Infectious Diseases

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.

According to a US cross-sectional study, every fifth hospital patient with a respiratory syncytial virus (RSV) infection develops an acute cardiovascular event. For patients with a preexisting cardiovascular condition, an acute cardiovascular event occurs in every third patient, as shown by data published in JAMA Internal Medicine.

RSV attacks the respiratory tract, especially the mucous membranes of the upper airways and the ciliated epithelium of the trachea and bronchi. It is not the first respiratory virus with devastating consequences for the cardiovascular system.

“In the COVID-19 pandemic, we painfully learned that patients with preexisting cardiovascular conditions have significantly higher mortality rates and that cardiovascular causes are essential in COVID-19 mortality,” said Stephan Baldus, MD, director of Clinic III for Internal Medicine at the Heart Center of the University Hospital Cologne in Cologne, Germany.

“A direct link between the virus and the development of acute coronary events has also been demonstrated for influenza. Studies have shown that in the early days of an influenza infection, the rates of heart attacks and subsequent deaths increase significantly,” Dr. Baldus added. “And now, this study shows that patients with cardiovascular diseases have a critically increased risk for an acute cardiovascular event during an RSV infection.”
 

RSV Surveillance

Rebecca C. Woodruff, PhD, of the Centers for Disease Control and Prevention in Atlanta, and her colleagues analyzed data from an RSV surveillance program involving hospitals in 12 US states. The data covered hospitalized adults aged 50 years and older from five RSV seasons (from 2014/2015 to 2017/2018 and 2022/2023).

The 6248 patients were hospitalized for various reasons. They had a mean age of 73 years, and 60% of them were women. RSV infection was detected through a physician-ordered test within 14 days of admission. Slightly more than half (56.4%) of the patients had a preexisting cardiovascular condition that did not necessitate hospital treatment.

The researchers reported that more than a fifth (22.4%) of the patients with RSV had an acute cardiovascular event. Acute heart failure was most common (15.8%), but there were also acute ischemic heart disease in 7.5%, hypertensive crisis in 1.3%, ventricular tachycardia in 1.1%, and cardiogenic shock in 0.6%.
 

Acute Cardiovascular Events

Among the study population, 8.5% had no documented cardiovascular preexisting conditions. However, the risk was particularly elevated in patients with cardiovascular preexisting conditions. Overall, 33.0% of them had an acute cardiovascular event during the RSV infection.

Patients with acute cardiovascular events were almost twice as likely to have a severe course as those without acute cardiovascular events. The researchers considered treatment in the intensive care unit, the need for invasive mechanical ventilation, or the patient’s death in the hospital as severe outcomes.

Of all hospitalized patients with RSV, 18.6% required intensive care unit treatment, and 4.9% died during hospitalization. Compared with those without acute cardiovascular events, those with acute cardiovascular events had a significantly higher risk for intensive care treatment (25.8% vs 16.5%) and death in the hospital (8.1% vs 4.0%).

Although the analysis is not a prospective controlled study, according to Dr. Baldus, the results strongly suggest that RSV has cardiovascular effects. “When one in five hospitalized patients develops a cardiovascular event, that’s very suggestive,” he said.
 

More Testing Needed?

The results add to the evidence that RSV infections in older patients are associated with considerable morbidity and mortality. Unlike for COVID-19 and influenza, however, there is hardly any surveillance for RSV infections. RSV testing in hospitals is rare. Many doctors opt against testing for RSV because they are not aware of the importance of RSV as a pathogen in adults, but also because the diagnosis of RSV has no therapeutic consequences, wrote Dr. Woodruff and her colleagues.

Because there is no targeted therapy for an RSV infection, the detection of RSV can only be used as a marker for a risk for the development of an acute cardiovascular event, according to Dr. Baldus. Even considering the new study data, he emphasized, “Not every patient with a cardiovascular preexisting condition needs to be tested for RSV.”

The crucial factor is the clinical presentation. “If there is a clinical indication of pulmonary impairment (shortness of breath, tachypnea, subfebrile temperatures, or a diminished general condition) it would be desirable to perform an RSV test. This is especially true for patients requiring intensive care who need respiratory support,” said Dr. Baldus.
 

Benefits of Vaccination

The results highlight the basic epidemiology of potential cardiovascular complications of RSV infections, but before RSV vaccination became available, wrote Dr. Woodruff and her colleagues.

In 2023, the first RSV vaccine for adults aged 60 years and older was approved. “Here, a door to additional possibilities opens,” said Dr. Baldus. Although there are currently no official vaccination recommendations from Germany’s Standing Vaccination Commission, medical societies of oncologists and pulmonologists recommend vaccination against RSV. “Given the relevance of cardiovascular diseases for the prognosis of patients, but also for the occurrence of an acute cardiovascular event upon detection of RSV, the corresponding recommendation is expected to come,” said Dr. Baldus.

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

According to a US cross-sectional study, every fifth hospital patient with a respiratory syncytial virus (RSV) infection develops an acute cardiovascular event. For patients with a preexisting cardiovascular condition, an acute cardiovascular event occurs in every third patient, as shown by data published in JAMA Internal Medicine.

RSV attacks the respiratory tract, especially the mucous membranes of the upper airways and the ciliated epithelium of the trachea and bronchi. It is not the first respiratory virus with devastating consequences for the cardiovascular system.

“In the COVID-19 pandemic, we painfully learned that patients with preexisting cardiovascular conditions have significantly higher mortality rates and that cardiovascular causes are essential in COVID-19 mortality,” said Stephan Baldus, MD, director of Clinic III for Internal Medicine at the Heart Center of the University Hospital Cologne in Cologne, Germany.

“A direct link between the virus and the development of acute coronary events has also been demonstrated for influenza. Studies have shown that in the early days of an influenza infection, the rates of heart attacks and subsequent deaths increase significantly,” Dr. Baldus added. “And now, this study shows that patients with cardiovascular diseases have a critically increased risk for an acute cardiovascular event during an RSV infection.”
 

RSV Surveillance

Rebecca C. Woodruff, PhD, of the Centers for Disease Control and Prevention in Atlanta, and her colleagues analyzed data from an RSV surveillance program involving hospitals in 12 US states. The data covered hospitalized adults aged 50 years and older from five RSV seasons (from 2014/2015 to 2017/2018 and 2022/2023).

The 6248 patients were hospitalized for various reasons. They had a mean age of 73 years, and 60% of them were women. RSV infection was detected through a physician-ordered test within 14 days of admission. Slightly more than half (56.4%) of the patients had a preexisting cardiovascular condition that did not necessitate hospital treatment.

The researchers reported that more than a fifth (22.4%) of the patients with RSV had an acute cardiovascular event. Acute heart failure was most common (15.8%), but there were also acute ischemic heart disease in 7.5%, hypertensive crisis in 1.3%, ventricular tachycardia in 1.1%, and cardiogenic shock in 0.6%.
 

Acute Cardiovascular Events

Among the study population, 8.5% had no documented cardiovascular preexisting conditions. However, the risk was particularly elevated in patients with cardiovascular preexisting conditions. Overall, 33.0% of them had an acute cardiovascular event during the RSV infection.

Patients with acute cardiovascular events were almost twice as likely to have a severe course as those without acute cardiovascular events. The researchers considered treatment in the intensive care unit, the need for invasive mechanical ventilation, or the patient’s death in the hospital as severe outcomes.

Of all hospitalized patients with RSV, 18.6% required intensive care unit treatment, and 4.9% died during hospitalization. Compared with those without acute cardiovascular events, those with acute cardiovascular events had a significantly higher risk for intensive care treatment (25.8% vs 16.5%) and death in the hospital (8.1% vs 4.0%).

Although the analysis is not a prospective controlled study, according to Dr. Baldus, the results strongly suggest that RSV has cardiovascular effects. “When one in five hospitalized patients develops a cardiovascular event, that’s very suggestive,” he said.
 

More Testing Needed?

The results add to the evidence that RSV infections in older patients are associated with considerable morbidity and mortality. Unlike for COVID-19 and influenza, however, there is hardly any surveillance for RSV infections. RSV testing in hospitals is rare. Many doctors opt against testing for RSV because they are not aware of the importance of RSV as a pathogen in adults, but also because the diagnosis of RSV has no therapeutic consequences, wrote Dr. Woodruff and her colleagues.

Because there is no targeted therapy for an RSV infection, the detection of RSV can only be used as a marker for a risk for the development of an acute cardiovascular event, according to Dr. Baldus. Even considering the new study data, he emphasized, “Not every patient with a cardiovascular preexisting condition needs to be tested for RSV.”

The crucial factor is the clinical presentation. “If there is a clinical indication of pulmonary impairment (shortness of breath, tachypnea, subfebrile temperatures, or a diminished general condition) it would be desirable to perform an RSV test. This is especially true for patients requiring intensive care who need respiratory support,” said Dr. Baldus.
 

Benefits of Vaccination

The results highlight the basic epidemiology of potential cardiovascular complications of RSV infections, but before RSV vaccination became available, wrote Dr. Woodruff and her colleagues.

In 2023, the first RSV vaccine for adults aged 60 years and older was approved. “Here, a door to additional possibilities opens,” said Dr. Baldus. Although there are currently no official vaccination recommendations from Germany’s Standing Vaccination Commission, medical societies of oncologists and pulmonologists recommend vaccination against RSV. “Given the relevance of cardiovascular diseases for the prognosis of patients, but also for the occurrence of an acute cardiovascular event upon detection of RSV, the corresponding recommendation is expected to come,” said Dr. Baldus.

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

According to a US cross-sectional study, every fifth hospital patient with a respiratory syncytial virus (RSV) infection develops an acute cardiovascular event. For patients with a preexisting cardiovascular condition, an acute cardiovascular event occurs in every third patient, as shown by data published in JAMA Internal Medicine.

RSV attacks the respiratory tract, especially the mucous membranes of the upper airways and the ciliated epithelium of the trachea and bronchi. It is not the first respiratory virus with devastating consequences for the cardiovascular system.

“In the COVID-19 pandemic, we painfully learned that patients with preexisting cardiovascular conditions have significantly higher mortality rates and that cardiovascular causes are essential in COVID-19 mortality,” said Stephan Baldus, MD, director of Clinic III for Internal Medicine at the Heart Center of the University Hospital Cologne in Cologne, Germany.

“A direct link between the virus and the development of acute coronary events has also been demonstrated for influenza. Studies have shown that in the early days of an influenza infection, the rates of heart attacks and subsequent deaths increase significantly,” Dr. Baldus added. “And now, this study shows that patients with cardiovascular diseases have a critically increased risk for an acute cardiovascular event during an RSV infection.”
 

RSV Surveillance

Rebecca C. Woodruff, PhD, of the Centers for Disease Control and Prevention in Atlanta, and her colleagues analyzed data from an RSV surveillance program involving hospitals in 12 US states. The data covered hospitalized adults aged 50 years and older from five RSV seasons (from 2014/2015 to 2017/2018 and 2022/2023).

The 6248 patients were hospitalized for various reasons. They had a mean age of 73 years, and 60% of them were women. RSV infection was detected through a physician-ordered test within 14 days of admission. Slightly more than half (56.4%) of the patients had a preexisting cardiovascular condition that did not necessitate hospital treatment.

The researchers reported that more than a fifth (22.4%) of the patients with RSV had an acute cardiovascular event. Acute heart failure was most common (15.8%), but there were also acute ischemic heart disease in 7.5%, hypertensive crisis in 1.3%, ventricular tachycardia in 1.1%, and cardiogenic shock in 0.6%.
 

Acute Cardiovascular Events

Among the study population, 8.5% had no documented cardiovascular preexisting conditions. However, the risk was particularly elevated in patients with cardiovascular preexisting conditions. Overall, 33.0% of them had an acute cardiovascular event during the RSV infection.

Patients with acute cardiovascular events were almost twice as likely to have a severe course as those without acute cardiovascular events. The researchers considered treatment in the intensive care unit, the need for invasive mechanical ventilation, or the patient’s death in the hospital as severe outcomes.

Of all hospitalized patients with RSV, 18.6% required intensive care unit treatment, and 4.9% died during hospitalization. Compared with those without acute cardiovascular events, those with acute cardiovascular events had a significantly higher risk for intensive care treatment (25.8% vs 16.5%) and death in the hospital (8.1% vs 4.0%).

Although the analysis is not a prospective controlled study, according to Dr. Baldus, the results strongly suggest that RSV has cardiovascular effects. “When one in five hospitalized patients develops a cardiovascular event, that’s very suggestive,” he said.
 

More Testing Needed?

The results add to the evidence that RSV infections in older patients are associated with considerable morbidity and mortality. Unlike for COVID-19 and influenza, however, there is hardly any surveillance for RSV infections. RSV testing in hospitals is rare. Many doctors opt against testing for RSV because they are not aware of the importance of RSV as a pathogen in adults, but also because the diagnosis of RSV has no therapeutic consequences, wrote Dr. Woodruff and her colleagues.

Because there is no targeted therapy for an RSV infection, the detection of RSV can only be used as a marker for a risk for the development of an acute cardiovascular event, according to Dr. Baldus. Even considering the new study data, he emphasized, “Not every patient with a cardiovascular preexisting condition needs to be tested for RSV.”

The crucial factor is the clinical presentation. “If there is a clinical indication of pulmonary impairment (shortness of breath, tachypnea, subfebrile temperatures, or a diminished general condition) it would be desirable to perform an RSV test. This is especially true for patients requiring intensive care who need respiratory support,” said Dr. Baldus.
 

Benefits of Vaccination

The results highlight the basic epidemiology of potential cardiovascular complications of RSV infections, but before RSV vaccination became available, wrote Dr. Woodruff and her colleagues.

In 2023, the first RSV vaccine for adults aged 60 years and older was approved. “Here, a door to additional possibilities opens,” said Dr. Baldus. Although there are currently no official vaccination recommendations from Germany’s Standing Vaccination Commission, medical societies of oncologists and pulmonologists recommend vaccination against RSV. “Given the relevance of cardiovascular diseases for the prognosis of patients, but also for the occurrence of an acute cardiovascular event upon detection of RSV, the corresponding recommendation is expected to come,” said Dr. Baldus.

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

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

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

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

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

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

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

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

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

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

Antibiotic Dilemma

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

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

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

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

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

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

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

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

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

Get on the BUS

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

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

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

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

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

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

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

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

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

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

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

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

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

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

A version of this article appeared on Medscape.com.

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

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

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

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

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

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

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

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

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

Antibiotic Dilemma

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

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

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

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

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

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

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

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

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

Get on the BUS

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

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

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

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

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

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

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

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

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

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

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

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

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

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

A version of this article appeared on Medscape.com.

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

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

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

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

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

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

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

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

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

Antibiotic Dilemma

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

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

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

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

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

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

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

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

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

Get on the BUS

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

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

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

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

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

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

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

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

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

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

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

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

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

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

A version of this article appeared on Medscape.com.

People with HIV who wish to breastfeed their infants should have sustained viral suppression, with a viral load below 50 copies per mL, to have the least risk of transmitting HIV to their baby aside from avoiding breastfeeding altogether, according to a new clinical report from the American Academy of Pediatrics (AAP).

“The risk of HIV transmission via breastfeeding from a parent with HIV who is receiving antiretroviral treatment (ART) and is virally suppressed is estimated to be less than 1%,” Lisa Abuogi, MD, an associate professor of pediatric infectious disease at the University of Colorado Anschutz Medical Campus, and her colleagues wrote in Pediatrics. For people living with HIV in the United States, however, the AAP recommends that “avoidance of breastfeeding is the only infant feeding option with 0% risk of HIV transmission.”

The authors go on to suggest that pediatricians “be prepared to offer a family-centered, nonjudgmental, harm reduction approach” to support people with HIV who do want to breastfeed and have sustained viral suppression. Parents with HIV who are not on ART or who do not have adequate viral suppression should be advised against breastfeeding, the report states. Members of the AAP Committee on Pediatric and Adolescent HIV and of the AAP Section on Breastfeeding coauthored the clinical report.

“The new guidelines emphasize the importance of patient-centered counseling as the foundation for shared decision-making, allowing patients and pediatric providers to make feeding decisions together and for the first time really giving support to people with HIV in the U.S. who want to breastfeed,” Danna Biala, MD, MS, an attending pediatrician at Children’s Hospital at Montefiore and an assistant professor at Albert Einstein College of Medicine, told MDedge News.

Dr. Biala was not involved in the development of the report, but she said the AAP’s guidance reflects the recent shift in the stance of the Centers for Disease Control and Prevention (CDC) regarding breastfeeding among people who are HIV+. Recommendations from the CDC and the U.S. Department of Health and Human Services (HHS) were updated in 2023.

“I’m glad that the AAP is putting out guidelines on infant feeding for people with HIV,” Dr. Biala said. “For so long in the U.S., pediatricians have been advising all mothers with HIV to avoid breastfeeding, believing that the risk of transmission outweighed the benefits of breastfeeding.”

The updated guidance from HHS in 2023 “was revolutionary in supporting people with HIV in low-risk situations who want to breastfeed,” Dr. Biala said, but “clear protocols for monitoring and follow-up were not in place,” which these AAP guidelines help address.
 

Prior Discordance Between Global, U.S. Guidance

An estimated 5,000 people with HIV give birth each year in the United States, and up to one third of pregnant people with HIV may be unaware of their HIV status, the AAP report notes. Pediatric healthcare professionals in the United States therefore need to be aware of recommendations related to HIV testing of pregnant people and of counseling the feeding of infants exposed to HIV. The report recommends opt-out HIV testing at the first prenatal visit and then possibly retesting in the third trimester in areas with high HIV incidence or for people at high risk for HIV or with signs or symptoms of acute HIV infection.

The report also highlights the health benefits of breastfeeding to both the infant and the breastfeeding parent, but notes the CDC’s historical recommendation against breastfeeding for people who are HIV+. The WHO, meanwhile, began recommending in 2016 that infants be breastfed through 12 to 24 months old if the parent was on ART and/or the infant was receiving antiretroviral (ARV) prophylaxis, since research showed those treatments were effective in reducing transmission risk.

Still, an estimated 30% of perinatal HIV transmission occurs via breastfeeding worldwide, primarily from people with HIV who are not on ART or are not adequately virally suppressed. Without parental ART or infant ARV prophylaxis, HIV transmission risk to infants via breastfeeding is highest, about 5%-6%, in the first 4-6 weeks of life. Risk then declines to about 0.9% a month thereafter. The AAP report goes on to describe factors that increase or decrease the likelihood of transmission during breastfeeding, but it notes that neither ART in the breastfeeding person nor ARV prophylaxis in the infant completely eliminates the risk of HIV transmission during breastfeeding. There have been rare cases where transmission occurred despite viral suppression in the person with HIV.

Among the reasons people with HIV have expressed a desire to breastfeed are wanting to bond with their infant, wanting to provide optimal nutrition and health benefits to their baby, and meeting cultural expectations, including the desire not to disclose their HIV infection status to family or friends by virtue of not breastfeeding.

“Among immigrant and refugee populations, the discordance between infant feeding guidelines in the United States and their country of birth may result in confusion, especially among parents who breastfed previous infants,” the AAP report also notes. Further, not breastfeeding could compound health disparities already more likely to be present among those living with HIV.

Discussions about infant feeding with parents with HIV should therefore “begin as early as possible and involve a multidisciplinary team that might include the pediatric primary care provider (once identified), a pediatric HIV expert, the breastfeeding parent’s HIV care and obstetric providers, and lactation consultants,” the report states. ”The parent’s motivations for breastfeeding should be explored and counseling provided on the risks and benefits of each feeding option, including breastfeeding, formula feeding, or certified, banked donor human milk.” The statement emphasizes the need for providing counseling in a “non-judgmental, respectful way, recognizing potential drivers for their decisions such as avoidance of stigma, prior experience with breastfeeding, and cultural contributors.”
 

Clear Recommendations Can Help Providers

The AAP’s statement that “replacement feeding (with formula or certified, banked donor human milk) is the only option that is 100% certain to prevent postnatal transmission of HIV” feels like it takes a “more conservative or discouraging approach” to breastfeeding than the CDC or WHO guidelines, Alissa Parker-Smith, APRN, DNP, CPNP-PC, IBCLC, a nurse practitioner and lactation consultant at PrimaryPlus, a Federally Qualified Health Clinic in Ashland, Kentucky, told MDedge. But she said they do clearly align with the CDC guidelines, and their differences from the WHO guidelines make sense in light of the different populations served by the WHO versus the U.S. agencies.

“Unclean water for formula preparation and a reduced or lack of access to formula in general can lead to many other risks of death for the infant other than the very small risk of HIV infection from breastfeeding from an HIV+ parent,” Ms. Parker-Smith said. “In the U.S. we generally have consistent access to clean water and safe formula as well as social structures to help families have access to formula, so the very small risk of HIV being passed to the infant is far greater than an infant in the U.S. dying as a result of unclean water or formula contamination.”

Ms. Parker-Smith also said the AAP recommendations seem thorough in helping pediatric practitioners counsel and support parents with HIV. “If I had a parent who is HIV+ walk in the door today wanting to breastfeed their infant, the AAP guidelines give me specific steps to make me feel confident in helping that parent breastfeed as safely as possible as well as providing education to assist that parent through the decision process,” she said.

Dr. Biala agreed, noting that the clinical report “very clearly delineates recommendations for different groups of people: those in labor or postpartum with undocumented HIV infection status, pregnant and postpartum people with HIV, those without HIV but at high risk of acquiring it, and those with suspected acute HIV infection while breastfeeding.” Dr. Biala said the report “provides concrete, detailed, and easy-to-follow guidance on comprehensive counseling, strategies to minimize risk of transmission, and infant screening timelines.”

How easily the guidelines can be implemented will depend on the existing resources at different institutions in the United States, Dr. Biala added.

“In hospitals and clinics that have, or could easily have, systems in place to ensure follow-up and regular assessment during breastfeeding, the guidelines could be implemented fairly quickly,” she said. “It might be more challenging in areas with inadequate or limited access to multidisciplinary team members, including HIV care providers and lactation consultants.”

The report did not use external funding, and the authors reported no disclosures. Dr. Abuogi and Ms. Parker-Smith have no disclosures.

People with HIV who wish to breastfeed their infants should have sustained viral suppression, with a viral load below 50 copies per mL, to have the least risk of transmitting HIV to their baby aside from avoiding breastfeeding altogether, according to a new clinical report from the American Academy of Pediatrics (AAP).

“The risk of HIV transmission via breastfeeding from a parent with HIV who is receiving antiretroviral treatment (ART) and is virally suppressed is estimated to be less than 1%,” Lisa Abuogi, MD, an associate professor of pediatric infectious disease at the University of Colorado Anschutz Medical Campus, and her colleagues wrote in Pediatrics. For people living with HIV in the United States, however, the AAP recommends that “avoidance of breastfeeding is the only infant feeding option with 0% risk of HIV transmission.”

The authors go on to suggest that pediatricians “be prepared to offer a family-centered, nonjudgmental, harm reduction approach” to support people with HIV who do want to breastfeed and have sustained viral suppression. Parents with HIV who are not on ART or who do not have adequate viral suppression should be advised against breastfeeding, the report states. Members of the AAP Committee on Pediatric and Adolescent HIV and of the AAP Section on Breastfeeding coauthored the clinical report.

“The new guidelines emphasize the importance of patient-centered counseling as the foundation for shared decision-making, allowing patients and pediatric providers to make feeding decisions together and for the first time really giving support to people with HIV in the U.S. who want to breastfeed,” Danna Biala, MD, MS, an attending pediatrician at Children’s Hospital at Montefiore and an assistant professor at Albert Einstein College of Medicine, told MDedge News.

Dr. Biala was not involved in the development of the report, but she said the AAP’s guidance reflects the recent shift in the stance of the Centers for Disease Control and Prevention (CDC) regarding breastfeeding among people who are HIV+. Recommendations from the CDC and the U.S. Department of Health and Human Services (HHS) were updated in 2023.

“I’m glad that the AAP is putting out guidelines on infant feeding for people with HIV,” Dr. Biala said. “For so long in the U.S., pediatricians have been advising all mothers with HIV to avoid breastfeeding, believing that the risk of transmission outweighed the benefits of breastfeeding.”

The updated guidance from HHS in 2023 “was revolutionary in supporting people with HIV in low-risk situations who want to breastfeed,” Dr. Biala said, but “clear protocols for monitoring and follow-up were not in place,” which these AAP guidelines help address.
 

Prior Discordance Between Global, U.S. Guidance

An estimated 5,000 people with HIV give birth each year in the United States, and up to one third of pregnant people with HIV may be unaware of their HIV status, the AAP report notes. Pediatric healthcare professionals in the United States therefore need to be aware of recommendations related to HIV testing of pregnant people and of counseling the feeding of infants exposed to HIV. The report recommends opt-out HIV testing at the first prenatal visit and then possibly retesting in the third trimester in areas with high HIV incidence or for people at high risk for HIV or with signs or symptoms of acute HIV infection.

The report also highlights the health benefits of breastfeeding to both the infant and the breastfeeding parent, but notes the CDC’s historical recommendation against breastfeeding for people who are HIV+. The WHO, meanwhile, began recommending in 2016 that infants be breastfed through 12 to 24 months old if the parent was on ART and/or the infant was receiving antiretroviral (ARV) prophylaxis, since research showed those treatments were effective in reducing transmission risk.

Still, an estimated 30% of perinatal HIV transmission occurs via breastfeeding worldwide, primarily from people with HIV who are not on ART or are not adequately virally suppressed. Without parental ART or infant ARV prophylaxis, HIV transmission risk to infants via breastfeeding is highest, about 5%-6%, in the first 4-6 weeks of life. Risk then declines to about 0.9% a month thereafter. The AAP report goes on to describe factors that increase or decrease the likelihood of transmission during breastfeeding, but it notes that neither ART in the breastfeeding person nor ARV prophylaxis in the infant completely eliminates the risk of HIV transmission during breastfeeding. There have been rare cases where transmission occurred despite viral suppression in the person with HIV.

Among the reasons people with HIV have expressed a desire to breastfeed are wanting to bond with their infant, wanting to provide optimal nutrition and health benefits to their baby, and meeting cultural expectations, including the desire not to disclose their HIV infection status to family or friends by virtue of not breastfeeding.

“Among immigrant and refugee populations, the discordance between infant feeding guidelines in the United States and their country of birth may result in confusion, especially among parents who breastfed previous infants,” the AAP report also notes. Further, not breastfeeding could compound health disparities already more likely to be present among those living with HIV.

Discussions about infant feeding with parents with HIV should therefore “begin as early as possible and involve a multidisciplinary team that might include the pediatric primary care provider (once identified), a pediatric HIV expert, the breastfeeding parent’s HIV care and obstetric providers, and lactation consultants,” the report states. ”The parent’s motivations for breastfeeding should be explored and counseling provided on the risks and benefits of each feeding option, including breastfeeding, formula feeding, or certified, banked donor human milk.” The statement emphasizes the need for providing counseling in a “non-judgmental, respectful way, recognizing potential drivers for their decisions such as avoidance of stigma, prior experience with breastfeeding, and cultural contributors.”
 

Clear Recommendations Can Help Providers

The AAP’s statement that “replacement feeding (with formula or certified, banked donor human milk) is the only option that is 100% certain to prevent postnatal transmission of HIV” feels like it takes a “more conservative or discouraging approach” to breastfeeding than the CDC or WHO guidelines, Alissa Parker-Smith, APRN, DNP, CPNP-PC, IBCLC, a nurse practitioner and lactation consultant at PrimaryPlus, a Federally Qualified Health Clinic in Ashland, Kentucky, told MDedge. But she said they do clearly align with the CDC guidelines, and their differences from the WHO guidelines make sense in light of the different populations served by the WHO versus the U.S. agencies.

“Unclean water for formula preparation and a reduced or lack of access to formula in general can lead to many other risks of death for the infant other than the very small risk of HIV infection from breastfeeding from an HIV+ parent,” Ms. Parker-Smith said. “In the U.S. we generally have consistent access to clean water and safe formula as well as social structures to help families have access to formula, so the very small risk of HIV being passed to the infant is far greater than an infant in the U.S. dying as a result of unclean water or formula contamination.”

Ms. Parker-Smith also said the AAP recommendations seem thorough in helping pediatric practitioners counsel and support parents with HIV. “If I had a parent who is HIV+ walk in the door today wanting to breastfeed their infant, the AAP guidelines give me specific steps to make me feel confident in helping that parent breastfeed as safely as possible as well as providing education to assist that parent through the decision process,” she said.

Dr. Biala agreed, noting that the clinical report “very clearly delineates recommendations for different groups of people: those in labor or postpartum with undocumented HIV infection status, pregnant and postpartum people with HIV, those without HIV but at high risk of acquiring it, and those with suspected acute HIV infection while breastfeeding.” Dr. Biala said the report “provides concrete, detailed, and easy-to-follow guidance on comprehensive counseling, strategies to minimize risk of transmission, and infant screening timelines.”

How easily the guidelines can be implemented will depend on the existing resources at different institutions in the United States, Dr. Biala added.

“In hospitals and clinics that have, or could easily have, systems in place to ensure follow-up and regular assessment during breastfeeding, the guidelines could be implemented fairly quickly,” she said. “It might be more challenging in areas with inadequate or limited access to multidisciplinary team members, including HIV care providers and lactation consultants.”

The report did not use external funding, and the authors reported no disclosures. Dr. Abuogi and Ms. Parker-Smith have no disclosures.

People with HIV who wish to breastfeed their infants should have sustained viral suppression, with a viral load below 50 copies per mL, to have the least risk of transmitting HIV to their baby aside from avoiding breastfeeding altogether, according to a new clinical report from the American Academy of Pediatrics (AAP).

“The risk of HIV transmission via breastfeeding from a parent with HIV who is receiving antiretroviral treatment (ART) and is virally suppressed is estimated to be less than 1%,” Lisa Abuogi, MD, an associate professor of pediatric infectious disease at the University of Colorado Anschutz Medical Campus, and her colleagues wrote in Pediatrics. For people living with HIV in the United States, however, the AAP recommends that “avoidance of breastfeeding is the only infant feeding option with 0% risk of HIV transmission.”

The authors go on to suggest that pediatricians “be prepared to offer a family-centered, nonjudgmental, harm reduction approach” to support people with HIV who do want to breastfeed and have sustained viral suppression. Parents with HIV who are not on ART or who do not have adequate viral suppression should be advised against breastfeeding, the report states. Members of the AAP Committee on Pediatric and Adolescent HIV and of the AAP Section on Breastfeeding coauthored the clinical report.

“The new guidelines emphasize the importance of patient-centered counseling as the foundation for shared decision-making, allowing patients and pediatric providers to make feeding decisions together and for the first time really giving support to people with HIV in the U.S. who want to breastfeed,” Danna Biala, MD, MS, an attending pediatrician at Children’s Hospital at Montefiore and an assistant professor at Albert Einstein College of Medicine, told MDedge News.

Dr. Biala was not involved in the development of the report, but she said the AAP’s guidance reflects the recent shift in the stance of the Centers for Disease Control and Prevention (CDC) regarding breastfeeding among people who are HIV+. Recommendations from the CDC and the U.S. Department of Health and Human Services (HHS) were updated in 2023.

“I’m glad that the AAP is putting out guidelines on infant feeding for people with HIV,” Dr. Biala said. “For so long in the U.S., pediatricians have been advising all mothers with HIV to avoid breastfeeding, believing that the risk of transmission outweighed the benefits of breastfeeding.”

The updated guidance from HHS in 2023 “was revolutionary in supporting people with HIV in low-risk situations who want to breastfeed,” Dr. Biala said, but “clear protocols for monitoring and follow-up were not in place,” which these AAP guidelines help address.
 

Prior Discordance Between Global, U.S. Guidance

An estimated 5,000 people with HIV give birth each year in the United States, and up to one third of pregnant people with HIV may be unaware of their HIV status, the AAP report notes. Pediatric healthcare professionals in the United States therefore need to be aware of recommendations related to HIV testing of pregnant people and of counseling the feeding of infants exposed to HIV. The report recommends opt-out HIV testing at the first prenatal visit and then possibly retesting in the third trimester in areas with high HIV incidence or for people at high risk for HIV or with signs or symptoms of acute HIV infection.

The report also highlights the health benefits of breastfeeding to both the infant and the breastfeeding parent, but notes the CDC’s historical recommendation against breastfeeding for people who are HIV+. The WHO, meanwhile, began recommending in 2016 that infants be breastfed through 12 to 24 months old if the parent was on ART and/or the infant was receiving antiretroviral (ARV) prophylaxis, since research showed those treatments were effective in reducing transmission risk.

Still, an estimated 30% of perinatal HIV transmission occurs via breastfeeding worldwide, primarily from people with HIV who are not on ART or are not adequately virally suppressed. Without parental ART or infant ARV prophylaxis, HIV transmission risk to infants via breastfeeding is highest, about 5%-6%, in the first 4-6 weeks of life. Risk then declines to about 0.9% a month thereafter. The AAP report goes on to describe factors that increase or decrease the likelihood of transmission during breastfeeding, but it notes that neither ART in the breastfeeding person nor ARV prophylaxis in the infant completely eliminates the risk of HIV transmission during breastfeeding. There have been rare cases where transmission occurred despite viral suppression in the person with HIV.

Among the reasons people with HIV have expressed a desire to breastfeed are wanting to bond with their infant, wanting to provide optimal nutrition and health benefits to their baby, and meeting cultural expectations, including the desire not to disclose their HIV infection status to family or friends by virtue of not breastfeeding.

“Among immigrant and refugee populations, the discordance between infant feeding guidelines in the United States and their country of birth may result in confusion, especially among parents who breastfed previous infants,” the AAP report also notes. Further, not breastfeeding could compound health disparities already more likely to be present among those living with HIV.

Discussions about infant feeding with parents with HIV should therefore “begin as early as possible and involve a multidisciplinary team that might include the pediatric primary care provider (once identified), a pediatric HIV expert, the breastfeeding parent’s HIV care and obstetric providers, and lactation consultants,” the report states. ”The parent’s motivations for breastfeeding should be explored and counseling provided on the risks and benefits of each feeding option, including breastfeeding, formula feeding, or certified, banked donor human milk.” The statement emphasizes the need for providing counseling in a “non-judgmental, respectful way, recognizing potential drivers for their decisions such as avoidance of stigma, prior experience with breastfeeding, and cultural contributors.”
 

Clear Recommendations Can Help Providers

The AAP’s statement that “replacement feeding (with formula or certified, banked donor human milk) is the only option that is 100% certain to prevent postnatal transmission of HIV” feels like it takes a “more conservative or discouraging approach” to breastfeeding than the CDC or WHO guidelines, Alissa Parker-Smith, APRN, DNP, CPNP-PC, IBCLC, a nurse practitioner and lactation consultant at PrimaryPlus, a Federally Qualified Health Clinic in Ashland, Kentucky, told MDedge. But she said they do clearly align with the CDC guidelines, and their differences from the WHO guidelines make sense in light of the different populations served by the WHO versus the U.S. agencies.

“Unclean water for formula preparation and a reduced or lack of access to formula in general can lead to many other risks of death for the infant other than the very small risk of HIV infection from breastfeeding from an HIV+ parent,” Ms. Parker-Smith said. “In the U.S. we generally have consistent access to clean water and safe formula as well as social structures to help families have access to formula, so the very small risk of HIV being passed to the infant is far greater than an infant in the U.S. dying as a result of unclean water or formula contamination.”

Ms. Parker-Smith also said the AAP recommendations seem thorough in helping pediatric practitioners counsel and support parents with HIV. “If I had a parent who is HIV+ walk in the door today wanting to breastfeed their infant, the AAP guidelines give me specific steps to make me feel confident in helping that parent breastfeed as safely as possible as well as providing education to assist that parent through the decision process,” she said.

Dr. Biala agreed, noting that the clinical report “very clearly delineates recommendations for different groups of people: those in labor or postpartum with undocumented HIV infection status, pregnant and postpartum people with HIV, those without HIV but at high risk of acquiring it, and those with suspected acute HIV infection while breastfeeding.” Dr. Biala said the report “provides concrete, detailed, and easy-to-follow guidance on comprehensive counseling, strategies to minimize risk of transmission, and infant screening timelines.”

How easily the guidelines can be implemented will depend on the existing resources at different institutions in the United States, Dr. Biala added.

“In hospitals and clinics that have, or could easily have, systems in place to ensure follow-up and regular assessment during breastfeeding, the guidelines could be implemented fairly quickly,” she said. “It might be more challenging in areas with inadequate or limited access to multidisciplinary team members, including HIV care providers and lactation consultants.”

The report did not use external funding, and the authors reported no disclosures. Dr. Abuogi and Ms. Parker-Smith have no disclosures.

Macadamia (Macadamia tetraphylla) is endemic to Australia and is now commercially cultivated worldwide.¹ It is closely related genetically to the other macadamia plants, including the other main one, M. integrifolia, cultivated for macadamia nuts. Known in Brazil as sapucaia or castanha-de-sapucaia, Lecythis pisonis (also referred to as “cream nut” or “monkey pot”) is a large, deciduous tropical tree and member of the Brazil nut family, Lecythidaceae.² Various parts of both of these plants have been associated with medicinal properties, including the potential for dermatologic activity. Notably, the leaves of L. pisonis have been used in traditional medicine to treat pruritus.² This column focuses on the studies suggesting the possible benefits of macadamia and sapucaia components for skin care.

Macadamia

Extraction to Harness Antioxidant Activity

In 2015, Dailey and Vuong developed an aqueous extraction process to recover the phenolic content and antioxidant functionality from the skin waste of M. tetraphylla using response surface methodology. As an environmentally suitable solvent that is also cheap and safe, water was chosen to maximize the extraction scenario. They identified the proper conditions (90° C, a time of 20 min, and a sample-to-solvent ratio of 5 g/100 mL) to obtain sufficient phenolic compounds, proanthocyanidins, and flavonoids to render robust antioxidant function.¹

Baumann Cosmetic & Research Institute

Early in 2023, Somwongin et al. investigated various green extraction methods for viability in harnessing the cosmetic/cosmeceutical ingredients of M. integrifolia pericarps. Extracts were assessed for total phenolic content as well as antioxidant and anti–skin aging functions. They found that among the green extraction methods (ultrasound, micellar, microwave, and pulsed electric field extraction with water used as a clean solvent), the ultrasound-assisted extraction method netted the greatest yield and total phenolic content. It was also associated with the most robust antioxidant and anti–skin aging activities. Indeed, the researchers reported that its antioxidant activities were comparable to ascorbic acid and Trolox and its anti–skin aging potency on a par with epigallocatechin-3-gallate and oleanolic acid. The ultrasound-assisted extract was also deemed safe as it did not provoke irritation. The authors concluded that this environmentally suitable extraction method for M. integrifolia is appropriate for obtaining effective macadamia extracts for use in cosmetics and cosmeceuticals.³

Anti-Aging Activity

In 2017, Addy et al. set out to characterize skin surface lipid composition and differences in an age- and sex-controlled population as a foundation for developing a botanically derived skin surface lipid mimetic agent. They noted that fatty acids, triglycerides, cholesterol, steryl esters, wax esters, and squalene are the main constituents of skin surface lipids. The investigators obtained skin surface lipid samples from the foreheads of 59 healthy 22-year-old women, analyzed them, and used the raw components of M. integrifolia, Simmondsia chinensis, and Olea europaea to engineer a mimetic product. They reported that the esterification reactions of jojoba, macadamia, and tall oils, combined with squalene derived from O. europaea, yielded an appropriate skin surface lipid mimetic, which, when applied to delipidized skin, assisted in recovering barrier function, enhancing skin hydration, and improving elasticity as well as firmness in aged skin. The researchers concluded that this skin surface lipid mimetic could serve as an effective supplement to human skin surface lipids in aged skin and for conditions in which the stratum corneum is impaired.⁴

Two years later, Hanum et al. compared the effects of macadamia nut oil nanocream and conventional cream for treating cutaneous aging over a 4-week period. The macadamia nut oil nanocream, which contained macadamia nut oil 10%, tween 80, propylene glycol, cetyl alcohol, methylparaben, propylparaben, and distilled water, was compared with the conventional cream based on effects on moisture, evenness, pore size, melanin, and wrinkling. The macadamia nut oil was found to yield superior anti-aging activity along each parameter as compared with the conventional cream. The researchers concluded that the macadamia nut oil in nanocream can be an effective formulation for providing benefits in addressing cutaneous aging.⁵

Matthieu Sontag/Wikimedia Commons/CC-BY-SA

Antifungal Activity

In 2015, Vieira et al. characterized 12 fractions enriched in peptides derived from L. pisonis seeds to determine inhibitory activity against Candida albicans. The fraction that exerted the strongest activity at 10 μg/mL, suppressing C. albicans growth by 38.5% and inducing a 69.3% loss of viability, was identified as similar to plant defensins and thus dubbed “L. pisonis defensin 1 (Lp-Def1).” The investigators concluded that Lp-Def1 acts on C. albicans by slightly elevating the induction of reactive oxygen species and causing a significant reduction in mitochondrial activity. They suggested that their findings support the use of plant defensins, particularly Lp-Def1, in the formulation of antifungal products, especially to address C. albicans.¹⁰

Pruritus

In 2012, Silva et al. studied the antipruritic impact of L. pisonis leaf extracts in mice and rats. Pretreatment with the various fractions of L. pisonis as well as constituent mixed triterpenes (ursolic and oleanolic acids) significantly blocked scratching behavior provoked by compound 48/80. The degranulation of rat peritoneal mast cells caused by compound 48/80 was also substantially decreased from pretreatment with the ethanol extract of L. pisonis, ether-L. pisonis fraction, and mixed triterpenes. The L. pisonis ether fraction suppressed edema induced by carrageenan administration and the ethanol extract displayed no toxicity up to an oral dose of 2g/kg. The investigators concluded that their results strongly support the antipruritic effects of L. pisonis leaves as well as the traditional use of the plant to treat pruritus.²

Stability for Cosmetic Creams

In 2020, Rampazzo et al. assessed the stability and cytotoxicity of a cosmetic cream containing sapucaia nut oil. All three tested concentrations (1%, 5%, and 10%) of the cream were found to be stable, with an effective preservative system, and deemed safe for use on human skin. To maintain a pH appropriate for a body cream, the formulation requires a stabilizing agent. The cream with 5% nut oil was identified as the most stable and satisfying for use on the skin.⁷

More recently, Hertel Pereira et al. investigated the benefits of using L. pisonis pericarp extract, known to exhibit abundant antioxidants, in an all-natural skin cream. They found that formulation instability increased proportionally with the concentration of the extract, but the use of the outer pericarp of L. pisonis was well suited for the cream formulation, with physical-chemical and organoleptic qualities unchanged after the stability test.¹¹

Conclusion

The available literature on the medical applications of macadamia and sapucaia plants is sparse. Some recent findings are promising regarding possible uses in skin health. However, much more research is necessary before considering macadamia and sapucaia as viable sources of botanical agents capable of delivering significant cutaneous benefits.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., an SaaS company used to generate skin care routines in office and as an e-commerce solution. Write to her at [email protected].

References

1. Dailey A and Vuong QV. Antioxidants (Basel). 2015 Nov 12;4(4):699-718.

2. Silva LL et al. J Ethnopharmacol. 2012 Jan 6;139(1):90-97.

3. Somwongin S et al. Ultrason Sonochem. 2023 Jan;92:106266.

4. Addy J et al. J Cosmet Sci. 2017 Jan/Feb;68(1):59-67.

5. Hanum TI et al. Open Access Maced J Med Sci. 2019 Nov 14;7(22):3917-3920.

6. Akhtar N and Yazan Y. Pak J Pharm Sci. 2008 Jan;21(1):45-50.

7. Rampazzo APS et al. J Cosmet Sci. 2020 Sep/Oct;71(5):239-250.

8. Rosa TLM et al. Food Res Int. 2020 Nov;137:109383.

9. Demoliner F et al. Food Res Int. 2018 Oct;112:434-442.

10. Vieira ME et al. Acta Biochim Biophys Sin (Shanghai). 2015 Sep;47(9):716-729.

11. Hertel Pereira AC et al. J Cosmet Sci. 2021 Mar-Apr;72(2):155-162.

Macadamia (Macadamia tetraphylla) is endemic to Australia and is now commercially cultivated worldwide.¹ It is closely related genetically to the other macadamia plants, including the other main one, M. integrifolia, cultivated for macadamia nuts. Known in Brazil as sapucaia or castanha-de-sapucaia, Lecythis pisonis (also referred to as “cream nut” or “monkey pot”) is a large, deciduous tropical tree and member of the Brazil nut family, Lecythidaceae.² Various parts of both of these plants have been associated with medicinal properties, including the potential for dermatologic activity. Notably, the leaves of L. pisonis have been used in traditional medicine to treat pruritus.² This column focuses on the studies suggesting the possible benefits of macadamia and sapucaia components for skin care.

Macadamia

Extraction to Harness Antioxidant Activity

In 2015, Dailey and Vuong developed an aqueous extraction process to recover the phenolic content and antioxidant functionality from the skin waste of M. tetraphylla using response surface methodology. As an environmentally suitable solvent that is also cheap and safe, water was chosen to maximize the extraction scenario. They identified the proper conditions (90° C, a time of 20 min, and a sample-to-solvent ratio of 5 g/100 mL) to obtain sufficient phenolic compounds, proanthocyanidins, and flavonoids to render robust antioxidant function.¹

Baumann Cosmetic & Research Institute

Early in 2023, Somwongin et al. investigated various green extraction methods for viability in harnessing the cosmetic/cosmeceutical ingredients of M. integrifolia pericarps. Extracts were assessed for total phenolic content as well as antioxidant and anti–skin aging functions. They found that among the green extraction methods (ultrasound, micellar, microwave, and pulsed electric field extraction with water used as a clean solvent), the ultrasound-assisted extraction method netted the greatest yield and total phenolic content. It was also associated with the most robust antioxidant and anti–skin aging activities. Indeed, the researchers reported that its antioxidant activities were comparable to ascorbic acid and Trolox and its anti–skin aging potency on a par with epigallocatechin-3-gallate and oleanolic acid. The ultrasound-assisted extract was also deemed safe as it did not provoke irritation. The authors concluded that this environmentally suitable extraction method for M. integrifolia is appropriate for obtaining effective macadamia extracts for use in cosmetics and cosmeceuticals.³

Anti-Aging Activity

In 2017, Addy et al. set out to characterize skin surface lipid composition and differences in an age- and sex-controlled population as a foundation for developing a botanically derived skin surface lipid mimetic agent. They noted that fatty acids, triglycerides, cholesterol, steryl esters, wax esters, and squalene are the main constituents of skin surface lipids. The investigators obtained skin surface lipid samples from the foreheads of 59 healthy 22-year-old women, analyzed them, and used the raw components of M. integrifolia, Simmondsia chinensis, and Olea europaea to engineer a mimetic product. They reported that the esterification reactions of jojoba, macadamia, and tall oils, combined with squalene derived from O. europaea, yielded an appropriate skin surface lipid mimetic, which, when applied to delipidized skin, assisted in recovering barrier function, enhancing skin hydration, and improving elasticity as well as firmness in aged skin. The researchers concluded that this skin surface lipid mimetic could serve as an effective supplement to human skin surface lipids in aged skin and for conditions in which the stratum corneum is impaired.⁴

Two years later, Hanum et al. compared the effects of macadamia nut oil nanocream and conventional cream for treating cutaneous aging over a 4-week period. The macadamia nut oil nanocream, which contained macadamia nut oil 10%, tween 80, propylene glycol, cetyl alcohol, methylparaben, propylparaben, and distilled water, was compared with the conventional cream based on effects on moisture, evenness, pore size, melanin, and wrinkling. The macadamia nut oil was found to yield superior anti-aging activity along each parameter as compared with the conventional cream. The researchers concluded that the macadamia nut oil in nanocream can be an effective formulation for providing benefits in addressing cutaneous aging.⁵

Matthieu Sontag/Wikimedia Commons/CC-BY-SA

Antifungal Activity

In 2015, Vieira et al. characterized 12 fractions enriched in peptides derived from L. pisonis seeds to determine inhibitory activity against Candida albicans. The fraction that exerted the strongest activity at 10 μg/mL, suppressing C. albicans growth by 38.5% and inducing a 69.3% loss of viability, was identified as similar to plant defensins and thus dubbed “L. pisonis defensin 1 (Lp-Def1).” The investigators concluded that Lp-Def1 acts on C. albicans by slightly elevating the induction of reactive oxygen species and causing a significant reduction in mitochondrial activity. They suggested that their findings support the use of plant defensins, particularly Lp-Def1, in the formulation of antifungal products, especially to address C. albicans.¹⁰

Pruritus

In 2012, Silva et al. studied the antipruritic impact of L. pisonis leaf extracts in mice and rats. Pretreatment with the various fractions of L. pisonis as well as constituent mixed triterpenes (ursolic and oleanolic acids) significantly blocked scratching behavior provoked by compound 48/80. The degranulation of rat peritoneal mast cells caused by compound 48/80 was also substantially decreased from pretreatment with the ethanol extract of L. pisonis, ether-L. pisonis fraction, and mixed triterpenes. The L. pisonis ether fraction suppressed edema induced by carrageenan administration and the ethanol extract displayed no toxicity up to an oral dose of 2g/kg. The investigators concluded that their results strongly support the antipruritic effects of L. pisonis leaves as well as the traditional use of the plant to treat pruritus.²

Stability for Cosmetic Creams

In 2020, Rampazzo et al. assessed the stability and cytotoxicity of a cosmetic cream containing sapucaia nut oil. All three tested concentrations (1%, 5%, and 10%) of the cream were found to be stable, with an effective preservative system, and deemed safe for use on human skin. To maintain a pH appropriate for a body cream, the formulation requires a stabilizing agent. The cream with 5% nut oil was identified as the most stable and satisfying for use on the skin.⁷

More recently, Hertel Pereira et al. investigated the benefits of using L. pisonis pericarp extract, known to exhibit abundant antioxidants, in an all-natural skin cream. They found that formulation instability increased proportionally with the concentration of the extract, but the use of the outer pericarp of L. pisonis was well suited for the cream formulation, with physical-chemical and organoleptic qualities unchanged after the stability test.¹¹

Conclusion

The available literature on the medical applications of macadamia and sapucaia plants is sparse. Some recent findings are promising regarding possible uses in skin health. However, much more research is necessary before considering macadamia and sapucaia as viable sources of botanical agents capable of delivering significant cutaneous benefits.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., an SaaS company used to generate skin care routines in office and as an e-commerce solution. Write to her at [email protected].

References

1. Dailey A and Vuong QV. Antioxidants (Basel). 2015 Nov 12;4(4):699-718.

2. Silva LL et al. J Ethnopharmacol. 2012 Jan 6;139(1):90-97.

3. Somwongin S et al. Ultrason Sonochem. 2023 Jan;92:106266.

4. Addy J et al. J Cosmet Sci. 2017 Jan/Feb;68(1):59-67.

5. Hanum TI et al. Open Access Maced J Med Sci. 2019 Nov 14;7(22):3917-3920.

6. Akhtar N and Yazan Y. Pak J Pharm Sci. 2008 Jan;21(1):45-50.

7. Rampazzo APS et al. J Cosmet Sci. 2020 Sep/Oct;71(5):239-250.

8. Rosa TLM et al. Food Res Int. 2020 Nov;137:109383.

9. Demoliner F et al. Food Res Int. 2018 Oct;112:434-442.

10. Vieira ME et al. Acta Biochim Biophys Sin (Shanghai). 2015 Sep;47(9):716-729.

11. Hertel Pereira AC et al. J Cosmet Sci. 2021 Mar-Apr;72(2):155-162.

Macadamia (Macadamia tetraphylla) is endemic to Australia and is now commercially cultivated worldwide.¹ It is closely related genetically to the other macadamia plants, including the other main one, M. integrifolia, cultivated for macadamia nuts. Known in Brazil as sapucaia or castanha-de-sapucaia, Lecythis pisonis (also referred to as “cream nut” or “monkey pot”) is a large, deciduous tropical tree and member of the Brazil nut family, Lecythidaceae.² Various parts of both of these plants have been associated with medicinal properties, including the potential for dermatologic activity. Notably, the leaves of L. pisonis have been used in traditional medicine to treat pruritus.² This column focuses on the studies suggesting the possible benefits of macadamia and sapucaia components for skin care.

Macadamia

Extraction to Harness Antioxidant Activity

In 2015, Dailey and Vuong developed an aqueous extraction process to recover the phenolic content and antioxidant functionality from the skin waste of M. tetraphylla using response surface methodology. As an environmentally suitable solvent that is also cheap and safe, water was chosen to maximize the extraction scenario. They identified the proper conditions (90° C, a time of 20 min, and a sample-to-solvent ratio of 5 g/100 mL) to obtain sufficient phenolic compounds, proanthocyanidins, and flavonoids to render robust antioxidant function.¹

Baumann Cosmetic & Research Institute

Early in 2023, Somwongin et al. investigated various green extraction methods for viability in harnessing the cosmetic/cosmeceutical ingredients of M. integrifolia pericarps. Extracts were assessed for total phenolic content as well as antioxidant and anti–skin aging functions. They found that among the green extraction methods (ultrasound, micellar, microwave, and pulsed electric field extraction with water used as a clean solvent), the ultrasound-assisted extraction method netted the greatest yield and total phenolic content. It was also associated with the most robust antioxidant and anti–skin aging activities. Indeed, the researchers reported that its antioxidant activities were comparable to ascorbic acid and Trolox and its anti–skin aging potency on a par with epigallocatechin-3-gallate and oleanolic acid. The ultrasound-assisted extract was also deemed safe as it did not provoke irritation. The authors concluded that this environmentally suitable extraction method for M. integrifolia is appropriate for obtaining effective macadamia extracts for use in cosmetics and cosmeceuticals.³

Anti-Aging Activity

In 2017, Addy et al. set out to characterize skin surface lipid composition and differences in an age- and sex-controlled population as a foundation for developing a botanically derived skin surface lipid mimetic agent. They noted that fatty acids, triglycerides, cholesterol, steryl esters, wax esters, and squalene are the main constituents of skin surface lipids. The investigators obtained skin surface lipid samples from the foreheads of 59 healthy 22-year-old women, analyzed them, and used the raw components of M. integrifolia, Simmondsia chinensis, and Olea europaea to engineer a mimetic product. They reported that the esterification reactions of jojoba, macadamia, and tall oils, combined with squalene derived from O. europaea, yielded an appropriate skin surface lipid mimetic, which, when applied to delipidized skin, assisted in recovering barrier function, enhancing skin hydration, and improving elasticity as well as firmness in aged skin. The researchers concluded that this skin surface lipid mimetic could serve as an effective supplement to human skin surface lipids in aged skin and for conditions in which the stratum corneum is impaired.⁴

Two years later, Hanum et al. compared the effects of macadamia nut oil nanocream and conventional cream for treating cutaneous aging over a 4-week period. The macadamia nut oil nanocream, which contained macadamia nut oil 10%, tween 80, propylene glycol, cetyl alcohol, methylparaben, propylparaben, and distilled water, was compared with the conventional cream based on effects on moisture, evenness, pore size, melanin, and wrinkling. The macadamia nut oil was found to yield superior anti-aging activity along each parameter as compared with the conventional cream. The researchers concluded that the macadamia nut oil in nanocream can be an effective formulation for providing benefits in addressing cutaneous aging.⁵

Matthieu Sontag/Wikimedia Commons/CC-BY-SA

Antifungal Activity

In 2015, Vieira et al. characterized 12 fractions enriched in peptides derived from L. pisonis seeds to determine inhibitory activity against Candida albicans. The fraction that exerted the strongest activity at 10 μg/mL, suppressing C. albicans growth by 38.5% and inducing a 69.3% loss of viability, was identified as similar to plant defensins and thus dubbed “L. pisonis defensin 1 (Lp-Def1).” The investigators concluded that Lp-Def1 acts on C. albicans by slightly elevating the induction of reactive oxygen species and causing a significant reduction in mitochondrial activity. They suggested that their findings support the use of plant defensins, particularly Lp-Def1, in the formulation of antifungal products, especially to address C. albicans.¹⁰

Pruritus

In 2012, Silva et al. studied the antipruritic impact of L. pisonis leaf extracts in mice and rats. Pretreatment with the various fractions of L. pisonis as well as constituent mixed triterpenes (ursolic and oleanolic acids) significantly blocked scratching behavior provoked by compound 48/80. The degranulation of rat peritoneal mast cells caused by compound 48/80 was also substantially decreased from pretreatment with the ethanol extract of L. pisonis, ether-L. pisonis fraction, and mixed triterpenes. The L. pisonis ether fraction suppressed edema induced by carrageenan administration and the ethanol extract displayed no toxicity up to an oral dose of 2g/kg. The investigators concluded that their results strongly support the antipruritic effects of L. pisonis leaves as well as the traditional use of the plant to treat pruritus.²

Stability for Cosmetic Creams

In 2020, Rampazzo et al. assessed the stability and cytotoxicity of a cosmetic cream containing sapucaia nut oil. All three tested concentrations (1%, 5%, and 10%) of the cream were found to be stable, with an effective preservative system, and deemed safe for use on human skin. To maintain a pH appropriate for a body cream, the formulation requires a stabilizing agent. The cream with 5% nut oil was identified as the most stable and satisfying for use on the skin.⁷

More recently, Hertel Pereira et al. investigated the benefits of using L. pisonis pericarp extract, known to exhibit abundant antioxidants, in an all-natural skin cream. They found that formulation instability increased proportionally with the concentration of the extract, but the use of the outer pericarp of L. pisonis was well suited for the cream formulation, with physical-chemical and organoleptic qualities unchanged after the stability test.¹¹

Conclusion

The available literature on the medical applications of macadamia and sapucaia plants is sparse. Some recent findings are promising regarding possible uses in skin health. However, much more research is necessary before considering macadamia and sapucaia as viable sources of botanical agents capable of delivering significant cutaneous benefits.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., an SaaS company used to generate skin care routines in office and as an e-commerce solution. Write to her at [email protected].

References

1. Dailey A and Vuong QV. Antioxidants (Basel). 2015 Nov 12;4(4):699-718.

2. Silva LL et al. J Ethnopharmacol. 2012 Jan 6;139(1):90-97.

3. Somwongin S et al. Ultrason Sonochem. 2023 Jan;92:106266.

4. Addy J et al. J Cosmet Sci. 2017 Jan/Feb;68(1):59-67.

5. Hanum TI et al. Open Access Maced J Med Sci. 2019 Nov 14;7(22):3917-3920.

6. Akhtar N and Yazan Y. Pak J Pharm Sci. 2008 Jan;21(1):45-50.

7. Rampazzo APS et al. J Cosmet Sci. 2020 Sep/Oct;71(5):239-250.

8. Rosa TLM et al. Food Res Int. 2020 Nov;137:109383.

9. Demoliner F et al. Food Res Int. 2018 Oct;112:434-442.

10. Vieira ME et al. Acta Biochim Biophys Sin (Shanghai). 2015 Sep;47(9):716-729.

11. Hertel Pereira AC et al. J Cosmet Sci. 2021 Mar-Apr;72(2):155-162.

TOPLINE:

Antiepileptic and anti-infectious agents were the most common drugs associated with Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) in children in an analysis of a World Health Organization (WHO) database.

METHODOLOGY:

• SJS and TEN are rare, life-threatening mucocutaneous reactions mainly associated with medications, but large pharmacovigilance studies of drugs associated with SJS-TEN in the pediatric population are still lacking.
• Using the WHO’s pharmacovigilance database (VigiBase) containing individual case safety reports from January 1967 to July 2022, researchers identified 7342 adverse drug reaction reports of SJS-TEN in children (younger than 18 years; median age, 9 years) in all six continents. Median onset was 5 days, and 3.2% were fatal.
• They analyzed drugs reported as suspected treatments, and for each molecule, they performed a case–non-case study to assess a potential pharmacovigilance signal by computing the information component (IC).
• A positive IC value suggested more frequent reporting of a specific drug-adverse reaction pair. A positive IC025, a traditional threshold for statistical signal detection, is suggestive of a potential pharmacovigilance signal.

TAKEAWAY:

• Overall, 165 drugs were associated with a diagnosis of SJS-TEN; antiepileptic and anti-infectious drugs were the most common drug classes represented.
• The five most frequently reported drugs were carbamazepine (11.7%), lamotrigine (10.6%), sulfamethoxazole-trimethoprim (9%), acetaminophen (8.4%), and phenytoin (6.6%). The five drugs with the highest IC025 were lamotrigine, carbamazepine, phenobarbital, phenytoin, and nimesulide.
• All antiepileptics, many antibiotic families, dapsone, antiretroviral drugs, some antifungal drugs, and nonsteroidal anti-inflammatory drugs were identified in reports, with penicillins the most frequently reported antibiotic family and sulfonamides having the strongest pharmacovigilance signal.
• Vaccines were not associated with significant signals.

IN PRACTICE:

The study provides an update on “the spectrum of drugs potentially associated with SJS-TEN in the pediatric population,” the authors concluded, and “underlines the importance of reporting to pharmacovigilance the suspicion of this severe side effect of drugs with the most precise and detailed clinical description possible.”

SOURCE:

The study, led by Pauline Bataille, MD, of the Department of Pediatric Dermatology, Hôpital Necker-Enfants Malades, Paris City University, France, was published online in the Journal of the European Academy of Dermatology and Venereology.

LIMITATIONS:

Limitations include the possibility that some cases could have had an infectious or idiopathic cause not related to a drug and the lack of detailed clinical data in the database.

DISCLOSURES:

This study did not receive any funding. The authors declared no conflict of interest.

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

TOPLINE:

Antiepileptic and anti-infectious agents were the most common drugs associated with Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) in children in an analysis of a World Health Organization (WHO) database.

METHODOLOGY:

• SJS and TEN are rare, life-threatening mucocutaneous reactions mainly associated with medications, but large pharmacovigilance studies of drugs associated with SJS-TEN in the pediatric population are still lacking.
• Using the WHO’s pharmacovigilance database (VigiBase) containing individual case safety reports from January 1967 to July 2022, researchers identified 7342 adverse drug reaction reports of SJS-TEN in children (younger than 18 years; median age, 9 years) in all six continents. Median onset was 5 days, and 3.2% were fatal.
• They analyzed drugs reported as suspected treatments, and for each molecule, they performed a case–non-case study to assess a potential pharmacovigilance signal by computing the information component (IC).
• A positive IC value suggested more frequent reporting of a specific drug-adverse reaction pair. A positive IC025, a traditional threshold for statistical signal detection, is suggestive of a potential pharmacovigilance signal.

TAKEAWAY:

• Overall, 165 drugs were associated with a diagnosis of SJS-TEN; antiepileptic and anti-infectious drugs were the most common drug classes represented.
• The five most frequently reported drugs were carbamazepine (11.7%), lamotrigine (10.6%), sulfamethoxazole-trimethoprim (9%), acetaminophen (8.4%), and phenytoin (6.6%). The five drugs with the highest IC025 were lamotrigine, carbamazepine, phenobarbital, phenytoin, and nimesulide.
• All antiepileptics, many antibiotic families, dapsone, antiretroviral drugs, some antifungal drugs, and nonsteroidal anti-inflammatory drugs were identified in reports, with penicillins the most frequently reported antibiotic family and sulfonamides having the strongest pharmacovigilance signal.
• Vaccines were not associated with significant signals.

IN PRACTICE:

The study provides an update on “the spectrum of drugs potentially associated with SJS-TEN in the pediatric population,” the authors concluded, and “underlines the importance of reporting to pharmacovigilance the suspicion of this severe side effect of drugs with the most precise and detailed clinical description possible.”

SOURCE:

The study, led by Pauline Bataille, MD, of the Department of Pediatric Dermatology, Hôpital Necker-Enfants Malades, Paris City University, France, was published online in the Journal of the European Academy of Dermatology and Venereology.

LIMITATIONS:

Limitations include the possibility that some cases could have had an infectious or idiopathic cause not related to a drug and the lack of detailed clinical data in the database.

DISCLOSURES:

This study did not receive any funding. The authors declared no conflict of interest.

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

TOPLINE:

Antiepileptic and anti-infectious agents were the most common drugs associated with Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) in children in an analysis of a World Health Organization (WHO) database.

METHODOLOGY:

• SJS and TEN are rare, life-threatening mucocutaneous reactions mainly associated with medications, but large pharmacovigilance studies of drugs associated with SJS-TEN in the pediatric population are still lacking.
• Using the WHO’s pharmacovigilance database (VigiBase) containing individual case safety reports from January 1967 to July 2022, researchers identified 7342 adverse drug reaction reports of SJS-TEN in children (younger than 18 years; median age, 9 years) in all six continents. Median onset was 5 days, and 3.2% were fatal.
• They analyzed drugs reported as suspected treatments, and for each molecule, they performed a case–non-case study to assess a potential pharmacovigilance signal by computing the information component (IC).
• A positive IC value suggested more frequent reporting of a specific drug-adverse reaction pair. A positive IC025, a traditional threshold for statistical signal detection, is suggestive of a potential pharmacovigilance signal.

TAKEAWAY:

• Overall, 165 drugs were associated with a diagnosis of SJS-TEN; antiepileptic and anti-infectious drugs were the most common drug classes represented.
• The five most frequently reported drugs were carbamazepine (11.7%), lamotrigine (10.6%), sulfamethoxazole-trimethoprim (9%), acetaminophen (8.4%), and phenytoin (6.6%). The five drugs with the highest IC025 were lamotrigine, carbamazepine, phenobarbital, phenytoin, and nimesulide.
• All antiepileptics, many antibiotic families, dapsone, antiretroviral drugs, some antifungal drugs, and nonsteroidal anti-inflammatory drugs were identified in reports, with penicillins the most frequently reported antibiotic family and sulfonamides having the strongest pharmacovigilance signal.
• Vaccines were not associated with significant signals.

IN PRACTICE:

The study provides an update on “the spectrum of drugs potentially associated with SJS-TEN in the pediatric population,” the authors concluded, and “underlines the importance of reporting to pharmacovigilance the suspicion of this severe side effect of drugs with the most precise and detailed clinical description possible.”

SOURCE:

The study, led by Pauline Bataille, MD, of the Department of Pediatric Dermatology, Hôpital Necker-Enfants Malades, Paris City University, France, was published online in the Journal of the European Academy of Dermatology and Venereology.

LIMITATIONS:

Limitations include the possibility that some cases could have had an infectious or idiopathic cause not related to a drug and the lack of detailed clinical data in the database.

DISCLOSURES:

This study did not receive any funding. The authors declared no conflict of interest.

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

Imagine this: A 15-year-old male presents to an urgent care center with a one-day history of fever, cough, and shortness of breath. He is mildly tachypneic with bilateral scattered crackles on lung exam. A rapid test for COVID-19 and influenza is positive for influenza A — a surprising result in June.

An oxygen saturation of 90% prompts transfer to the emergency department at the local children’s hospital. The emergency medicine fellow is skeptical of the presumptive diagnosis. Influenza in the summer in a boy who had not traveled outside his small hometown in the southeastern United States? A respiratory viral panel also detected influenza A, but the specimen did not type as influenza A H1 or H3. This result prompted the laboratory technician to place a call to the ordering physician. “Does this patient have risk factors for avian flu?” the tech asked.

University of Louisville

Highly pathogenic avian influenza (HPAI) A(H5N1) is not a new virus. It was discovered in waterfowl in China in 1996 and has since evolved into multiple clades and subclades, spreading to every continent on the globe except Oceania. It is called highly pathogenic because it kills a large number of the birds that it infects. In 2021, Clade 2.3.4.4b HPAI A(H5N1) viruses emerged in North America, causing large outbreaks in wild birds and farmed poultry populations, including backyard flocks. Sporadic infections have been identified in a diverse group of mammals, including foxes, raccoons, baby goats, bears, and harbor seals. In March of this year, HPAI A(H5N1) was detected for the first time in United States dairy cattle. As we go to press, the United States Department of Agriculture has detected HPAI A(H5N1) in dairy cattle on 36 farms in 9 states.

Human infections are rare, but often severe. Following a 1997 outbreak of HPAI A(H5N1) in Hong Kong, 18 people were infected and 6 died. Since then, more than 900 cases have been reported in humans and approximately half of these have been fatal. The spectrum of disease includes asymptomatic infection and mild disease, as occurred recently in Texas. A dairy farm worker who was exposed to dairy cattle presumed to be infected with HPAI A(H5N1) developed conjunctivitis and no other symptoms. An individual infected in Colorado in 2022 had no symptoms other than fatigue and recovered.

Human-to-human transmission was not identified with either of these cases, although very limited, non-sustained transmission has been observed in the past, usually in family members of infected people after prolonged close exposure.

Right now, most people in the United States are not at risk for HPAI A(H5N1) infection. The Centers for Disease Control and Prevention (CDC) urges clinicians to consider the possibility of HPAI A (H5N1) infection in people who show signs and symptoms of acute respiratory illness, including conjunctivitis, who have had close contact with potentially infected sick or dead birds, livestock, or other animals within the week before the onset of symptoms.

Careful history taking with our illustrative and hypothetical case revealed exposure to farm animals but in a state without known cases of HPAI A(H5N1) in dairy cattle. State health department officials nevertheless agreed with further testing of the patient. Some influenza diagnostic tests cleared by the US Food and Drug Administration (FDA) can detect some novel influenza A viruses such as HPAI A(H5N1) but cannot distinguish between infection with seasonal influenza A or novel influenza A viruses. Molecular assays may give an “influenza A untypeable” result, as in our case. The CDC urges further testing on these untypeable specimens at local or state public health laboratories. When HPAI A(H5N1) is suspected, a negative result on a commercially available test is not considered sufficient to exclude the possibility of infection.

Our patient was admitted to the hospital and droplet, contact, and airborne precautions were instituted along with antiviral treatment with oseltamivir. Preliminary analysis of HPAI A(H5N1) viruses predicts susceptibility to currently available antivirals. The admitting physician confirmed that the boy had received influenza vaccine in the preceding season but, unfortunately, seasonal vaccines do not protect against HPAI A(H5N1) infection.
 

Advice for Clinicians

Given the recent media attention and public health focus on HPAI A(H5N1), frontline clinicians may start receiving questions from patients and families and perhaps requests for testing. At this point, testing is generally recommended only for individuals with risk factors or known exposures. Healthcare providers with questions about testing are encouraged to reach out to their local or state health departments.

Public health authorities have provided recommendations for protection from HPAI. These include avoiding unprotected exposures to sick or dead wild birds, poultry, other domesticated birds, and wild or domesticated animals (including cattle). People should avoid unprotected contact with animals with suspected or confirmed HPAI A(H5N1)-virus infection or products from these animals, including raw or unpasteurized milk and raw milk products.

We can, however, reassure families that the commercial milk supply is safe. In late April, the FDA reported that HPAI viral fragments were found in one of five retail milk samples by polymerase chain reaction testing. Additional testing did not detect any live, infectious virus, indicating the effectiveness of pasteurization at inactivating the virus. Of importance to pediatricians and others pediatric clinicians, limited sampling of retail powdered infant formula and powdered milk products marketed as toddler formula revealed no viral fragments or viable virus.

The million-dollar question is whether HPAI A(H5N1) could start a new pandemic. To date, the virus has not acquired the mutations that would make it easily transmissible from person to person. If that changes and the virus does start spreading more widely, candidate vaccines that could protect against HPAI A(H5N1) have been developed and are part of the national stockpile. Let’s hope we don’t need them.

Dr. Bryant is a pediatrician specializing in infectious diseases at the University of Louisville (Ky.) and Norton Children’s Hospital, also in Louisville. She is a member of the American Academy of Pediatrics’ Committee on Infectious Diseases and the physician lead for Red Book Online. The opinions expressed in this article are her own. Dr. Bryant discloses that she has served as an investigator on clinical trials funded by Pfizer, Enanta and Gilead. Email her at [email protected]. (Also [email protected].)

Imagine this: A 15-year-old male presents to an urgent care center with a one-day history of fever, cough, and shortness of breath. He is mildly tachypneic with bilateral scattered crackles on lung exam. A rapid test for COVID-19 and influenza is positive for influenza A — a surprising result in June.

An oxygen saturation of 90% prompts transfer to the emergency department at the local children’s hospital. The emergency medicine fellow is skeptical of the presumptive diagnosis. Influenza in the summer in a boy who had not traveled outside his small hometown in the southeastern United States? A respiratory viral panel also detected influenza A, but the specimen did not type as influenza A H1 or H3. This result prompted the laboratory technician to place a call to the ordering physician. “Does this patient have risk factors for avian flu?” the tech asked.

University of Louisville

Highly pathogenic avian influenza (HPAI) A(H5N1) is not a new virus. It was discovered in waterfowl in China in 1996 and has since evolved into multiple clades and subclades, spreading to every continent on the globe except Oceania. It is called highly pathogenic because it kills a large number of the birds that it infects. In 2021, Clade 2.3.4.4b HPAI A(H5N1) viruses emerged in North America, causing large outbreaks in wild birds and farmed poultry populations, including backyard flocks. Sporadic infections have been identified in a diverse group of mammals, including foxes, raccoons, baby goats, bears, and harbor seals. In March of this year, HPAI A(H5N1) was detected for the first time in United States dairy cattle. As we go to press, the United States Department of Agriculture has detected HPAI A(H5N1) in dairy cattle on 36 farms in 9 states.

Human infections are rare, but often severe. Following a 1997 outbreak of HPAI A(H5N1) in Hong Kong, 18 people were infected and 6 died. Since then, more than 900 cases have been reported in humans and approximately half of these have been fatal. The spectrum of disease includes asymptomatic infection and mild disease, as occurred recently in Texas. A dairy farm worker who was exposed to dairy cattle presumed to be infected with HPAI A(H5N1) developed conjunctivitis and no other symptoms. An individual infected in Colorado in 2022 had no symptoms other than fatigue and recovered.

Human-to-human transmission was not identified with either of these cases, although very limited, non-sustained transmission has been observed in the past, usually in family members of infected people after prolonged close exposure.

Right now, most people in the United States are not at risk for HPAI A(H5N1) infection. The Centers for Disease Control and Prevention (CDC) urges clinicians to consider the possibility of HPAI A (H5N1) infection in people who show signs and symptoms of acute respiratory illness, including conjunctivitis, who have had close contact with potentially infected sick or dead birds, livestock, or other animals within the week before the onset of symptoms.

Careful history taking with our illustrative and hypothetical case revealed exposure to farm animals but in a state without known cases of HPAI A(H5N1) in dairy cattle. State health department officials nevertheless agreed with further testing of the patient. Some influenza diagnostic tests cleared by the US Food and Drug Administration (FDA) can detect some novel influenza A viruses such as HPAI A(H5N1) but cannot distinguish between infection with seasonal influenza A or novel influenza A viruses. Molecular assays may give an “influenza A untypeable” result, as in our case. The CDC urges further testing on these untypeable specimens at local or state public health laboratories. When HPAI A(H5N1) is suspected, a negative result on a commercially available test is not considered sufficient to exclude the possibility of infection.

Our patient was admitted to the hospital and droplet, contact, and airborne precautions were instituted along with antiviral treatment with oseltamivir. Preliminary analysis of HPAI A(H5N1) viruses predicts susceptibility to currently available antivirals. The admitting physician confirmed that the boy had received influenza vaccine in the preceding season but, unfortunately, seasonal vaccines do not protect against HPAI A(H5N1) infection.
 

Advice for Clinicians

Given the recent media attention and public health focus on HPAI A(H5N1), frontline clinicians may start receiving questions from patients and families and perhaps requests for testing. At this point, testing is generally recommended only for individuals with risk factors or known exposures. Healthcare providers with questions about testing are encouraged to reach out to their local or state health departments.

Public health authorities have provided recommendations for protection from HPAI. These include avoiding unprotected exposures to sick or dead wild birds, poultry, other domesticated birds, and wild or domesticated animals (including cattle). People should avoid unprotected contact with animals with suspected or confirmed HPAI A(H5N1)-virus infection or products from these animals, including raw or unpasteurized milk and raw milk products.

We can, however, reassure families that the commercial milk supply is safe. In late April, the FDA reported that HPAI viral fragments were found in one of five retail milk samples by polymerase chain reaction testing. Additional testing did not detect any live, infectious virus, indicating the effectiveness of pasteurization at inactivating the virus. Of importance to pediatricians and others pediatric clinicians, limited sampling of retail powdered infant formula and powdered milk products marketed as toddler formula revealed no viral fragments or viable virus.

The million-dollar question is whether HPAI A(H5N1) could start a new pandemic. To date, the virus has not acquired the mutations that would make it easily transmissible from person to person. If that changes and the virus does start spreading more widely, candidate vaccines that could protect against HPAI A(H5N1) have been developed and are part of the national stockpile. Let’s hope we don’t need them.

Dr. Bryant is a pediatrician specializing in infectious diseases at the University of Louisville (Ky.) and Norton Children’s Hospital, also in Louisville. She is a member of the American Academy of Pediatrics’ Committee on Infectious Diseases and the physician lead for Red Book Online. The opinions expressed in this article are her own. Dr. Bryant discloses that she has served as an investigator on clinical trials funded by Pfizer, Enanta and Gilead. Email her at [email protected]. (Also [email protected].)

Imagine this: A 15-year-old male presents to an urgent care center with a one-day history of fever, cough, and shortness of breath. He is mildly tachypneic with bilateral scattered crackles on lung exam. A rapid test for COVID-19 and influenza is positive for influenza A — a surprising result in June.

An oxygen saturation of 90% prompts transfer to the emergency department at the local children’s hospital. The emergency medicine fellow is skeptical of the presumptive diagnosis. Influenza in the summer in a boy who had not traveled outside his small hometown in the southeastern United States? A respiratory viral panel also detected influenza A, but the specimen did not type as influenza A H1 or H3. This result prompted the laboratory technician to place a call to the ordering physician. “Does this patient have risk factors for avian flu?” the tech asked.

University of Louisville

Highly pathogenic avian influenza (HPAI) A(H5N1) is not a new virus. It was discovered in waterfowl in China in 1996 and has since evolved into multiple clades and subclades, spreading to every continent on the globe except Oceania. It is called highly pathogenic because it kills a large number of the birds that it infects. In 2021, Clade 2.3.4.4b HPAI A(H5N1) viruses emerged in North America, causing large outbreaks in wild birds and farmed poultry populations, including backyard flocks. Sporadic infections have been identified in a diverse group of mammals, including foxes, raccoons, baby goats, bears, and harbor seals. In March of this year, HPAI A(H5N1) was detected for the first time in United States dairy cattle. As we go to press, the United States Department of Agriculture has detected HPAI A(H5N1) in dairy cattle on 36 farms in 9 states.

Human infections are rare, but often severe. Following a 1997 outbreak of HPAI A(H5N1) in Hong Kong, 18 people were infected and 6 died. Since then, more than 900 cases have been reported in humans and approximately half of these have been fatal. The spectrum of disease includes asymptomatic infection and mild disease, as occurred recently in Texas. A dairy farm worker who was exposed to dairy cattle presumed to be infected with HPAI A(H5N1) developed conjunctivitis and no other symptoms. An individual infected in Colorado in 2022 had no symptoms other than fatigue and recovered.

Human-to-human transmission was not identified with either of these cases, although very limited, non-sustained transmission has been observed in the past, usually in family members of infected people after prolonged close exposure.

Right now, most people in the United States are not at risk for HPAI A(H5N1) infection. The Centers for Disease Control and Prevention (CDC) urges clinicians to consider the possibility of HPAI A (H5N1) infection in people who show signs and symptoms of acute respiratory illness, including conjunctivitis, who have had close contact with potentially infected sick or dead birds, livestock, or other animals within the week before the onset of symptoms.

Careful history taking with our illustrative and hypothetical case revealed exposure to farm animals but in a state without known cases of HPAI A(H5N1) in dairy cattle. State health department officials nevertheless agreed with further testing of the patient. Some influenza diagnostic tests cleared by the US Food and Drug Administration (FDA) can detect some novel influenza A viruses such as HPAI A(H5N1) but cannot distinguish between infection with seasonal influenza A or novel influenza A viruses. Molecular assays may give an “influenza A untypeable” result, as in our case. The CDC urges further testing on these untypeable specimens at local or state public health laboratories. When HPAI A(H5N1) is suspected, a negative result on a commercially available test is not considered sufficient to exclude the possibility of infection.

Our patient was admitted to the hospital and droplet, contact, and airborne precautions were instituted along with antiviral treatment with oseltamivir. Preliminary analysis of HPAI A(H5N1) viruses predicts susceptibility to currently available antivirals. The admitting physician confirmed that the boy had received influenza vaccine in the preceding season but, unfortunately, seasonal vaccines do not protect against HPAI A(H5N1) infection.
 

Advice for Clinicians

Given the recent media attention and public health focus on HPAI A(H5N1), frontline clinicians may start receiving questions from patients and families and perhaps requests for testing. At this point, testing is generally recommended only for individuals with risk factors or known exposures. Healthcare providers with questions about testing are encouraged to reach out to their local or state health departments.

Public health authorities have provided recommendations for protection from HPAI. These include avoiding unprotected exposures to sick or dead wild birds, poultry, other domesticated birds, and wild or domesticated animals (including cattle). People should avoid unprotected contact with animals with suspected or confirmed HPAI A(H5N1)-virus infection or products from these animals, including raw or unpasteurized milk and raw milk products.

We can, however, reassure families that the commercial milk supply is safe. In late April, the FDA reported that HPAI viral fragments were found in one of five retail milk samples by polymerase chain reaction testing. Additional testing did not detect any live, infectious virus, indicating the effectiveness of pasteurization at inactivating the virus. Of importance to pediatricians and others pediatric clinicians, limited sampling of retail powdered infant formula and powdered milk products marketed as toddler formula revealed no viral fragments or viable virus.

The million-dollar question is whether HPAI A(H5N1) could start a new pandemic. To date, the virus has not acquired the mutations that would make it easily transmissible from person to person. If that changes and the virus does start spreading more widely, candidate vaccines that could protect against HPAI A(H5N1) have been developed and are part of the national stockpile. Let’s hope we don’t need them.

Dr. Bryant is a pediatrician specializing in infectious diseases at the University of Louisville (Ky.) and Norton Children’s Hospital, also in Louisville. She is a member of the American Academy of Pediatrics’ Committee on Infectious Diseases and the physician lead for Red Book Online. The opinions expressed in this article are her own. Dr. Bryant discloses that she has served as an investigator on clinical trials funded by Pfizer, Enanta and Gilead. Email her at [email protected]. (Also [email protected].)

Interest is growing in a standard European treatment for bacterial vaginosis (BV).

In a commentary published in JAMA Network Open, researchers and doctors from the Johns Hopkins University School of Medicine in Baltimore and the University of Maryland, Baltimore, urged clinical trials in the United States to determine if dequalinium chloride — an antiseptic that inhibits the growth of bacteria and fungi — is on par with or better than treatments currently available.

Dequalinium has been used throughout Europe for decades and is recommended as an alternative or second-line BV treatment by the World Health Organization; the International Society for the Study of Vulvovaginal Disease; and the Austrian, German, Portuguese, Spanish, and Swiss Societies of Gynecology and Obstetrics. However, the product has not been approved for clinical use in the United States, no trials studying the drug have been registered on ClinicalTrials.gov, and the US Food and Drug Administration has not received an application for approval, according to agency records.

Treatments in the United States for BV include metronidazole and clindamycin that, while effective, have a recurrence rate of up to 60%.

“Current treatments for bacterial vaginosis often fall short, primarily due to frequent recurrences after treatment,” said Rebecca M. Brotman, PhD, MPH, a professor in the Department of Epidemiology and Public Health at the Institute for Genome Sciences at the University of Maryland School of Medicine, and the corresponding author of the commentary. 

More than 40% of people with recurrent BV do not receive adequate treatment, according to Caroline M. Mitchell, MD, MPH, director of the Vulvovaginal Disorders Program at Massachusetts General Hospital Vincent Center for Reproductive Biology, Boston, Massachusetts. 

“BV is very disruptive to people’s daily lives and causes significant distress,” said Dr. Mitchell, who was not a coauthor of the new article. “Additionally, BV is associated with higher risk for HPV [human papillomavirus] infection, progression of HPV to cervical dysplasia, as well as risk for acquisition of other sexually transmitted infections.”

Dr. Mitchell said she hopes a recent trial from Europe comparing dequalinium chloride to metronidazole spurs researchers to study its efficacy and safety among women in the United States.

“Dequalinium has some antifungal activity, so it might offer a lower chance of yeast infection after treatment, which is important because posttreatment vulvovaginal candidiasis is one of the downsides to conventional antibiotic treatments,” Dr. Mitchell said.

The recent clinical trial included 147 premenopausal women with BV who received 10 mg of dequalinium per day for 6 days or oral metronidazole (500 mg twice daily for 7 days). 

Dr. Brotman said any studies in the United States would need to examine long-term recurrence of vaginosis after treatment with dequalinium chloride and its use during pregnancy.

The study was funded by various grants from the National Institutes of Health and the Gates Foundation. Various authors reported receiving royalties from UpToDate outside the submitted work or receiving a donation of sexually transmitted infection testing kits from Hologic for a study outside the submitted work. No other disclosures were reported.

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

Interest is growing in a standard European treatment for bacterial vaginosis (BV).

In a commentary published in JAMA Network Open, researchers and doctors from the Johns Hopkins University School of Medicine in Baltimore and the University of Maryland, Baltimore, urged clinical trials in the United States to determine if dequalinium chloride — an antiseptic that inhibits the growth of bacteria and fungi — is on par with or better than treatments currently available.

Dequalinium has been used throughout Europe for decades and is recommended as an alternative or second-line BV treatment by the World Health Organization; the International Society for the Study of Vulvovaginal Disease; and the Austrian, German, Portuguese, Spanish, and Swiss Societies of Gynecology and Obstetrics. However, the product has not been approved for clinical use in the United States, no trials studying the drug have been registered on ClinicalTrials.gov, and the US Food and Drug Administration has not received an application for approval, according to agency records.

Treatments in the United States for BV include metronidazole and clindamycin that, while effective, have a recurrence rate of up to 60%.

“Current treatments for bacterial vaginosis often fall short, primarily due to frequent recurrences after treatment,” said Rebecca M. Brotman, PhD, MPH, a professor in the Department of Epidemiology and Public Health at the Institute for Genome Sciences at the University of Maryland School of Medicine, and the corresponding author of the commentary. 

More than 40% of people with recurrent BV do not receive adequate treatment, according to Caroline M. Mitchell, MD, MPH, director of the Vulvovaginal Disorders Program at Massachusetts General Hospital Vincent Center for Reproductive Biology, Boston, Massachusetts. 

“BV is very disruptive to people’s daily lives and causes significant distress,” said Dr. Mitchell, who was not a coauthor of the new article. “Additionally, BV is associated with higher risk for HPV [human papillomavirus] infection, progression of HPV to cervical dysplasia, as well as risk for acquisition of other sexually transmitted infections.”

Dr. Mitchell said she hopes a recent trial from Europe comparing dequalinium chloride to metronidazole spurs researchers to study its efficacy and safety among women in the United States.

“Dequalinium has some antifungal activity, so it might offer a lower chance of yeast infection after treatment, which is important because posttreatment vulvovaginal candidiasis is one of the downsides to conventional antibiotic treatments,” Dr. Mitchell said.

The recent clinical trial included 147 premenopausal women with BV who received 10 mg of dequalinium per day for 6 days or oral metronidazole (500 mg twice daily for 7 days). 

Dr. Brotman said any studies in the United States would need to examine long-term recurrence of vaginosis after treatment with dequalinium chloride and its use during pregnancy.

The study was funded by various grants from the National Institutes of Health and the Gates Foundation. Various authors reported receiving royalties from UpToDate outside the submitted work or receiving a donation of sexually transmitted infection testing kits from Hologic for a study outside the submitted work. No other disclosures were reported.

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

Interest is growing in a standard European treatment for bacterial vaginosis (BV).

In a commentary published in JAMA Network Open, researchers and doctors from the Johns Hopkins University School of Medicine in Baltimore and the University of Maryland, Baltimore, urged clinical trials in the United States to determine if dequalinium chloride — an antiseptic that inhibits the growth of bacteria and fungi — is on par with or better than treatments currently available.

Dequalinium has been used throughout Europe for decades and is recommended as an alternative or second-line BV treatment by the World Health Organization; the International Society for the Study of Vulvovaginal Disease; and the Austrian, German, Portuguese, Spanish, and Swiss Societies of Gynecology and Obstetrics. However, the product has not been approved for clinical use in the United States, no trials studying the drug have been registered on ClinicalTrials.gov, and the US Food and Drug Administration has not received an application for approval, according to agency records.

Treatments in the United States for BV include metronidazole and clindamycin that, while effective, have a recurrence rate of up to 60%.

“Current treatments for bacterial vaginosis often fall short, primarily due to frequent recurrences after treatment,” said Rebecca M. Brotman, PhD, MPH, a professor in the Department of Epidemiology and Public Health at the Institute for Genome Sciences at the University of Maryland School of Medicine, and the corresponding author of the commentary. 

More than 40% of people with recurrent BV do not receive adequate treatment, according to Caroline M. Mitchell, MD, MPH, director of the Vulvovaginal Disorders Program at Massachusetts General Hospital Vincent Center for Reproductive Biology, Boston, Massachusetts. 

“BV is very disruptive to people’s daily lives and causes significant distress,” said Dr. Mitchell, who was not a coauthor of the new article. “Additionally, BV is associated with higher risk for HPV [human papillomavirus] infection, progression of HPV to cervical dysplasia, as well as risk for acquisition of other sexually transmitted infections.”

Dr. Mitchell said she hopes a recent trial from Europe comparing dequalinium chloride to metronidazole spurs researchers to study its efficacy and safety among women in the United States.

“Dequalinium has some antifungal activity, so it might offer a lower chance of yeast infection after treatment, which is important because posttreatment vulvovaginal candidiasis is one of the downsides to conventional antibiotic treatments,” Dr. Mitchell said.

The recent clinical trial included 147 premenopausal women with BV who received 10 mg of dequalinium per day for 6 days or oral metronidazole (500 mg twice daily for 7 days). 

Dr. Brotman said any studies in the United States would need to examine long-term recurrence of vaginosis after treatment with dequalinium chloride and its use during pregnancy.

The study was funded by various grants from the National Institutes of Health and the Gates Foundation. Various authors reported receiving royalties from UpToDate outside the submitted work or receiving a donation of sexually transmitted infection testing kits from Hologic for a study outside the submitted work. No other disclosures were reported.

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