Mortality in patients with sepsis is lower for those who receive prolonged intravenous infusions of antipseudomonal beta-lactams than for those who receive short-term infusions, according to a systematic review and meta-analysis of randomized trials.

“In a previous meta-analysis published in 2013 in Clinical Infectious Diseases, we showed that prolonged infusion was associated with lower mortality,” Dr. Konstantinos Z. Vardakas from Alfa Institute of Biomedical Sciences, in Athens, Greece, told Reuters Health by email.

“That analysis was limited by the inclusion of small and mainly observational studies; the mortality benefit was modest and the outcome was supported by low-quality data. In this analysis, we included only randomized controlled trials; the benefit was significant and the quality of the supporting data was high.”

The effectiveness of beta-lactams is increased when their plasma concentration at steady-state is more than four times the pathogen’s minimum inhibitory concentration (MIC), and the fluctuation of beta-lactam plasma concentration improves with prolonged infusions, at least in patients with normal renal function.

Dr. Vardakas’s team assessed the effect of prolonged infusion of antipseudomonal beta-lactams (carbapenems, penicillins, and cephalosporins) on mortality of patients with sepsis, compared with short-term administration (60 minutes or less), in their meta-analysis of 22 randomized controlled trials including 1,876 enrolled patients.

Overall, prolonged infusion of beta-lactams reduced all-cause mortality by 30% compared with short-term infusion, they write in The Lancet Infectious Diseases, online October 25.

Findings were similar in almost all subgroup and sensitivity analyses.

In contrast, clinical cure or improvement rates did not differ significantly between the prolonged and short-term infusion groups.

“Although a discrepancy between the primary (i.e., mortality) and secondary (i.e., clinical effectiveness, which was marginally nonsignificantly different) outcomes was observed, this should have been attributed to factors like the sample size, lack of supporting microbiological data, and timing of assessment,” Dr. Vardakas said. “We should also acknowledge that clinical effectiveness is a more subjective outcome, especially in ICU patients.”

Treatment groups did not differ significantly in reported adverse event rates or in the development of resistance.

“The issue is not over,” Dr. Vardakas said. “We found that a benefit could be seen in all patients, but we suspect that some patients may benefit more. In this category, we may consider those infected by multidrug-resistant pathogens, pathogens with MICs at the highest level of susceptibility, P. aeruginosa and A. baumannii.”

“We should examine whether cephalosporin-treated patients might benefit, whether there is discordance between patients with normal or impaired renal function, specific types of infections (like bacteremia, pneumonia, etc.), and patients with high severity scores, older age, or immunocompromise,” he said. “Finally, we should examine whether additional modalities like therapeutic drug monitoring, combination therapies with additional antibiotics, and adjuvant therapies (e.g., vitamins, hydrocortisone) could have additional impact.”

Dr. Mical Paul from Israel Institute of Technology, in Haifa, who coauthored an accompanying editorial, told Reuters Health by email, “Prolonged intravenous administration of beta-lactams in the ICU setting may have a benefit, has biological rationale, and is harmless. It should be used.”

“Treatment duration is an unresolved issue,” he said. “For many infections, we are probably giving longer treatments than necessary. But this is a different question to assess in randomized controlled trials comparing treatment durations.”