Superbugs have long plagued the healthcare system but one particular organism — once dubbed a “nightmare bacteria” by a CDC staffer — is alarming health officials. Between 2019 and 2023, prevalence of a highly resistant superbug NDM-CRE increased by 461% in the United States, according to the CDC. It’s fearsome because it not only causes potentially deadly and extremely difficult-to-treat infections, including pneumonia, bloodstream and urinary tract infections, but it has the potential to spread quickly.
The explosive rise of the superbug is reemphasizing the need for therapies to fight the stubborn infections.
NDM-CRE is one of the most recent and dangerous strains of carbapenem-resistant Enterobacterales, a group of antibiotic-resistant Gram-negative bacteria. CRE first began surging around 2010, presenting a new hurdle for doctors, said Romney Humphries, professor of pathology, microbiology and immunology at Vanderbilt University Medical Center. “The thing that made them very challenging is that not only did they have resistance mechanisms to the carbapenems, which are last line, big-gun drugs, but also resistance mechanisms to every other antibiotic class,” she said.
At the time, patients who developed infections caused by these bacteria had high mortality rates because there were no effective treatments, she said. The tide turned around 2015 when new drugs were developed to target the most common type of this resistance mechanism, Klebsiella pneumoniae carbapenemase, Humphries said.
But it was a short-lived victory. Soon after, the more resistant strain, NDM-CRE, was identified in India. In an era of global travel and medical tourism, it wasn’t long before it made its way to the U.S.
A few drugs, including Shionogi’s Fetroja and AbbVie and Pfizer’s recently approved Emblaveo, have some efficacy against the strain, but more needs to be done to address the threat, Humphries said. Many investigational options for CRE are still in early stages despite the urgent threat.
Overall, antimicrobial development is still hampered by slow investment, which is allowing CRE and a new generation of superbugs to outrun existing treatments. Without additional treatments, drug-resistant infections, including CRE, could kill 39 million people by 2050, according to a 2025 report by the World Health Organization.
High need, low investment
Establishing a steady pipeline of new drugs to stay ahead of NDM-CRE and other superbugs should be treated as an infrastructure project, said Kevin Outterson, executive director of CARB-X, a nonprofit global partnership developing new tests and drugs to treat bacterial infections. Antimicrobial drugs are as critical as bridges, which are all routinely funded with development and maintenance dollars, he said. But antibiotic development is a cash-strapped field because it’s far less lucrative for private companies than fields like oncology.
While risks related to superbugs are rising, antimicrobial drug development is declining, according to the Access to Medicine Foundation. The AMR Action Fund, the Global Antibiotic Research and Development Partnership, and CARB-X have stepped in to fill funding gaps, but those contributions can only go so far. Larger structural changes are also needed.
Some private companies have made tentative steps back into the field. “We are seeing some of the big pharma companies getting back into the antibiotic game. Ten to 15 years ago all of big pharma abandoned antibiotic development, which was really alarming to people in our community,” Humphries said.
Several have moved to make up for lost ground. GSK, along with Spero Therapeutics, gained approval for the first FDA-approved oral carbapenem antibiotic, Utebzi, for complicated, sometimes multi-drug resistant, urinary tract infections in June. Roche is advancing a small molecule drug, zosurabalpin, against another troubling bug, Acinetobacter baumannii.
But despite $75 million in investments from CARB-X alone in the past 10 years to fight CRE, the pipeline is still slim.
Basilea has a phase 1 drug, BAL2420, a lipopolysaccharide transport protein A inhibitor, which is a mechanism that has shown the ability to target Enterobacteriaceae, including resistant strains. Other investigational drugs include two phase 1 combination candidates from Qpex and several preclinical programs from companies like Vedanta Biosciences, Tamrisa and GangaGen Biotechnologies.
But getting a drug to market is only half the battle. A number of companies that gained FDA approval for new treatments have gone bankrupt, Outterson said. Achaogen, which received CARB-X funding, declared bankruptcy in 2019 less than a year after its drug Zemdri received a narrower than anticipated approval and saw slow sales. Zemdri, which was used for treatment-resistant urinary tract infections, including CRE, is now sold by Cipla Therapeutics.
Broader changes to payment models for antimicrobial drugs are needed to make development more feasible for private industry. Outterson said many are hoping Congress will finally take up and pass the proposed federal Pioneering Antimicrobial Subscriptions to End Upsurging Resistance Act, which could create a new subscription-based payment model to spur drug development. Instead of reimbursing manufacturers for individual antibiotic doses, the government would pay a subscription price for certain critical antimicrobial drugs.
“We just need to change the way that we pay and support antibiotic R&D, so we maintain the effectiveness of these drugs over generations,” Outterson said.
There are a lot of innovative ideas, Outterson said, but “the problem is turning them into companies, and turning the companies into something that is profitable.”
