A new study suggests that newer antibiotics designed for some of the most drug-resistant bacterial infections are being used more frequently but aren’t making a dent in survival rates.
The study, published in The Lancet Infectious Diseases, found that, among patients hospitalized with a difficult-to-treat (DTR) gram-negative bacterial infections, initial treatment with one of six antibiotics approved in recent years rose by nearly 300% from 2016 to 2023. But there was no observed reduction in mortality among the patients.
Furthermore, over the entire study period, more than three-quarters of patients with DTR infections received initial treatment with discordant antibiotics—defined as antibiotics that either weren’t active against the pathogen or to which the pathogen was actively resistant.
The authors of the National Institutes of Health (NIH)-funded study say the findings suggest that new antibiotics alone aren’t enough to improve survival in patients with highly resistant infections.
“We were hopeful that mortality would have improved over time. However, survival from most if not all infections is also related to the timing of the diagnosis and early initiation of antibiotics,” first author Morgan Walker, MD, a critical care and infectious diseases physician at the NIH Clinical Center, told CIDRAP News.
Most patients receive inadequate initial treatment
The six “next-generation” antibiotics analyzed in the study are among nine that have been approved by the US Food and Drug Administration (FDA) since 2014 with activity against drug-resistant gram-negative pathogens, which are some of the hardest to combat because of the mechanisms they’ve acquired to ward off traditional antibiotics. They include antibiotics designed specifically to counter those mechanisms, such as ceftazidime-avibactam and meropenem-vaborbactam.
These drugs were developed to fight the type of infections the study authors have classified as DTR, which they define as resistant to all first-line safe and effective antibiotics. But previous studies have indicated that uptake of these new treatment options has been slow, and data on their effectiveness have been scarce.
“Understanding how survival from resistant Gram-negative infections is changing, especially in regions where these newer antibiotics have become available, is crucial,” the study authors wrote.
Using data from a large health insurance database, the researchers conducted a retrospective cohort study on patients with microbiologic evidence of a DTR gram-negative infection who received antibiotic treatment at US hospitals from 2016 through August 2023. They characterized the proportion of patients receiving new DTR-active antibiotics, traditional DTR-active antibiotics, and non–DTR-active antibiotics for at least three consecutive days for infections caused by Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii and examined changes in in-hospital mortality.
We were hopeful that mortality would have improved over time. However, survival from most if not all infections is also related to the timing of the diagnosis and early initiation of antibiotics.
The proportion of hospitals reporting use of at least one newer antibiotic rose from 12% to 63% from 2016 to 2013, and the share reporting antibiotic susceptibility testing for newer antibiotics rose from 4% to 71%. The proportion of patients with DTR infections who received initial treatment with DTR-active newer antibiotics rose from 4% to 15%, while the share who received initial treatment with traditional DTR-active antibiotics fell from 29% to 13%.
But of the 4,875 patients with DTR infections treated over the entire study period, 77% received inadequate initial antibiotic treatment, a figure the authors say is “unacceptably high.” Most were treated with antibiotics that weren’t active against the pathogen or for which lab tests indicated the infection was resistant.
The estimated mortality for patients with DTR Enterobacterales and P aeruginosa infections was 20%; for A baumannii, it was 25%. After adjustments for patient-, treatment-, and hospital-related factors, no change was observed in mortality for the three infections over the study period. The lone exception was a 4.5% decrease in mortality for P aeruginosa bloodstream infections.
Traditional diagnostics delay appropriate treatment
Walker and his co-authors say that while newer antibiotics provide a welcome alternative for patients with limited treatment options, mortality remains high in patients with DTR infections because they tend to be older and have multiple comorbidities. In addition, nearly two-thirds of the patients in the study had a sepsis diagnosis, which calls for prompt, empiric antibiotic treatment. Sometimes the selected antibiotic doesn’t work.
Walker said one reason newer antibiotics weren’t used more for initial therapy is that some hospitals might restrict such use. But the underlying problem is that, when treating sepsis, which can quickly become life-threatening, clinicians don’t have time to wait for bacterial culture results that would guide appropriate antibiotic treatment.
“The issue here is not that the antibiotics are restricted but rather that our traditional diagnostic methods (e.g., bacterial culture) may take several days to [provide a] result, and, therefore, delay appropriate treatment,” Walker explained.
Another reason clinicians may not have chosen newer antibiotics for initial therapy is the lack of evidence that they’re more effective against DTR infections. The authors note that most phase 3 trials for antibiotics use patients with susceptible infections, or infections that are only resistant to one antibiotic, because patients with multidrug-resistant infection infections are rare.
In an accompanying commentary, experts from the Centers for Disease Control and Prevention add that clinicians also may be reluctant to use newer antibiotics because they’re more expensive, or they want to preserve their effectiveness.
“Data-driven approaches that incorporate patient-level risk factors, local resistance patterns, and clinical acuity could further refine the selection of empiric therapy and support targeted use of newer agents for uncommon DTR infections,” Sarah Kabbani, MD, and L. Clifford McDonald, MD, wrote.
Walker and his colleagues say rapid diagnostic tests that provide early identification of resistant pathogens could lead to quicker treatment with newer antibiotics, which may be more effective when used earlier. But ultimately, Walker said, improving mortality rates for DTR infections will require a multifaceted effort.
“The take-home message from this study is that we need to do better with early recognition of resistance, prompt and appropriate empiric antibiotic therapy, and look into investigating non-antibiotic therapies as well to test whether they can move the dial on survival in highly resistant infections,” he said.
