotten Cryptococcus neoformans, Aspergillus fumigatus, or Histoplasma species, among others, trigger new health emergencies on the scale of the one generated by SARS-CoV-2?

We cannot forget that a coronavirus has already confirmed that reality can surpass fiction. However, Edith Sánchez Paredes, a biologist, doctor in biomedical sciences, and specialist in medical mycology, provided a reassuring response to Medscape Spanish Edition on this point.

“That would be very difficult to see because the way fungal infections are acquired is not from person to person, in most cases,” said Dr. Sánchez Paredes, from the Mycology Unit of the Faculty of Medicine at the National Autonomous University of Mexico.

Close to 300 species have already been classified as pathogenic in humans. Although the numbers are not precise and are increasing, it is estimated that around 1,500,000 people worldwide die each year of systemic fungal infections.

“However, it is important to emphasize that establishment of an infection depends not only on the causal agent. A crucial factor is the host, in this case, the human. Generally, these types of infections will develop in individuals with some deficiency in their immune system. The more deficient the immune response, the more likely a fungal infection may occur,” stated Dr. Sánchez Paredes.

The possibility of a pandemic like the one experienced with SARS-CoV-2 in the short term is remote, but the threat posed by fungal infections persists.

In 2022, the World Health Organization (WHO) defined a priority list of pathogenic fungi, with the aim of guiding actions to control them. It is mentioned there that invasive fungal diseases are on the rise worldwide, particularly in immunocompromised populations.

“Despite the growing concern, fungal infections receive very little attention and resources, leading to a paucity of quality data on fungal disease distribution and antifungal resistance patterns. Consequently, it is impossible to estimate their exact burden,” as stated in the document.

In line with this, an article published in Mycoses in 2022 concluded that fungal infections are neglected diseases in Latin America. Among other difficulties, deficiencies in access to tests such as polymerase chain reaction or serum detection of beta-1,3-D-glucan have been reported there.

In terms of treatments, most countries encounter problems with access to liposomal amphotericin B and new azoles, such as posaconazole and isavuconazole.

“Unfortunately, in Latin America, we suffer from a poor infrastructure for diagnosing fungal infections; likewise, we have limited access to antifungals available in the global market. What’s more, we lack reliable data on the epidemiology of fungal infections in the region, so many times governments are unaware of the true extent of the problem,” said Rogelio de Jesús Treviño Rangel, PhD, a medical microbiologist and expert in clinical mycology, professor, and researcher at the Faculty of Medicine of the Autonomous University of Nuevo León in Mexico.
 

Need for More Medical Mycology Training

Dr. Fernando Messina is a medical mycologist with the Mycology Unit of the Francisco Javier Muñiz Infectious Diseases Hospital in Buenos Aires, Argentina. He has noted an increase in the number of cases of cryptococcosis, histoplasmosis, and aspergillosis in his daily practice.

“Particularly, pulmonary aspergillosis is steadily increasing. This is because many patients have structural lung alterations that favor the appearance of this mycosis. This is related to the increase in cases of tuberculosis and the rise in life expectancy of patients with chronic obstructive pulmonary disease or other pulmonary or systemic diseases,” Dr. Messina stated.

For Dr. Messina, the main obstacle in current clinical practice is the low level of awareness among nonspecialist physicians regarding the presence of systemic fungal infections, and because these infections are more common than realized, it is vital to consider fungal etiology before starting empirical antibiotic therapy.

“Health professionals usually do not think about mycoses because mycology occupies a very small space in medical education at universities. As the Venezuelan mycologist Gioconda Cunto de San Blas once said, ‘Mycology is the Cinderella of microbiology.’ To change this, we need to give more space to mycoses in undergraduate and postgraduate studies,” Dr. Messina asserted.

He added, “The main challenge is to train professionals with an emphasis on the clinical interpretation of cases. Current medicine has a strong trend toward molecular biology and the use of rapid diagnostic methods, without considering the clinical symptoms or the patient’s history. Determinations are very useful, but it is necessary to interpret the results.”

Dr. Messina sees it as unlikely in the short term for a pandemic to be caused by fungi, but if it were to occur, he believes it would happen in healthcare systems in regions that are not prepared in terms of infrastructure. However, as seen in the health emergency resulting from SARS-CoV-2, he thinks the impact would be mitigated by the performance of healthcare professionals.

“In general, we have the ability to adapt to any adverse situation or change — although it is clear that we need more doctors, biochemists, and microbiologists trained in mycology,” emphasized Dr. Messina.

More than 40 interns pass through Muñiz Hospital each year. They are doctors and biochemists from Argentina, other countries in the region, or even Europe, seeking to enhance their training in mycology. Regarding fungal infection laboratory work, the interest lies in learning to use traditional techniques and innovative molecular methods.

“Rapid diagnostic methods, especially the detection of circulating antigens, have marked a change in the prognosis of deep mycosis in immunocompromised hosts. The possibility of screening and monitoring in this group of patients is very important and has a great benefit,” said Gabriela Santiso, PhD, a biochemist and head of the Mycology Unit of the Francisco Javier Muñiz Infectious Diseases Hospital.

According to Dr. Santiso, the current landscape includes the ability to identify genus and species, which can help in understanding resistance to antifungals. Furthermore, conducting sensitivity tests to these drugs, using standardized commercial methods, also provides timely information for treatment.

But Dr. Santiso warns that Latin America is a vast region with great disparity in human and technological resources. Although most countries in the region have networks facilitating access to timely diagnosis, resources are generally more available in major urban centers.

This often clashes with the epidemiology of most fungal infections. “Let’s not forget that many fungal pathologies affect low-income people who have difficulties accessing health centers, which sometimes turns them into chronic diseases that are hard to treat,” Dr. Santiso pointed out.

In mycology laboratories, the biggest cost is incurred by new diagnostic tests, such as those allowing molecular identification. Conventional methods are not usually expensive, but they require time and effort to train human resources to handle them.

Because new methodologies are not always available or easily accessible throughout the region, Dr. Santiso recommended not neglecting traditional mycological techniques. “Molecular methods, rapid diagnostic methods, and conventional mycology techniques are complementary and not mutually exclusive tests. Continuous training and updating are needed in this area,” she emphasized.
 

Why Are Resistant Fungal Infections Becoming Increasingly Common?

The first barrier for fungi to cause infection in humans is body temperature; most of them cannot withstand 37 °C. However, they also struggle to evade the immune response that is activated when they try to enter the body. 

“We are normally exposed to many of these fungi, almost all the time, but if our immune system is adequate, it may not go beyond a mild infection, in most cases subclinical, which will resolve quickly,” Dr. Sánchez Paredes stated.

However, according to Dr. Sánchez Paredes, if the immune response is weak, “the fungus will have no trouble establishing itself in our organs. Some are even part of our microbiota, such as Candida albicans, which in the face of an imbalance or immunocompromise, can lead to serious infections.”

It is clear that the population at risk for immunosuppression has increased. According to the WHO, this is due to the high prevalence of such diseases as tuberculosis, cancer, and HIV infection, among others.

But the WHO also believes that the increase in fungal infections is related to greater population access to critical care units, invasive procedures, chemotherapy, or immunotherapy treatments.

Furthermore, factors related to the fungus itself and the environment play a role. “These organisms have enzymes, proteins, and other molecules that allow them to survive in the environment in which they normally inhabit. When they face a new and stressful one, they must express other molecules that will allow them to survive. All of this helps them evade elements of the immune system, antifungals, and, of course, body temperature,” according to Dr. Sánchez Paredes.

It is possible that climate change is also behind the noticeable increase in fungal infections and that this crisis may have an even greater impact in the future. The temperature of the environment has increased, and fungi will have to adapt to the planet’s temperature, to the point where body temperature may no longer be a significant barrier for them.

Environmental changes would also be responsible for modifications in the distribution of endemic mycoses, and it is believed that fungi will more frequently find new ecological niches, be able to survive in other environments, and alter distribution zones.

This is what is happening between Mexico and the United States with coccidioidomycosis, or valley fever. “We will begin to see cases of some mycoses where they were not normally seen, so we will have to conduct more studies to confirm that the fungus is inhabiting these new areas or is simply appearing in new sites owing to migration and the great mobility of populations,” Dr. Sánchez Paredes said.

Finally, exposure to environmental factors would partly be responsible for the increasing resistance to first-line antifungals observed in these microorganisms. This seems to be the case with A. fumigatus when exposed to azoles used as fungicides in agriculture.
 

One Health in Fungal Infections

The increasing resistance to antifungals is a clear testament that human, animal, and environmental health are interconnected. This is why a multidisciplinary approach that adopts the perspective of One Health is necessary for its management.

“The use of fungicides in agriculture, structurally similar to the azoles used in clinics, generates resistance in Aspergillus fumigatus found in the environment. These fungi in humans can be associated with infections that do not respond to first-line treatment,” explained Carlos Arturo Álvarez, an infectious diseases physician and professor at the Faculty of Medicine at the National University of Colombia.

According to Dr. Álvarez, the approach to control them should not only focus on the search for diagnostic methods that allow early detection of antifungal resistance or research on new antifungal treatments. He believes that progress must also be made with strategies that allow for the proper use of antifungals in agriculture.

“Unfortunately, the One Health approach is not yet well implemented in the region, and in my view, there is a lack of articulation in the different sectors. That is, there is a need for true coordination between government offices of agriculture, animal and human health, academia, and international organizations. This is not happening yet, and I believe we are in the initial stage of visibility,” Dr. Álvarez opined.

Veterinary public health is another pillar of the aforementioned approach. For various reasons, animals experience a higher frequency of fungal infections. A few carry and transmit true zoonoses that affect human health, but most often, animals act only as sentinels indicating a potential source of transmission.

Carolina Segundo Zaragoza, PhD, has worked in veterinary mycology for 30 years. She currently heads the veterinary mycology laboratory at the Animal Production Teaching, Research, and Extension Center in Altiplano, under the Faculty of Veterinary Medicine and Animal Husbandry at the National Autonomous University of Mexico. Because she has frequent contact with specialists in human mycology, during her professional career she has received several patient consultations, most of which were for cutaneous mycoses.

“They detect some dermatomycosis and realize that the common factor is owning a companion animal or a production animal with which the patient has contact. Both animals and humans present the same type of lesions, and then comes the question: Who infected whom? I remind them that the main source of infection is the soil and that animals should not be blamed in the first instance,” Dr. Segundo Zaragoza clarified.

She is currently collaborating on a research project analyzing the presence of Coccidioides immitis in the soil. This pathogen is responsible for coccidioidomycosis in dogs and humans, and she sees with satisfaction how these types of initiatives, which include some components of the One Health vision, are becoming more common in Mexico.

“Fortunately, human mycologists are increasingly providing more space for the dissemination of veterinary mycology. So I have had the opportunity to be invited to different forums on medical mycology to present the clinical cases we can have in animals and talk about the research projects we carry out. I have more and more opportunities to conduct joint research with human mycologists and veterinary doctors,” she said.

Dr. Segundo Zaragoza believes that to better implement the One Health vision, standardizing the criteria for detecting, diagnosing, and treating mycoses is necessary. She considers that teamwork will be key to achieving the common goal of safeguarding the well-being and health of humans and animals.
 

Alarms Sound for Candida auris

The WHO included the yeast Candida auris in its group of pathogens with critical priority, and since 2009, it has raised alarm owing to the ease with which it grows in hospitals. In that setting, C auris is known for its high transmissibility, its ability to cause outbreaks, and the high mortality rate from disseminated infections.

“It has been a concern for the mycological community because it shows resistance to most antifungals used clinically, mainly azoles, but also for causing epidemic outbreaks,” emphasized Dr. Sánchez Paredes.

Its mode of transmission is not very clear, but it has been documented to be present on the skin and persist in hospital materials and furniture. It causes nosocomial infections in critically ill patients, such as those in intensive care, and those with cancer or who have received a transplant.

Risk factors for its development include renal insufficiency, hospital stays of more than 15 days, mechanical ventilation, central lines, use of parenteral nutrition, and presence of sepsis.

As for other mycoses, there are no precise studies reporting global incidence rates, but the trend indicates an increase in the detection of outbreaks in various countries lately — something that began to be visible during the COVID-19 pandemic.

In Mexico, Dr. Treviño Rangel and colleagues from Nuevo León reported the first case of candidemia caused by this agent. It occurred in May 2020 and involved a 58-year-old woman with a history of severe endometriosis and multiple complications in the gastrointestinal tract. The patient’s condition improved favorably thanks to antifungal therapy with caspofungin and liposomal amphotericin B.

However, 3 months after that episode, the group reported an outbreak of C. auris at the same hospital in 12 critically ill patients co-infected with SARS-CoV-2. All were on mechanical ventilation, had peripherally inserted central catheters and urinary catheters, and had a prolonged hospital stay (20-70 days). The mortality in patients with candidemia in this cohort was 83.3%.
 

Open Ending

As seen in some science fiction series, fungal infections in the region still have an open ending, and Global Action For Fungal Infections (GAFFI) has estimated that with better diagnostics and treatments, deaths caused by fungi could decrease to less than 750,000 per year worldwide.

But if everything continues as is, some aspects of what is to come may resemble the dystopia depicted in The Last of Us. No zombies, but emerging and reemerging fungi in a chaotic distribution, and resistant to all established treatments.

“The risk factors of patients and their immune status, combined with the behavior of mycoses, bring a complicated scenario. But therapeutic failure resulting from multidrug resistance to antifungals could make it catastrophic,” Dr. Sánchez Paredes summarized.

At the moment, there are only four families of drugs capable of counteracting fungal infections — and as mentioned, some are already scarce in Latin America’s hospital pharmacies.

“Historically, fungal infections have been given less importance than those caused by viruses or bacteria. Even in some developed countries, the true extent of morbidity and mortality they present is unknown. This results in less investment in the development of new antifungal molecules because knowledge is lacking about the incidence and prevalence of these diseases,” Dr. Treviño Rangel pointed out.

He added that the main limitation for the development of new drugs is economic. “Unfortunately, not many pharmaceutical companies are willing to invest in the development of new antifungals, and there are no government programs specifically promoting and supporting research into new therapeutic options against these neglected diseases,” he asserted.

Development of vaccines to prevent fungal infections faces the same barriers. Although, according to Dr. Treviño Rangel, the difficulties are compounded by the great similarity between fungal cells and human cells. This makes it possible for harmful cross-reactivity to occur. In addition, because most severe fungal infections occur in individuals with immunosuppression, a vaccine would need to trigger an adequate immune response despite this issue.

Meanwhile, fungi quietly continue to do what they do best: resist and survive. For millions of years, they have mutated and adapted to new environments. Some theories even blame them for the extinction of dinosaurs and the subsequent rise of mammals. They exist on the edge of life and death, decomposing and creating. There is consensus that at the moment, it does not seem feasible for them to generate a pandemic like the one due to SARS-CoV-2, given their transmission mechanism. But who is willing to rule out that this may not happen in the long or medium term?

Dr. Sánchez Paredes, Dr. Treviño Rangel, Dr. Messina, Dr. Santiso, Dr. Álvarez, and Dr. Segundo Zaragoza have declared no relevant financial conflicts of interest. 
 

This story was translated from Medscape Spanish Edition 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.

SAN DIEGO — Avoiding the use of antianaerobic antibiotics for empiric treatment of patients with sepsis can prevent depletion of beneficial bacteria in the gut microbiome and reduce both organ dysfunction and in-hospital mortality, a critical care specialists contends.

“You may not be personally moved by a 2- to 5-percent absolute difference in mortality, but sepsis is so common and so lethal that even small differences in outcomes can actually translate into enormous public health implications,” said Robert P. Dickson, MD a pulmonary and critical care specialist at the University of Michigan in Ann Arbor.

Neil Osterweil/MDedge News

If instead of prescribing piperacillin-tazobactam (Zosyn; pip-tazo) for sepsis critical care specialists were to switch to cefepime “even if you make very conservative assumptions like a modest effect size, you’re still talking about [saving] thousands of lives a year,” he said in a scientific symposium at the American Thoracic Society’s international conference.

“This is why I say this isn’t really over the horizon; this is microbiome modulation that’s happening all the time,” he said.

Most patients with sepsis in a medical ICU with respiratory, urinary or bloodstream sources of infection do not have indications for antianaerobic antibiotics, and there are no head-to-head clinical trials demonstrating a benefit for one anti-sepsis antibiotic strategy over another he said.

“In contrast, every observational study between antianaerobic and non-antianaerobic shows benefits to the anaerobe-sparing [drugs], and it’s been shown with animal models too. So to my mind, it’s already practice changing. I need to be talked into giving antianaerobic antibiotics for septic patients” he said.
 

Targeting gut microbiota

There are three basic approaches to focusing on the gut microbiome as a therapeutic target. The hardest is attempting to engineer an ecosystem — a fiendishly complex task with unpredictable results that has never been shown to work in either the gut or in the ICU, Dr. Dickson said.

A second approach, the use of probiotics to repopulate the gut with beneficial bacteria, is largely futile in the ICU, as the large majority of patients are on antibiotics and can’t be safely weaned off of them while in critical care. In this situation, giving probiotics would be akin to try to repopulate a forest while a forest fire is raging, he said.

The third and easiest approach is to minimize dysbiosis — imbalance of organisms in the gut — in the first place.

Anaerobic bacteria in the gut have been shown in several different disease states and animals models to be protective against pneumonia, organ failure, and death.

To see whether antianaerobic antibiotics could increase risk for adverse outcomes in the ICU, Dr. Dickson and colleagues previously conducted a retrospective study of 3032 mechanically ventilated patients in their center who received antibiotics either with or without anaerobic coverage in the first 72 hours.

They found that patients treated with early antianaerobic antibiotics had decreased ventilator-associated pneumonia-free survival (hazard ratio [HR] 1.24), infection-free survival (HR 1.22), and overall survival (HR 1.14) compared with patients who received antibiotics without anaerobic cover (all comparisons statistically significant by confidence intervals).

In a subcohort of 116 patients for whom gut microbiota data compositions were available, those who received antianaerobic antibiotics had decreased initial gut bacterial density (P = .00038), increased microbiome expansion during hospitalization (P = .011), and domination of the microbiome by Enterobacteriaceae species (P = .045). They also found that Enterobacteriaceae were enriched among respiratory pathogens in antianaerobic treated patients, and that in murine models, treatment with antianaerobic antibiotics increased susceptibility to Enterobacteriaceae pneumonia and increased the risk of death from non-infectious injuries.
 

Pip-tazo vs. cefepime

In the ACORN (Antibiotic Choice on Renal Outcomes) trial, results of which were reported by this news organization in November 2023, there were no differences in the highest stage of acute kidney injury or death in the first 14 days between piperacillin-tazobactam and cefepime. Remarking on the results, lead investigator Edward T. Qian, MD, MSc from Vanderbilt University in Nashville, Tennessee, said “I think the big takeaway is that you should feel comfortable starting or using pip-tazo for your patients who are coming into the hospital and receiving empiric antibiotics for acute infection.”

But as Dr. Dickson’s group reported more recently in JAMA Internal Medicine, a 15-month pip-tazo shortage allowed the investigators to conduct a natural experiment comparing 90-day outcomes among 7569 patients with sepsis who received vancomycin plus either pip-tazo or cefepime.

They found in an instrumental variable analysis that piperacillin-tazobactam was associated with an absolute increase in mortality at 90 days of 5.0%, and that patients who received this antianaerobic antibiotic had 2.1 fewer organ failure–free days, 1.1 fewer ventilator-free days, and 1.5 fewer vasopressor-free days.

“Our study reveals the potential risks associated with empirical piperacillin-tazobactam in patients with sepsis without a specific indication for antianaerobic therapy. These findings should prompt reconsideration and further study of the widespread use of empirical antianaerobic antibiotics in sepsis,” the investigators concluded.
 

Who gets what?

In the question-and-answer at the end of the session, comoderator Christina Sarah Thornton, MD, PhD, FRCPC from the University of Calgary, Alberta, asked Dr. Dickson whether the question of antianaerobic overuse in the ICU “is a function that we aren’t able yet from a diagnostic perspective to identify the group that may need antianaerobes? Because we often don’t get culture data back in time for a critically ill patient. Do you think there could maybe be a more rapid diagnostic for these patients?”

He replied that “a lot of our problems would be solved if we had really good, reliable rapid diagnostics for infection,” but noted that most of the patients in the study mentioned above did not have indications for antianaerobics.

Asked by this reporter whether Dr. Dickson’s presentation changed her mind about the use of piperacillin-tazobactam in her patients, Dr. Thornton replied “Yes! It did for me.”

She noted that although in Canada respirologists don’t work in intensive care units, “it makes me wonder about just giving pip-tazo to patients that are really sick. It definitely changed my mind.”

The work of Dr. Dickson and colleagues is supported by National Institute of Health and Agency for Healthcare Research and Quality grants. He reported no other relevant disclosures. Dr. Thornton had no relevant disclosures.

SAN DIEGO — Avoiding the use of antianaerobic antibiotics for empiric treatment of patients with sepsis can prevent depletion of beneficial bacteria in the gut microbiome and reduce both organ dysfunction and in-hospital mortality, a critical care specialists contends.

“You may not be personally moved by a 2- to 5-percent absolute difference in mortality, but sepsis is so common and so lethal that even small differences in outcomes can actually translate into enormous public health implications,” said Robert P. Dickson, MD a pulmonary and critical care specialist at the University of Michigan in Ann Arbor.

Neil Osterweil/MDedge News

If instead of prescribing piperacillin-tazobactam (Zosyn; pip-tazo) for sepsis critical care specialists were to switch to cefepime “even if you make very conservative assumptions like a modest effect size, you’re still talking about [saving] thousands of lives a year,” he said in a scientific symposium at the American Thoracic Society’s international conference.

“This is why I say this isn’t really over the horizon; this is microbiome modulation that’s happening all the time,” he said.

Most patients with sepsis in a medical ICU with respiratory, urinary or bloodstream sources of infection do not have indications for antianaerobic antibiotics, and there are no head-to-head clinical trials demonstrating a benefit for one anti-sepsis antibiotic strategy over another he said.

“In contrast, every observational study between antianaerobic and non-antianaerobic shows benefits to the anaerobe-sparing [drugs], and it’s been shown with animal models too. So to my mind, it’s already practice changing. I need to be talked into giving antianaerobic antibiotics for septic patients” he said.
 

Targeting gut microbiota

There are three basic approaches to focusing on the gut microbiome as a therapeutic target. The hardest is attempting to engineer an ecosystem — a fiendishly complex task with unpredictable results that has never been shown to work in either the gut or in the ICU, Dr. Dickson said.

A second approach, the use of probiotics to repopulate the gut with beneficial bacteria, is largely futile in the ICU, as the large majority of patients are on antibiotics and can’t be safely weaned off of them while in critical care. In this situation, giving probiotics would be akin to try to repopulate a forest while a forest fire is raging, he said.

The third and easiest approach is to minimize dysbiosis — imbalance of organisms in the gut — in the first place.

Anaerobic bacteria in the gut have been shown in several different disease states and animals models to be protective against pneumonia, organ failure, and death.

To see whether antianaerobic antibiotics could increase risk for adverse outcomes in the ICU, Dr. Dickson and colleagues previously conducted a retrospective study of 3032 mechanically ventilated patients in their center who received antibiotics either with or without anaerobic coverage in the first 72 hours.

They found that patients treated with early antianaerobic antibiotics had decreased ventilator-associated pneumonia-free survival (hazard ratio [HR] 1.24), infection-free survival (HR 1.22), and overall survival (HR 1.14) compared with patients who received antibiotics without anaerobic cover (all comparisons statistically significant by confidence intervals).

In a subcohort of 116 patients for whom gut microbiota data compositions were available, those who received antianaerobic antibiotics had decreased initial gut bacterial density (P = .00038), increased microbiome expansion during hospitalization (P = .011), and domination of the microbiome by Enterobacteriaceae species (P = .045). They also found that Enterobacteriaceae were enriched among respiratory pathogens in antianaerobic treated patients, and that in murine models, treatment with antianaerobic antibiotics increased susceptibility to Enterobacteriaceae pneumonia and increased the risk of death from non-infectious injuries.
 

Pip-tazo vs. cefepime

In the ACORN (Antibiotic Choice on Renal Outcomes) trial, results of which were reported by this news organization in November 2023, there were no differences in the highest stage of acute kidney injury or death in the first 14 days between piperacillin-tazobactam and cefepime. Remarking on the results, lead investigator Edward T. Qian, MD, MSc from Vanderbilt University in Nashville, Tennessee, said “I think the big takeaway is that you should feel comfortable starting or using pip-tazo for your patients who are coming into the hospital and receiving empiric antibiotics for acute infection.”

But as Dr. Dickson’s group reported more recently in JAMA Internal Medicine, a 15-month pip-tazo shortage allowed the investigators to conduct a natural experiment comparing 90-day outcomes among 7569 patients with sepsis who received vancomycin plus either pip-tazo or cefepime.

They found in an instrumental variable analysis that piperacillin-tazobactam was associated with an absolute increase in mortality at 90 days of 5.0%, and that patients who received this antianaerobic antibiotic had 2.1 fewer organ failure–free days, 1.1 fewer ventilator-free days, and 1.5 fewer vasopressor-free days.

“Our study reveals the potential risks associated with empirical piperacillin-tazobactam in patients with sepsis without a specific indication for antianaerobic therapy. These findings should prompt reconsideration and further study of the widespread use of empirical antianaerobic antibiotics in sepsis,” the investigators concluded.
 

Who gets what?

In the question-and-answer at the end of the session, comoderator Christina Sarah Thornton, MD, PhD, FRCPC from the University of Calgary, Alberta, asked Dr. Dickson whether the question of antianaerobic overuse in the ICU “is a function that we aren’t able yet from a diagnostic perspective to identify the group that may need antianaerobes? Because we often don’t get culture data back in time for a critically ill patient. Do you think there could maybe be a more rapid diagnostic for these patients?”

He replied that “a lot of our problems would be solved if we had really good, reliable rapid diagnostics for infection,” but noted that most of the patients in the study mentioned above did not have indications for antianaerobics.

Asked by this reporter whether Dr. Dickson’s presentation changed her mind about the use of piperacillin-tazobactam in her patients, Dr. Thornton replied “Yes! It did for me.”

She noted that although in Canada respirologists don’t work in intensive care units, “it makes me wonder about just giving pip-tazo to patients that are really sick. It definitely changed my mind.”

The work of Dr. Dickson and colleagues is supported by National Institute of Health and Agency for Healthcare Research and Quality grants. He reported no other relevant disclosures. Dr. Thornton had no relevant disclosures.

SAN DIEGO — Avoiding the use of antianaerobic antibiotics for empiric treatment of patients with sepsis can prevent depletion of beneficial bacteria in the gut microbiome and reduce both organ dysfunction and in-hospital mortality, a critical care specialists contends.

“You may not be personally moved by a 2- to 5-percent absolute difference in mortality, but sepsis is so common and so lethal that even small differences in outcomes can actually translate into enormous public health implications,” said Robert P. Dickson, MD a pulmonary and critical care specialist at the University of Michigan in Ann Arbor.

Neil Osterweil/MDedge News

If instead of prescribing piperacillin-tazobactam (Zosyn; pip-tazo) for sepsis critical care specialists were to switch to cefepime “even if you make very conservative assumptions like a modest effect size, you’re still talking about [saving] thousands of lives a year,” he said in a scientific symposium at the American Thoracic Society’s international conference.

“This is why I say this isn’t really over the horizon; this is microbiome modulation that’s happening all the time,” he said.

Most patients with sepsis in a medical ICU with respiratory, urinary or bloodstream sources of infection do not have indications for antianaerobic antibiotics, and there are no head-to-head clinical trials demonstrating a benefit for one anti-sepsis antibiotic strategy over another he said.

“In contrast, every observational study between antianaerobic and non-antianaerobic shows benefits to the anaerobe-sparing [drugs], and it’s been shown with animal models too. So to my mind, it’s already practice changing. I need to be talked into giving antianaerobic antibiotics for septic patients” he said.
 

Targeting gut microbiota

There are three basic approaches to focusing on the gut microbiome as a therapeutic target. The hardest is attempting to engineer an ecosystem — a fiendishly complex task with unpredictable results that has never been shown to work in either the gut or in the ICU, Dr. Dickson said.

A second approach, the use of probiotics to repopulate the gut with beneficial bacteria, is largely futile in the ICU, as the large majority of patients are on antibiotics and can’t be safely weaned off of them while in critical care. In this situation, giving probiotics would be akin to try to repopulate a forest while a forest fire is raging, he said.

The third and easiest approach is to minimize dysbiosis — imbalance of organisms in the gut — in the first place.

Anaerobic bacteria in the gut have been shown in several different disease states and animals models to be protective against pneumonia, organ failure, and death.

To see whether antianaerobic antibiotics could increase risk for adverse outcomes in the ICU, Dr. Dickson and colleagues previously conducted a retrospective study of 3032 mechanically ventilated patients in their center who received antibiotics either with or without anaerobic coverage in the first 72 hours.

They found that patients treated with early antianaerobic antibiotics had decreased ventilator-associated pneumonia-free survival (hazard ratio [HR] 1.24), infection-free survival (HR 1.22), and overall survival (HR 1.14) compared with patients who received antibiotics without anaerobic cover (all comparisons statistically significant by confidence intervals).

In a subcohort of 116 patients for whom gut microbiota data compositions were available, those who received antianaerobic antibiotics had decreased initial gut bacterial density (P = .00038), increased microbiome expansion during hospitalization (P = .011), and domination of the microbiome by Enterobacteriaceae species (P = .045). They also found that Enterobacteriaceae were enriched among respiratory pathogens in antianaerobic treated patients, and that in murine models, treatment with antianaerobic antibiotics increased susceptibility to Enterobacteriaceae pneumonia and increased the risk of death from non-infectious injuries.
 

Pip-tazo vs. cefepime

In the ACORN (Antibiotic Choice on Renal Outcomes) trial, results of which were reported by this news organization in November 2023, there were no differences in the highest stage of acute kidney injury or death in the first 14 days between piperacillin-tazobactam and cefepime. Remarking on the results, lead investigator Edward T. Qian, MD, MSc from Vanderbilt University in Nashville, Tennessee, said “I think the big takeaway is that you should feel comfortable starting or using pip-tazo for your patients who are coming into the hospital and receiving empiric antibiotics for acute infection.”

But as Dr. Dickson’s group reported more recently in JAMA Internal Medicine, a 15-month pip-tazo shortage allowed the investigators to conduct a natural experiment comparing 90-day outcomes among 7569 patients with sepsis who received vancomycin plus either pip-tazo or cefepime.

They found in an instrumental variable analysis that piperacillin-tazobactam was associated with an absolute increase in mortality at 90 days of 5.0%, and that patients who received this antianaerobic antibiotic had 2.1 fewer organ failure–free days, 1.1 fewer ventilator-free days, and 1.5 fewer vasopressor-free days.

“Our study reveals the potential risks associated with empirical piperacillin-tazobactam in patients with sepsis without a specific indication for antianaerobic therapy. These findings should prompt reconsideration and further study of the widespread use of empirical antianaerobic antibiotics in sepsis,” the investigators concluded.
 

Who gets what?

In the question-and-answer at the end of the session, comoderator Christina Sarah Thornton, MD, PhD, FRCPC from the University of Calgary, Alberta, asked Dr. Dickson whether the question of antianaerobic overuse in the ICU “is a function that we aren’t able yet from a diagnostic perspective to identify the group that may need antianaerobes? Because we often don’t get culture data back in time for a critically ill patient. Do you think there could maybe be a more rapid diagnostic for these patients?”

He replied that “a lot of our problems would be solved if we had really good, reliable rapid diagnostics for infection,” but noted that most of the patients in the study mentioned above did not have indications for antianaerobics.

Asked by this reporter whether Dr. Dickson’s presentation changed her mind about the use of piperacillin-tazobactam in her patients, Dr. Thornton replied “Yes! It did for me.”

She noted that although in Canada respirologists don’t work in intensive care units, “it makes me wonder about just giving pip-tazo to patients that are really sick. It definitely changed my mind.”

The work of Dr. Dickson and colleagues is supported by National Institute of Health and Agency for Healthcare Research and Quality grants. He reported no other relevant disclosures. Dr. Thornton had no relevant disclosures.