Resistant Gram-Negative Infections: New Data & Insights
- Enterobacterales (CRE) are increasing worldwide and are considered an urgent health threat by the CDC.
- The anti-CRE drug renaissance began in 2015 with the approval of ceftazidime-avibactam,which paired an existing beta-lactam with a novel beta-lactamase inhibitor (BLI).
- A novel siderophore cephalosporin, cefiderocol uses the iron transport pathway to overcome resistance, and was the frist available beta-lactam with activity against MBL-producing pathogens. In 2025, aztreonam-avibactam became...
January 12, 2026
5 min read
Enterobacterales (CRE) are increasing worldwide and are considered an urgent health threat by the CDC. Fortunately, in the last decade, the number of effective antimicrobial options for treating CRE has expanded substantially, but to answer the question above, clinicians must understand the relationship between these various newer agents and the carbapenemases encountered in practice.
The anti-CRE drug renaissance began in 2015 with the approval of ceftazidime-avibactam,which paired an existing beta-lactam with a novel beta-lactamase inhibitor (BLI). Following the same formula, meropenem-vaborbactam and imipenem-cilastatin-relebactam reached the market in 2017 and 2019, respectively.All of these novel BLIs improved beta-lactam activity against KPC-producing bacteria, but none were effective against MBLs. That changed in 2019 with the approval of cefiderocol.
A novel siderophore cephalosporin, cefiderocol uses the iron transport pathway to overcome resistance, and was the frist available beta-lactam with activity against MBL-producing pathogens. In 2025, aztreonam-avibactam became the second beta-lactam-based product on the market with MBL activity.Aztreonam is not hydrolyzed by MBLs, and the addition of avibactam shields aztreonam from any serine beta-lactamases that may also be present, broadening the spectrum of the combination to include CRE. With this new approval and new trial data for cefiderocol perhaps changing the CRE treatment game, a review of the playing field is warranted.
A game-changer?
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Cefiderocol has demonstrated safety and efficacy in both complicated UTIs and nosocomial pneumonia. Unfortunately, despite its potent activity against CRE, including MBL producers, cefiderocol stumbled a bit as a CRE therapy in the CREDIBLE-CR trial. In this phase 3 study comparing cefiderocol with best available therapy for treatment of serious infections due to carbapenem-resistant gram-negative organisms,there were numerically more deaths in the cefiderocol arm at end of study (34% vs. 18%), though imbalances between study groups preclude drawing firm conclusions.
In light of these data,the recently published GAME-CHANGER trial sought to clarify cefiderocol’s role in treating gram-negative bloodstream infections (BSI),including those due to CRE. In this phase 3 clinical trial,504 adult patients with BSI due to gram-negative pathogens were random
In the opening case,the patient’s carbapenem-resistant enterobacterales (CRE) isolate was susceptible to ceftazidime-avibactam,which is often a reliable option for treating MBL-producing organisms. However, the patient’s clinical status deteriorated despite ceftazidime-avibactam therapy. This highlights the importance of considering the potential for other resistance mechanisms and the need for ongoing clinical assessment to influence a final treatment decision.
Additionally, the specific mechanism of carbapenem resistance needs to be considered.In the opening case, the isolate was resistant to ceftazidime-avibactam, which could indicate MBL production. However, carbapenemase mutations, such as the D179Y substitution seen in KPCs, can also lead to ceftazidime-avibactam resistance. These KPC variants demonstrate increased affinity for ceftazidime and decreased avibactam binding. Growing data suggest cross-resistance to cefiderocol occurs with these mutations, and aztreonam-avibactam may be affected as well. Consequently, these isolates are likely better treated with an choice agent, such as meropenem-vaborbactam. Phenotypically, both KPC variants and MBLs can appear resistant to ceftazidime-avibactam, highlighting the need for genotypic testing for resistance mechanisms and phenotypic antimicrobial susceptibility testing to ensure that the moast effective treatment is chosen.
the therapeutic armamentarium for managing gram-negative infections continues to expand, and new data highlight some potential options for some of the most resistant pathogens encountered in practice, including MBL-producing CRE. Increasing specificity of these agents for specific resistance mechanisms, combined with ever-present evolutionary pressure from antibiotic use, necessitates that clinicians keep abreast of current data to ensure optimal therapy is chosen in each case.
For more information:
Gregory B. Tallman, PharmD, MS, BCPS, BCIDP, is a clinical pharmacy specialist in infectious diseases and program director of the PGY2 infectious diseases pharmacy residency at Providence St. Joseph Health. He can be reached at gregory.tallman@providence.org.
Antimicrobial Resistance Threatens Gains in Cancer Treatment
A growing body of research indicates that antimicrobial resistance (AMR) is increasingly impacting the outcomes of cancer treatment, particularly for patients receiving chemotherapy and hematopoietic stem cell transplantation. Infections caused by drug-resistant organisms are leading to prolonged hospital stays, increased healthcare costs, and higher mortality rates among vulnerable cancer patients.
the Link Between Cancer Treatment and Infection Risk
Cancer and its treatments significantly weaken the immune system, making patients highly susceptible to infections. Chemotherapy, in particular, causes neutropenia – a deficiency of neutrophils, a type of white blood cell crucial for fighting bacterial and fungal infections. Hematopoietic stem cell transplantation (HSCT) further suppresses the immune system, creating a prolonged period of vulnerability. This immunosuppression provides an possibility for opportunistic pathogens, including those resistant to antibiotics and antifungals, to thrive.
Rising Rates of Antimicrobial Resistance
The global rise of AMR is exacerbating the risks for cancer patients. According to a study published in Journal of Global Antimicrobial Resistance in March 2024, rates of carbapenem-resistant Klebsiella pneumoniae (CRKP) and vancomycin-resistant enterococci (VRE) are increasing in healthcare settings, posing a significant threat to immunocompromised individuals. These organisms are often arduous to treat, requiring the use of last-resort antibiotics with potentially severe side effects.
Specific Infections and Outcomes
Several studies have highlighted the impact of specific infections on cancer patients. A 2020 study in The Lancet Infectious Diseases by Wunderink RG, et al., demonstrated that hospital-acquired pneumonia caused by multidrug-resistant bacteria was associated with a 30-day mortality rate of 25.8% in critically ill patients, a significant proportion of whom had underlying malignancies. Furthermore, invasive fungal infections, particularly those caused by Candida auris, are emerging as a major concern, often exhibiting resistance to multiple antifungal agents. Candida auris infections have been linked to outbreaks in cancer centers and are associated with high mortality rates.
Strategies to Mitigate the Risk
Addressing the threat of AMR in cancer care requires a multifaceted approach:
- Antimicrobial Stewardship: Implementing programs to optimize antibiotic and antifungal use, reducing unnecessary exposure and slowing the development of resistance.
- Infection prevention and Control: Strict adherence to hygiene protocols, including handwashing, isolation of infected patients, and environmental disinfection.
- rapid Diagnostics: Utilizing rapid diagnostic tests to quickly identify pathogens and their resistance profiles, enabling targeted therapy.
- Novel Therapies: Developing new antibiotics and antifungals, as well as alternative strategies such as phage therapy and immunotherapy.
- Vaccination: Promoting vaccination against preventable infections, such as influenza and pneumococcal disease, to reduce the burden on the immune system.
The increasing threat of antimicrobial resistance demands urgent attention to protect cancer patients and preserve the effectiveness of life-saving treatments.