https://www.cidrap.umn.edu/antimicr...stance-gene-s-causing-nightmares-us-hospitals
The resistance gene that’s causing ‘nightmares’ in US hospitals
Chris Dall, MA
Today at 11:00 a.m.
Antimicrobial Stewardship
The woman ultimately died from the infection, which was caused by Klebsiella pneumoniae, an opportunistic pathogen that infects the lungs, urinary tract, bloodstream, and wounds. What made the infection unique was that it carried an enzyme-encoded gene—New Delhi metallo-beta-lactamase, or NDM—that makes bacteria resistant to carbapenems, a class of last-resort antibiotics that physicians reach for when infections don’t respond to first- and second-line treatment options.
NDM is one of several resistance genes that bacteria have acquired in their never-ending battle to defeat antibiotics. At the time, bacteria carrying NDM were fairly rare in the United States. In fact, investigators believed the woman likely acquired the infection in India, where the NDM gene was first detected. She had been travelling (and was hospitalized) in India prior to returning to Nevada.
But that’s no longer the case. In a report published last September, the CDC said surveillance data from labs across the country showed that the incidence of carbapenem-resistant Enterobacterales (CRE, the family of pathogens that includes K pneumoniae) infections carrying NDM genes rose 461% from 2019 through 2023. And CDC officials are worried about the implications.
“The rapid increase is a major concern for CDC due to the implications for treating serious CRE infections and potential for NDM to spread outside of healthcare,” Richard Stanton, PhD, a bioinformatician with the CDC’s Division of Healthcare Quality Promotion, told CIDRAP News.
Limited treatment options
Dubbed a “nightmare bacteria,” all CRE infections present a challenge for physicians because they tend to target already sick hospital patients and limit treatment options. And they can be deadly, with a mortality rate that ranges from 30% to 50%. In a 2019 report, the CDC labeled CRE an “urgent threat.”
“CRE is a concern, period,” said Brad Spellberg, MD, chief medical officer at the Los Angeles General Medical Center.
NDM is one member of an alphabet soup of carbapenemase genes that CRE pathogens have acquired to evade carbapenems. K pneumoniae carbapenemase (KPC) and Verona Integron-encoded metallo-beta-lactamase (VIM) are other commonly found pathogens that dwell in US hospitals. Carbapenemase genes often carry resistance mechanisms for other antibiotics, too, making the pathogens that carry them even harder to treat.
The rapid increase is a major concern for CDC due to the implications for treating serious CRE infections and potential for NDM to spread outside of healthcare
Richard Stanton, PhD, CDC Division of Healthcare Quality Promotion
But NDM-CRE infections present an additional problem because the newer combination drugs that were developed to defeat other carbapenemase genes “don’t treat NDM-CRE pathogens,” Spellberg explained. In other words, NDM-CRE has outfoxed these newer antibiotics.
“For years, NDM-CRE infections put clinicians in a position where the best new weapons in the arsenal simply didn't apply,” said Amesh Adalja, MD, an infectious disease physician and senior scholar at the Johns Hopkins Center for Health Security.
Newer options are now available, Spellberg and Adalja said. But one of the CDC’s concerns is that physicians need to know that a patient has an NDM-CRE infection to provide the proper treatment, and many clinical laboratories lack the molecular testing required to detect them.
"Selecting the right treatment has never been more complicated, so it is vitally important that healthcare providers have access to testing to help them select the proper targeted therapies,” CDC epidemiologist Danielle Rankin, PhD, MPH, said when the agency released its report last September.
New research by Stanton and CDC colleagues indicates that the growth of NDM-CRE infections is being driven primarily by a handful of strains from three members of the CRE family: K pneumoniae, Escherichia coli, and Enterobacter cloacae complex.
Stanton said that knowing which strains are driving the increase is important because it “can help the public health community recognize that there may be increased risk of local spread when these high-risk strains are encountered.”
An extremely mobile gene
But the tricky thing about the NDM gene is that it’s almost always carried by small pieces of DNA called plasmids that can move between bacteria. Plasmids allow the sharing of resistance traits between many types of bacteria, both pathogenic and non-pathogenic. While antibiotic resistance traditionally develops from bacteria exposed to an antibiotic, bacteria can acquire the NDM gene via a plasmid (or any other resistance gene) and become resistant without ever having encountered an antibiotic.
“It’s by nature an extremely mobile gene, and it can spread amongst any compatible host species that can hold on to the plasmids that carry it,” said Nathan Raabe, PhD, MPH, a genomic epidemiologist researching plasmids at the University of Pittsburgh School of Medicine.
This makes NDM-CRE more threatening than just clonal spread of a single strain of resistant bacteria, added colleague Alex Sundermann, DrPH. “All the different bacteria just want to eat it up because they’ll survive better,” he said.
And that can make it harder to detect and prevent hospital outbreaks, because when those outbreaks occur, most hospitals are looking for transmission of a particular pathogen between patients. But in a study published in 2024, Raabe, Sundermann, and colleagues described an outbreak of NDM-CRE at UPMC Presbyterian Hospital involving 15 patients and seven different bacterial species in which some of the transmission involved the sharing of an NDM-carrying plasmid between different pathogens.
“Sometimes we were just seeing the plasmid move, then be integrated into different species that caused an infection,” Raabe explained. But not many hospitals have the ability to track that type of spread in real time.
Wastewater surveillance
NDM-CRE are primarily a threat in hospitals, a reservoir of resistant bacteria. But while the CDC data indicate that NDM is becoming more of a familiar presence and risk in hospitals, new wastewater analysis from 163 US sites suggests that in some parts of the country, the gene is spreading in the community.
In a study published in Nature Communications in April, a team led by researchers at the University of California (UC), Berkeley, found that though NDM was undetected in some areas of the country, concentrations of the gene were higher in wastewater from communities with hospitals and nursing homes, particularly in southern and western states.
It’s by nature an extremely mobile gene, and it can spread amongst any compatible host species that can hold on to the plasmids that carry it.
Nathan Raabe, PhD, MPH, University of Pittsburg School of Medicine
First author Sooyeol Kim, PhD, now a lecturer at the University of Sydney, said the variability of NDM in wastewater was notable because some of the 10 other antibiotic-resistant genes they analyzed were found in high concentrations at all sites.
“That wouldn't necessarily tell us anything specific about whether the community is experiencing more antibiotic resistance or less,” she said. “But with genes like NDM, you could potentially say, ‘oh, there is more antibiotic resistance in regard to that particular gene within this community compared to the rest of the country,’ or track it across time to see whether antibiotic resistance is increasing in a community.”
The study also found an interesting correlation: the presence of NDM was significantly associated with socioeconomic factors like a lack of health insurance, overcrowding, and being under housing burden.
Senior author Amy Pickering, PhD, an associate professor at UC Berkeley, said that the mechanisms behind these associations are unclear and need to be further investigated. But she said the value of using wastewater surveillance, which has become a critical part of respiratory infection surveillance since the beginning of the COVID pandemic, is that it could reveal new clues about how and where clinically relevant drug resistance is spreading.
“Antibiotic resistance is often called a silent pandemic because there's a lot of transmission outside of the healthcare environment,” she said. “Being able to capture concentrations in the wastewater helps us better understand what's happening in the entire community.”
The findings have prompted WastewaterSCAN, which monitors municipal wastewater systems across the country for viruses like SARS-CoV-2, influenza, and respiratory syncytial virus, to add the NDM gene to its nationwide dashboard. WastewaterSCAN’s scientific program manager, Amanda Bidwell, MS, said the public health importance of the gene and the differences in prevalence across regions call for a “deeper dive into those patterns to see what we can find.”
But understanding how to interpret NDM levels in watersheds will take time, she noted, because it’s not like monitoring for seasonal viruses such as flu. “We see a very clear signal when flu starts to take off in the fall,” Bidwell said. “NDM is a little bit different.”
Antibiotic resistance is often called a silent pandemic because there's a lot of transmission outside of the healthcare environment.
Amy Pickering, UC Berkeley
For example, it’s unclear if sites that currently appear to have high concentrations of NDM in wastewater are seeing a spike or just have a high baseline because of the presence of a large hospital. Bidwell said it will take a few months’ worth of data and conversations with public health partners to figure it out.
Adalja said drug-resistant organisms should be a baseline target for any national wastewater surveillance strategy, and NDM is “the right gene to start with.”
“Tracking it in wastewater gives you a community-level reservoir signal, not just a clinical case count,” he said. “It gauges the environmental reservoir that feeds clinical cases.”
No endgame in sight
In the meantime, healthcare systems need to be on the lookout for NDM-CRE because of the ease with which they spread, especially in hospital intensive care units, where invasive devices like ventilators and catheters are magnets for bacterial contamination.
Sundermann said that any time you have a clinical infection with NDM in your hospital, “red alarms” should be going off. That means intensified surveillance and infection prevention and control measures like screening patients and isolating those who are infected or are just carrying the bacteria.
But Sundermann, who works on bringing real-time surveillance for drug-resistant pathogens into routine care, said there’s “no silver bullet” for NDM-CRE.
“We have been aggressively doing surveillance and trying to stop all of it, but you see persistence over time,” he said.
For now, the combination drug aztreonam-avibactam, approved by the Food and Drug Administration in early 2025, gives clinicians another option for treating NDM-CRE infections. But ultimately, bacteria will find a way to evade that drug, too. Spellberg said we need to stop pretending this is a “winnable war with an endgame.”
“Whatever we come up with, resistance will eventually emerge to,” Spellberg said. “We need to do a much better job of controlling our antibiotic use so we stop selecting out these pathogens and stop enriching them in healthcare settings.”
The resistance gene that’s causing ‘nightmares’ in US hospitals
Chris Dall, MA
Today at 11:00 a.m.
Antimicrobial Stewardship
In a well-publicized case in 2016 that alerted many Americans to the rising threat of drug-resistant bacterial infections, the Centers for Disease Control and Prevention (CDC) and health officials in Nevada reported a bacterial infection in a 70-year-old woman that was resistant to all 26 of the antibiotics available to her doctors.The woman ultimately died from the infection, which was caused by Klebsiella pneumoniae, an opportunistic pathogen that infects the lungs, urinary tract, bloodstream, and wounds. What made the infection unique was that it carried an enzyme-encoded gene—New Delhi metallo-beta-lactamase, or NDM—that makes bacteria resistant to carbapenems, a class of last-resort antibiotics that physicians reach for when infections don’t respond to first- and second-line treatment options.
NDM is one of several resistance genes that bacteria have acquired in their never-ending battle to defeat antibiotics. At the time, bacteria carrying NDM were fairly rare in the United States. In fact, investigators believed the woman likely acquired the infection in India, where the NDM gene was first detected. She had been travelling (and was hospitalized) in India prior to returning to Nevada.
But that’s no longer the case. In a report published last September, the CDC said surveillance data from labs across the country showed that the incidence of carbapenem-resistant Enterobacterales (CRE, the family of pathogens that includes K pneumoniae) infections carrying NDM genes rose 461% from 2019 through 2023. And CDC officials are worried about the implications.
“The rapid increase is a major concern for CDC due to the implications for treating serious CRE infections and potential for NDM to spread outside of healthcare,” Richard Stanton, PhD, a bioinformatician with the CDC’s Division of Healthcare Quality Promotion, told CIDRAP News.
Limited treatment options
Dubbed a “nightmare bacteria,” all CRE infections present a challenge for physicians because they tend to target already sick hospital patients and limit treatment options. And they can be deadly, with a mortality rate that ranges from 30% to 50%. In a 2019 report, the CDC labeled CRE an “urgent threat.”
“CRE is a concern, period,” said Brad Spellberg, MD, chief medical officer at the Los Angeles General Medical Center.
NDM is one member of an alphabet soup of carbapenemase genes that CRE pathogens have acquired to evade carbapenems. K pneumoniae carbapenemase (KPC) and Verona Integron-encoded metallo-beta-lactamase (VIM) are other commonly found pathogens that dwell in US hospitals. Carbapenemase genes often carry resistance mechanisms for other antibiotics, too, making the pathogens that carry them even harder to treat.
The rapid increase is a major concern for CDC due to the implications for treating serious CRE infections and potential for NDM to spread outside of healthcare
Richard Stanton, PhD, CDC Division of Healthcare Quality Promotion
But NDM-CRE infections present an additional problem because the newer combination drugs that were developed to defeat other carbapenemase genes “don’t treat NDM-CRE pathogens,” Spellberg explained. In other words, NDM-CRE has outfoxed these newer antibiotics.
“For years, NDM-CRE infections put clinicians in a position where the best new weapons in the arsenal simply didn't apply,” said Amesh Adalja, MD, an infectious disease physician and senior scholar at the Johns Hopkins Center for Health Security.
Newer options are now available, Spellberg and Adalja said. But one of the CDC’s concerns is that physicians need to know that a patient has an NDM-CRE infection to provide the proper treatment, and many clinical laboratories lack the molecular testing required to detect them.
"Selecting the right treatment has never been more complicated, so it is vitally important that healthcare providers have access to testing to help them select the proper targeted therapies,” CDC epidemiologist Danielle Rankin, PhD, MPH, said when the agency released its report last September.
New research by Stanton and CDC colleagues indicates that the growth of NDM-CRE infections is being driven primarily by a handful of strains from three members of the CRE family: K pneumoniae, Escherichia coli, and Enterobacter cloacae complex.
Stanton said that knowing which strains are driving the increase is important because it “can help the public health community recognize that there may be increased risk of local spread when these high-risk strains are encountered.”
An extremely mobile gene
But the tricky thing about the NDM gene is that it’s almost always carried by small pieces of DNA called plasmids that can move between bacteria. Plasmids allow the sharing of resistance traits between many types of bacteria, both pathogenic and non-pathogenic. While antibiotic resistance traditionally develops from bacteria exposed to an antibiotic, bacteria can acquire the NDM gene via a plasmid (or any other resistance gene) and become resistant without ever having encountered an antibiotic.
“It’s by nature an extremely mobile gene, and it can spread amongst any compatible host species that can hold on to the plasmids that carry it,” said Nathan Raabe, PhD, MPH, a genomic epidemiologist researching plasmids at the University of Pittsburgh School of Medicine.
This makes NDM-CRE more threatening than just clonal spread of a single strain of resistant bacteria, added colleague Alex Sundermann, DrPH. “All the different bacteria just want to eat it up because they’ll survive better,” he said.
And that can make it harder to detect and prevent hospital outbreaks, because when those outbreaks occur, most hospitals are looking for transmission of a particular pathogen between patients. But in a study published in 2024, Raabe, Sundermann, and colleagues described an outbreak of NDM-CRE at UPMC Presbyterian Hospital involving 15 patients and seven different bacterial species in which some of the transmission involved the sharing of an NDM-carrying plasmid between different pathogens.
“Sometimes we were just seeing the plasmid move, then be integrated into different species that caused an infection,” Raabe explained. But not many hospitals have the ability to track that type of spread in real time.
Wastewater surveillance
NDM-CRE are primarily a threat in hospitals, a reservoir of resistant bacteria. But while the CDC data indicate that NDM is becoming more of a familiar presence and risk in hospitals, new wastewater analysis from 163 US sites suggests that in some parts of the country, the gene is spreading in the community.
In a study published in Nature Communications in April, a team led by researchers at the University of California (UC), Berkeley, found that though NDM was undetected in some areas of the country, concentrations of the gene were higher in wastewater from communities with hospitals and nursing homes, particularly in southern and western states.
It’s by nature an extremely mobile gene, and it can spread amongst any compatible host species that can hold on to the plasmids that carry it.
Nathan Raabe, PhD, MPH, University of Pittsburg School of Medicine
First author Sooyeol Kim, PhD, now a lecturer at the University of Sydney, said the variability of NDM in wastewater was notable because some of the 10 other antibiotic-resistant genes they analyzed were found in high concentrations at all sites.
“That wouldn't necessarily tell us anything specific about whether the community is experiencing more antibiotic resistance or less,” she said. “But with genes like NDM, you could potentially say, ‘oh, there is more antibiotic resistance in regard to that particular gene within this community compared to the rest of the country,’ or track it across time to see whether antibiotic resistance is increasing in a community.”
The study also found an interesting correlation: the presence of NDM was significantly associated with socioeconomic factors like a lack of health insurance, overcrowding, and being under housing burden.
Senior author Amy Pickering, PhD, an associate professor at UC Berkeley, said that the mechanisms behind these associations are unclear and need to be further investigated. But she said the value of using wastewater surveillance, which has become a critical part of respiratory infection surveillance since the beginning of the COVID pandemic, is that it could reveal new clues about how and where clinically relevant drug resistance is spreading.
“Antibiotic resistance is often called a silent pandemic because there's a lot of transmission outside of the healthcare environment,” she said. “Being able to capture concentrations in the wastewater helps us better understand what's happening in the entire community.”
The findings have prompted WastewaterSCAN, which monitors municipal wastewater systems across the country for viruses like SARS-CoV-2, influenza, and respiratory syncytial virus, to add the NDM gene to its nationwide dashboard. WastewaterSCAN’s scientific program manager, Amanda Bidwell, MS, said the public health importance of the gene and the differences in prevalence across regions call for a “deeper dive into those patterns to see what we can find.”
But understanding how to interpret NDM levels in watersheds will take time, she noted, because it’s not like monitoring for seasonal viruses such as flu. “We see a very clear signal when flu starts to take off in the fall,” Bidwell said. “NDM is a little bit different.”
Antibiotic resistance is often called a silent pandemic because there's a lot of transmission outside of the healthcare environment.
Amy Pickering, UC Berkeley
For example, it’s unclear if sites that currently appear to have high concentrations of NDM in wastewater are seeing a spike or just have a high baseline because of the presence of a large hospital. Bidwell said it will take a few months’ worth of data and conversations with public health partners to figure it out.
Adalja said drug-resistant organisms should be a baseline target for any national wastewater surveillance strategy, and NDM is “the right gene to start with.”
“Tracking it in wastewater gives you a community-level reservoir signal, not just a clinical case count,” he said. “It gauges the environmental reservoir that feeds clinical cases.”
No endgame in sight
In the meantime, healthcare systems need to be on the lookout for NDM-CRE because of the ease with which they spread, especially in hospital intensive care units, where invasive devices like ventilators and catheters are magnets for bacterial contamination.
Sundermann said that any time you have a clinical infection with NDM in your hospital, “red alarms” should be going off. That means intensified surveillance and infection prevention and control measures like screening patients and isolating those who are infected or are just carrying the bacteria.
But Sundermann, who works on bringing real-time surveillance for drug-resistant pathogens into routine care, said there’s “no silver bullet” for NDM-CRE.
“We have been aggressively doing surveillance and trying to stop all of it, but you see persistence over time,” he said.
For now, the combination drug aztreonam-avibactam, approved by the Food and Drug Administration in early 2025, gives clinicians another option for treating NDM-CRE infections. But ultimately, bacteria will find a way to evade that drug, too. Spellberg said we need to stop pretending this is a “winnable war with an endgame.”
“Whatever we come up with, resistance will eventually emerge to,” Spellberg said. “We need to do a much better job of controlling our antibiotic use so we stop selecting out these pathogens and stop enriching them in healthcare settings.”