NIH experts note risks of 'difficult-to-treat' bloodstream infections

Bacteria in bloodstream
Bacteria in bloodstream

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Editor's note: This story has been updated with comments from Sameer Kadri, MD, MS.

A new study by researchers with the National Institutes of Health suggests that a novel category of multidrug resistance could be more useful for clinicians treating patients with gram-negative bloodstream infections (GNBSIs).

The study, published in Clinical Infectious Diseases, looked at more than 45,000 GNBSI episodes at 173 US hospitals over 5 years and found that, at 92 of those hospitals, there were 471 (1%) that exhibited resistance to all reported antibiotics in the carbapenem, beta-lactam, and fluoroquinolone categories. These infections, labeled as difficult-to-treat (DTR), were associated with decreased survival in patients, with the risk of death 20% higher than bloodstream infections with other resistance phenotypes.

The authors of the study say the findings indicate that the DTR label, which signifies that a GNBSI will not respond to any first-line, high-efficacy, low-toxicity antibiotics, could help give clinicians both a better sense of the severity of DTR bloodstream infections, and the potential effects of treating them with less effective, more toxic agents.

"As a category that considers the count, efficacy, and toxicity of available antibiotics, DTR more fully encompasses key aspects of antimicrobial resistance that affect mortality risk," they write.

Higher mortality risk

In addition to the 471 DTR infections, the retrospective cohort study found that 1,048 GNBSI episodes (2.3%) were carbapenem resistant (CR), 4,065 (9.0%) were extended-spectrum cephalosporin resistant (ECR), and 10,240 (22%) were fluoroquinolone resistant (FQR). The prevalence of GNBSIs displaying DTR varied across bacterial species, from 0.04% for Escherichia coli to 18.3% for Acinetobacter baumannii.

Among the 440 patients with DTR GNBSIs, there were 190 deaths, for an unadjusted mortality rate of 43%; in comparison, the unadjusted mortality rate was 35% for CR infections (183 of 526 patients), 22% for ECR (609 of 2,756), and 18% for FQR (795 of 4,342) infections. After adjustment for confounders, patients with DTR GNBSIs had a 40% higher adjusted mortality risk compared with patients with non-resistant infections, and a 20% higher adjusted mortality risk than patients with CR, ECR, FQR infections. DTR patients had longer hospital stays, as well.

The researchers also found that nearly 4 out of 5 DTR patients received reserve antibiotics that would otherwise be avoided when first-line agents are effective. Aminoglycosides were the most frequently prescribed reserve antibiotic, followed by tigecycline and polymyxin-B. This is significant because aminoglycosides and polymyxin-B can both damage the kidneys, while tigecycline is associated with increased mortality rates.

Furthermore, the analysis showed that 33% of DTR isolates were resistant to all aminoglycosides, and 80% were resistant to at least one aminoglycoside.

"The high proportion of aminoglycoside resistance among DTR bloodstream isolates emphasizes the difficulty of choosing salvage antibiotics for clinical decompensation due to suspected resistance," the authors write.

The authors conclude, "Owing to its simplicity and ease of recognition, our analysis of DTR should alert all providers to its serious implications, and ideally it will encourage infection specialists and clinical pharmacists to help direct and monitor the use of agents that are less frequently used and more toxic and/or less effective."

Lead study author Sameer Kadri, MD, MS, a staff clinician with the NIH Clinical Center, said in an email that despite the low prevalence of DTR bloodstream infections found in the study, he and his colleagues believe they should be an important target for antimicrobial resistance surveillance going forward.

"Although only 1% of GNBSI showed DTR, DTR was identified at 1 in every 2 hospitals in the 173 hospital sample, so prevalence is relatively low but it’s everywhere," Kadri said. "And without infection control and stewardship, it could increase." 

See also:

Jul 23 Clin Infect Dis study

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