Even with results delivered hours earlier, rapid diagnostic testing did not translate into better survival or recovery, highlighting the complex realities of treating drug-resistant infections worldwide.
Study: Fast Antimicrobial Susceptibility Testing for GramNegative Bacteremia. Image credit: TopMicrobialStock/Shutterstock.com
A randomized clinical trial involving patients with gram-negative bacterial infection reports that rapid antimicrobial susceptibility testing directly from positive blood cultures is not superior to standard susceptibility testing in achieving better clinical outcomes. A detailed trial report is published in JAMA.
Global burden and risks of gram-negative bloodstream infections
Gram-negative bacteria, such as Escherichia coli, are responsible for up to 50 % of blood infections worldwide. These infections are associated with high mortality rates due to ineffective therapy, especially in low- and middle-income countries.
Rapid and accurate identification of the most effective antibiotics for a specific gram-negative bacterial infection is expected to have several clinical benefits, including timely administration of pathogen-directed antimicrobial therapy, more optimal antibiotic utilization, lower risk of developing antimicrobial resistance, and better clinical outcomes.
In this context, novel and rapid antimicrobial susceptibility testing, which is a phenotypic method of detecting antimicrobial resistance, may provide a platform for detecting known and novel resistance mechanisms.
Several observational studies comparing novel and rapid blood culture antimicrobial susceptibility testing procedures with standard procedures have shown faster pathogen identification, and have suggested shorter hospital stay and lower mortality. However, these claims have not been supported by recent clinical trials, which have mostly been conducted in high-income countries with low prevalence of antimicrobial resistance.
Given these limitations in study design and discrepancies in findings, an open-label randomized trial involving 899 randomized patients (850 included in the primary analysis) with gram-negative bacterial blood infections was conducted at 7 medical centers across four countries where the prevalence of antimicrobial resistance in gram-negative bacterial infection is high.
The participants were randomized to either a rapid or a standard antimicrobial susceptibility testing group to assess and compare desirable clinical outcomes at day 30. In the rapid testing group, antimicrobial susceptibility testing was conducted by directly using samples from positive blood culture bottles in addition to standard testing; whereas, the standard testing was conducted on sub-cultured bacteria. All patients in both groups also received review and recommendations from antimicrobial stewardship teams.
Rapid testing fails to improve 30-day clinical outcomes
The analysis of clinical outcomes at day 30 revealed that the rapid antimicrobial susceptibility testing is not superior to the standard testing in achieving more desirable outcomes, including patients being alive without deleterious events (such as unsuccessful discharge, lack of clinical response, or adverse events), alive with at least one deleterious event, and patient’s death.
Similarly, no significant differences were observed between the two groups in other clinical outcomes, including 30-day mortality, duration of hospital stay, admission to the intensive care unit (ICU), acquisition of hospital-acquired infections, time to receipt of effective antibiotic therapy within 3 days, and time to antibiotic escalation or deescalation within 3 days. However, the rapid testing group had faster antibiotic escalation or deescalation overall.
Rapid testing substantially reduced the time to availability of antimicrobial susceptibility results (approximately 7.5 hours vs 44 hours with standard testing), although this did not translate into improved primary clinical outcomes.
Faster diagnostics improve stewardship but not patient outcomes
This multinational randomized clinical trial reveals that rapid antimicrobial susceptibility testing directly from positive blood culture samples is not superior to standard susceptibility testing in terms of improving clinical outcomes in patients with gram-negative bacterial blood infections.
However, the trial finds associations of rapid testing with improved timely antibiotic modifications and targeted antibiotic therapy in certain subsets of patients, more frequent guidance from antimicrobial stewardship teams on antimicrobial use, and greater acceptance of stewardship recommendations.
In patients with carbapenem-resistant infections, rapid testing showed an association with fewer patients remaining hospitalized at day 30 (rather than a clear reduction in overall length of stay), which may be due to faster targeted treatment with the use of rapid testing. However, the trial investigators have warranted further study for more conclusive interpretation.
In accordance with previous findings, this trial could not find any benefits of rapid testing in reducing mortality risk. The all-cause mortality assessed in the trial may have occurred due to illness severity or comorbidities other than bacterial infections in the blood. Additionally, nearly two-thirds of patients in both groups were already receiving effective antibiotic therapy at enrollment, which may have limited the ability to detect outcome differences.
Furthermore, some trial sites caring for patients with resistant infections may not always have had access to the most effective antibiotic therapies available. This treatment gap may have contributed to the lack of association between rapid testing and mortality risk. Given these shortcomings, the trial investigators have highlighted the need for reasonable access to optimal antibiotic therapies together with diagnostic innovation to improve patients’ clinical outcomes.
Several institution-specific factors, such as patient complexity, antimicrobial susceptibility testing methods, local pathogen prevalence, and resistance rates, can influence the effect of blood culture diagnostics. Because of this reason, the findings of this trial may not be generalizable to all institutions.
The trial has used a combination of rapid testing and antimicrobial stewardship review, as previous studies have demonstrated more optimal antibiotic use when rapid blood culture diagnostics are paired with stewardship. However, the trial did not evaluate the independent effect of rapid testing separate from stewardship and the cost-effectiveness of combining rapid testing and stewardship. These factors could serve as an important area for future research, as suggested by the investigators.
Additionally, approximately one-fifth of patients had organisms not included on the rapid testing panel, which may have reduced the overall impact of the intervention.
Despite these limitations, the large sample size and inclusion of countries with high prevalence of antimicrobial resistance potentially strengthen the trial findings, which may help inform the use of rapid susceptibility testing in clinical practice.
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