Rising Threat of Drug-Resistant Gram-Negative Infections Driven by Global Spread and Antibiotic Pressure

The increasing incidence of Gram-negative bacilli resistant to extended-spectrum cephalosporins in hospital settings reflects a convergence of global and local pressures, according to Mariana Castanheira, PhD, FIDSA, FAAM, chief scientific officer at JMI Laboratories. She explains that resistance mechanisms long observed in other regions are now emerging more frequently in the United States, driven in large part by extended-spectrum beta-lactamases (ESBLs). These enzymes, often carried on plasmids, can spread quickly between bacterial species, while the widespread use of cephalosporins creates a selective environment that favors resistant strains.

At the same time, increased reliance on carbapenems has introduced new challenges. While these agents have historically served as critical therapies, their growing use has contributed to the selection of carbapenem-resistant organisms, particularly in hospital environments. Gram-negative pathogens have developed multiple resistance strategies, including carbapenemase production, efflux pump upregulation, and reduced membrane permeability. Compounding the issue, co-selection driven by other antibiotic classes, such as fluoroquinolones, can promote multidrug resistance. Castanheira highlights that this evolving resistance landscape underscores the urgent need to deploy effective therapies earlier and more strategically in treatment pathways.

Among the most concerning resistance mechanisms are metallo-β-lactamases (MBLs), which can inactivate a broad range of beta-lactam antibiotics and are not inhibited by currently available beta-lactamase inhibitors. Their frequent location on mobile genetic elements, including plasmids, integrons, and gene cassettes, enables rapid dissemination across bacterial populations, particularly in healthcare settings. Rapid diagnostic tools, such as nucleic acid or antigen testing, are critical for identifying these organisms and guiding treatment decisions. While therapeutic options remain limited, newer agents such as cefiderocol—and to a lesser extent aztreonam-avibactam—offer potential activity against MBL-producing pathogens. However, Castanheira cautions that the continued evolution and spread of these resistance mechanisms represent a significant and ongoing public health challenge.

Contagion spoke to Castanheira about increases in incidence rates for resistance, how reliance on carbapenems has influenced antimicrobial resistance patterns, and an agent showing efficacy against pathogens carrying Metallo-beta-lactamases (MBLs).

Contagion: What factors are driving the increasing incidence of Gram-negative bacilli resistant to extended-spectrum cephalosporins in hospital settings?

Castanheira: Resistance is a constantly evolving process.¹ We are now seeing resistance mechanisms that have been present in Europe and other parts of the world for several years make their way to the US.^2,3

A common mechanism of resistance to extended-spectrum cephalosporins is the production of beta-lactamases, particularly extended-spectrum beta-lactamases (ESBLs).⁴ ESBLs are often carried on plasmids, allowing them to spread rapidly within and across bacterial species.² The extensive use of cephalosporins creates a selective pressure that favors these resistant isolates. ² We have seen this happen in many other countries and it is largely considered unavoidable that the same will occur in the US. It is not a question of if, but when.³

Contagion: How has the increased reliance on carbapenems influenced antimicrobial resistance patterns, particularly in nosocomial environments?

Castanheira: Increased reliance on carbapenems is a factor in the selection of resistance to these critical therapies.⁵ Furthermore, the use of other potent antibiotics, particularly fluoroquinolones, can also drive the emergence of carbapenem resistance through co-selection, where bacteria develop mechanisms that confer resistance to multiple antibiotic classes simultaneously.⁶

Gram-negative pathogens have evolved multiple mechanisms for carbapenem resistance, including acquisition of carbapenemases, beta-lactamases that can degrade carbapenems, as well as the upregulation of efflux pumps and/or reduced permeability that prevent carbapenems from reaching their targets inside the cell.⁷

The increasing prevalence of carbapenem-resistant pathogens underscores the need for more effective anti-infective options, which includes usage of antibiotics that can overcome carbapenem resistance to be used earlier in the treatment paradigm.⁷

Contagion: Can you explain the role of metallo-β-lactamases (MLs) in carbapenem resistance, and why they pose such a significant clinical challenge compared to other β-lactamases?

Castanheira: Bacteria can become resistant to beta-lactam (BL) antibiotics such as penicillins, cephalosporins, and carbapenems by producing enzymes called beta-lactamases, which break down the antibiotic and prevent it from working.⁸ MBLs are a distinct class of beta-lactamases (Ambler Class B) that possess broad substrate specificity, allowing them to inactivate a wide range of beta-lactam antibiotics.⁹ MBLs often reside on plasmids, which enables resistance to spread rapidly across different bacterial species.¹⁰ This is particularly the case with New Delhi MBLs.¹⁰ The primary clinical challenge with MBLs is that they are not inhibited by any currently marketed beta-lactamase inhibitors, severely limiting therapeutic options for infections caused by MBL-producing pathogens.¹¹ It is also likely that the increased use of beta-lactam/beta-lactamase inhibitor (BL/BLI) combinations has created a selective pressure that has contributed to the rise in MBLs.¹²

The threat of bacteria not being susceptible to these combination agents is a major public health concern because it severely limits treatment options for infections caused by multidrug-resistant pathogens.^13,14 Cefiderocol continues to be an option in treating those Gram-negative infections, even for infections by isolates that are not susceptible to BL-BLIs.^15,16

Contagion: What are the most effective phenotypic or laboratory methods for detecting MBL-producing organisms, and how do these tools support infection prevention efforts?

Castanheira: Nucleic acid or antigen testing is the best way to detect MBL-producing organisms because it is rapid and can identify the exact type of MBL.¹⁷ This knowledge is important for guiding treatment decisions.¹⁷

Contagion: How do mobile genetic elements like integrons and gene cassettes contribute to the rapid dissemination of MBL genes across different Gram-negative species?

Castanheira: Mobile genetic elements can accelerate the spread of resistance by facilitating the horizontal transfer of genes conferring antimicrobial resistance. This is a particular concern in hospital settings, where multiple resistance genes can circulate among different pathogens.⁷

Contagion: Are there any specific antimicrobials showing efficacy against pathogens carrying MBLs?

Castanheira: Cefiderocol, developed by Shionogi, is a siderophore cephalosporin antibiotic that can circumvent the major mechanisms of carbapenem resistance by entering cells via active transport and passive diffusion, overcoming efflux pump-up regulation and being stable against all classes of beta-lactamases. Cefiderocol works by binding to iron, an essential nutrient for bacteria, and then exploiting the bacteria’s natural iron transport system to cross into the bacterial outer membrane. Once inside the bacterial cell, cefiderocol acts like other β-lactam antibiotics by binding to penicillin-binding proteins (PBPs), mainly PBP3, which disrupts cell wall synthesis and leads to bacterial death.¹⁸

In addition to cefiderocol, Aztreonam-avibactam (ATM-AVI) is another agent with efficacy against MBL-producing Enterobacterales, but unlike cefiderocol, it is not very effective against P aeruginosa or A baumannii.¹⁹

Older agents like tetracyclines and colistin may also be considered as possibilities, but these are generally less preferred options due to concerns about side effects and/or poor performance in specific sites, such as lung infections.^20,21

Data from the SENTRY Antimicrobial Surveillance Program presented at IDWeek 2025 demonstrated that high activity of cefiderocol against multiple species of Gram-negative isolates (Enterobacterales, P aeruginosa, A baumannii, S maltophilia), including carbapenem non-susceptible subsets, was observed consistently over a five-year period with no substantial change in activity.²²

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