Prolonged Infusion of β-lactams Lowers Mortality in Sepsis Patients

A recent study showed that, compared with short-term infusion, prolonged infusion of antipseudomonal β-lactams in patients with sepsis was associated with significantly less mortality.

Konstantinos Z Vardakas, MD, from Alfa Institute of Biomedical Sciences (AIBS), Athens, Greece, and colleagues published the results of their systematic review

and meta-analysis October 25 in Lancet Infectious Diseases.

“The risk of death in patients with sepsis treated with prolonged infusion of antipseudomonal β-lactams was 30% lower compared with patients treated with short-term infusion,” the authors write.

However, they noted that “[c]linical cure was not significantly higher with prolonged infusions.”

In an interview with Contagion^®, Dr. Vardakas explained that prolonged infusion of antibiotics, especially β-lactams, is a relatively commonly used modality to improve the pharmacokinetics (PK), and subsequently the pharmacodynamics (PD), of these drugs.

“This is of particular interest in patients with sepsis, either in the intensive care unit or in the wards,” he said. “In these patients, the volume of distribution (lower albumin levels, increased capillary permeability, and higher extracellular volume) and renal clearance increase, resulting in lower antibiotic concentrations.”

However, findings from previous small randomized controlled trials (RCT), observational studies, and meta-analyses regarding the effectiveness of prolonged β-lactam infusion have varied widely.

Therefore, Dr. Vardakas and colleagues performed a meta-analysis to examine the effect of prolonged infusion of antipseudomonal β-lactams on mortality of patients with sepsis compared with short-term infusion.

In their study, they evaluated 22 RCTs that included 1,876 patients and compared the effect of prolonged (continuous or ≥3 hours) infusion versus short-term (≤60 min) infusion of antipseudomonal β-lactams (carbapenems, penicillins, cephalosporins, and monobactams) for treatment of patients with sepsis.

The analysis showed a clear mortality benefit for extended or continuous infusion of β-lactams among critically ill patients.

Compared with short-term infusion, prolonged infusion was associated with lower all-cause mortality (risk ratio, 0.70; 95% confidence interval, 0.56 to 0.87).

“It is possible that these findings will change clinical practice,” said Dr. Vardakas. “For the first time, we have high-quality data supporting what we have been suspecting for years.”

Indeed, in an accompanying editorial, Mical Paul, MD, from Israel Institute of Technology, Haifa, and Ursula Theuretzbacher, PhD, from the Center for Anti-Infective Agents, Vienna, Austria, call for immediate implementation of β-lactam prolonged infusion in patients with sepsis.

Nevertheless, Dr. Vardakas stressed that more research is still needed to evaluate prolonged infusion of β-lactams in critically ill patients. “We found that a benefit could be seen in all patients, but we suspect that some patients may benefit more,” he said—including those infected by problematic multi-drug resistant pathogens such as Pseudomonas aeruginosa and Acinetobacter baumannii.

He suggested that further studies would be useful to examine how prolonged infusion of β-lactams affects different patient subgroups according to the degree of renal dysfunction, type of infection (such as bacteremia or pneumonia), sepsis severity score, age, or immunocompetence.

“We should also examine whether additional modalities like therapeutic drug monitoring, combination therapies with additional antibiotics, and adjuvant therapies (such as vitamins or hydrocortisone) could have an additional impact,” Dr. Vardakas concluded.

Dr. Parry graduated from the University of Liverpool, England in 1997 and is a board-certified veterinary pathologist. After 13 years working in academia, she founded Midwest Veterinary Pathology, LLC where she now works as a private consultant. She is passionate about veterinary education and serves on the Indiana Veterinary Medical Association’s Continuing Education Committee. She regularly writes continuing education articles for veterinary organizations and journals and has also served on the American College of Veterinary Pathologists’ Examination Committee and Education Committee.