By Jake Scott, MD
Associate Clinical Professor of Medicine, Stanford University
SYNOPSIS: In a systematic review and meta-analysis, the administration of beta-lactam antibiotics by prolonged infusions was associated with a significantly reduced risk of mortality at 90 days for critically ill patients with sepsis or septic shock as compared with intermittent infusions.
SOURCE: Abdul-Aziz MH, Hammond NE, Brett SJ, et al. Prolonged vs intermittent infusions of β-lactam antibiotics in adults with sepsis or septic shock: A systematic review and meta-analysis. JAMA 2024;June 12:e249803. doi:10.1001/jama.2024.9803. [Online ahead of print].
Abdula-Aziz and colleagues conducted a systematic review and Bayesian meta-analysis of randomized clinical trials (RCTs) comparing prolonged and intermittent infusions of beta-lactam antibiotics given to critically ill adults with sepsis or septic shock.1 Prolonged infusions included either an intravenous infusion of a beta-lactam antibiotic administered for two hours or longer during the dosing interval or a continuous infusion, whereas intermittent infusions were defined as being administered for less than two hours during a dosing interval. The primary outcome assessed was all-cause 90-day mortality. Secondary outcomes included intensive care unit (ICU) mortality, ICU length of stay, clinical cure, microbiologic cure, and adverse events. Seven prespecified comparative subgroups for the primary outcome were analyzed. The primary statistical analysis used a Bayesian framework, and the secondary approach used a frequentist framework.
The analysis included 18 RCTs consisting of 9,108 critically ill adult participants (5,961 men [65%] and 3,147 women [35%]) with sepsis or septic shock. Trial participants were recruited from a total of 18 countries across five continents. The trials had a median of 59 participants with a median age of 54 years (interquartile range [IQR], 48-57 years). The median Acute Physiology and Chronic Health Evaluation II (APACHE II) score was 20 (IQR, 18-22), and the median Sequential (sepsis-related) Organ Failure Assessment (SOFA) score was 8 (IQR, 6-11). Seventeen of the trials compared continuous infusions with intermittent infusions, and one trial compared extended infusions with intermittent infusions. Meropenem was studied in the greatest number of trials (11), followed by piperacillin-tazobactam (eight trials), cefepime (three trials), and ticarcillin-clavulanate (two trials). Amoxicillin-clavulanate, ampicillin-sulbactam, ceftriaxone, and imipenem-cilastin were studied in one trial each. The median duration of randomly assigned antibiotics was seven days (IQR, six to 10 days) for prolonged infusions and nine days (IQR, six to 11 days) for intermittent infusions. The risk of bias was determined to be low overall for 10 of the 17 trials that contributed data to the primary outcome of all-cause 90-day mortality.
Using a Bayesian analysis of the 17 trials that contributed data to the primary outcome, the pooled estimated relative reduction (RR) in the risk of all-cause mortality at 90 days for prolonged infusions of beta-lactam antibiotics vs. intermittent infusions was 0.86 (95% credible intervals [CrIs], 0.72 to 0.98; τ = 0.11; I2 = 21.5%), with a 99.1% posterior probability that prolonged infusions were associated with lower 90-day mortality. The number needed to treat for prolonged beta-lactam antibiotic infusions to prevent one death was 26 patients. The level of certainty in the evidence was adjudicated as high, and the primary outcome results were similar in sensitivity analyses using Bayesian and frequentist methods. There were no differences in all-cause 90-day mortality in the seven prespecified comparative subgroups, which included meropenem vs. piperacillin-tazobactam; culture-positive vs. culture-negative infection; gram-negative vs. gram-positive infection; kidney replacement therapy vs. no kidney replacement therapy; lung infection vs. other infections; sepsis vs. septic shock; and male vs. female participants. In terms of secondary outcomes, prolonged infusions also were associated with a reduced risk of ICU mortality (RR, 0.84; 95% CrI, 0.70 to 0.97; high certainty) and an increase in clinical cure (RR, 1.16; 95% CrI, 1.07 to 1.31; moderate certainty), as compared with intermittent infusions. There were no statistically significant differences between groups in microbiologic cure, adverse events, or duration of ICU length of stay.
COMMENTARY
To effectively treat patients with sepsis or septic shock, it is imperative that the right antibiotic be given against the right pathogen at the right dose. Beta-lactam antibiotics are time-dependent killing agents, as opposed to concentration-dependent agents, such as aminoglycosides, which means that the time spent above the minimum inhibitory concentration (MIC) is the main determinant of efficacy.2 There are three ways in which the time above the MIC can be maximized: increasing the dose, shortening the dosing interval, or prolonging the infusion time. Beta-lactam antibiotics have traditionally been administered as multiple, intermittent boluses.3 However, infusing a beta-lactam antibiotic over a prolonged period of time has become more popular over the past few decades, since this approach is more likely to attain pharmacodynamic target levels compared with intermittent infusions.4,5 In addition to a clear biologic rationale, clinical trials have demonstrated that continuous infusions of beta-lactam antibiotics achieve higher plasma antibiotic concentrations, as well as improvements in clinical cure.6,7
The optimization of antibiotic dosing is especially important when treating critically ill patients with sepsis and septic shock for several reasons. The pharmacokinetics of beta-lactam antibiotics have been found to often be grossly altered in critically ill patients because of the dynamic and unpredictable pathophysiological changes that occur. These alterations include changes in protein binding, abnormal fluid balance, increases in the volume of distribution, and variability in drug clearance, all of which potentially could lead to subtherapeutic plasma concentrations at the site of infection.8-10
Prior to the current review by Abdula-Aziz and colleagues, a meta-analysis by Falagas and colleagues that was published in 2013 had found that, in total, extended or continuous infusion of a carbapenem or piperacillin-tazobactam resulted in lower mortality compared to intermittent infusion.11 However, only three out of the 14 trials included in the analysis were RCTs. In 2018, a meta-analysis of 22 randomised trials that assessed prolonged vs. short-term infusions of antipseudomonal beta-lactam antibiotics was published.12 This study, by Vardakas and colleagues, found that prolonged infusion of antipseudomonal beta-lactams for the treatment of patients with sepsis was associated with significantly lower all-cause mortality (RR, 0.70; 95% confidence interval [CI], 0.56 to 0.87). However, many of the trials included in this meta-analysis were small, and the definitions of sepsis used in most of the trials were not in accordance with current definitions.
Two large RCTs that investigated continuous vs. intermittent infusions of beta-lactams were published within the last two years, both of which were included in the meta-analysis by Abdula-Aziz and colleagues.13,14 In the MERCY trial, 607 critically ill patients with sepsis were randomized to receive intravenous meropenem by intermittent infusion or continuous infusion. The study found no significant difference in the composite primary outcome of all-cause mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at 28 days, neither were there significant differences observed for any of the four secondary outcomes.14 In BLING III, a significantly larger study that included 7,202 critically ill patients randomized to receive a beta-lactam antibiotic by either continuous or intermittent infusion, there was no statistically significant difference in the primary outcome of all-cause 90-day mortality.13 Eight hundred sixty-four of 3,473 patients (24.9%) assigned to receive continuous infusion had died, compared with 939 of 3,507 patients (26.8%) assigned to receive intermittent infusion (absolute difference, -1.9% [95% CI, -4.9% to 1.1%]; odds ratio, 0.91 [95% CI, 0.81 to 1.01]; P = 0.08). However, the rate of clinical cure was higher in the continuous infusion group compared to the intermittent infusion group (1,930/3,467 [55.7%] and 1,744/3,491 [50.0%], respectively; absolute difference, 5.7% [95% CI, 2.4% to 9.1%]).
Lastly, in a recent cohort study that included 4,861 patients hospitalized with gram-negative bloodstream infections, extended-infusion beta-lactam therapy was associated with reduced mortality compared with intermittent infusion (adjusted odds ratio, 0.71 [95% CI, 0.52-0.97]).15 The benefit was largely associated with critical illness and gram-negative bloodstream infections with elevated antibiotic MICs (i.e., intermediate or susceptible dose-dependent range).
In summary, although the administration of antibiotics via prolonged infusion is associated with potential challenges, including drug stability, compatibility with other coadministered medications, and clinical workload, a significantly reduced risk of mortality was observed among critically ill patients with sepsis or septic shock who received prolonged vs. intermittent beta-lactam infusions in this high-quality systematic review and meta-analysis.
REFERENCES
- Abdul-Aziz MH, Hammond NE, Brett SJ, et al. Prolonged vs intermittent infusions of β-lactam antibiotics in adults with sepsis or septic shock: A systematic review and meta-analysis. JAMA 2024;June 12:e249803. doi:10.1001/jama.2024.9803. [Online ahead of print].
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- Craig WA. Pharmacokinetic/pharmacodynamic parameters: Rationale for antibacterial dosing of mice and men. Clin Infect Dis 1998;26:1-10; quiz 11-12.
- Mouton JW, Vinks AA. Continuous infusion of beta-lactams. Curr Opin Crit Care 2007;13:598-606.
- Dulhunty JM, Roberts JA, Davis JS, et al. A multicenter randomized trial of continuous versus intermittent β-lactam infusion in severe sepsis. Am J Respir Crit Care Med 2015;192:1298-1305.
- Roberts JA, Kirkpatrick CMJ, Roberts MS, et al. Meropenem dosing in critically ill patients with sepsis and without renal dysfunction: Intermittent bolus versus continuous administration? Monte Carlo dosing simulations and subcutaneous tissue distribution. J Antimicrob Chemother 2009;64:142-150.
- Niemiec PW Jr, Allo MD, Miller CF. Effect of altered volume of distribution on aminoglycoside levels in patients in surgical intensive care. Arch Surg 1987;122:207-212.
- Joukhadar C, Frossard M, Mayer BX, et al. Impaired target site penetration of beta-lactams may account for therapeutic failure in patients with septic shock. Crit Care Med 2001;29:385-391.
- Roberts JA, Paul SK, Akova M, et al. DALI: Defining antibiotic levels in intensive care unit patients: Are current β-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis 2014;58:1072-1083.
- Falagas ME, Tansarli GS, Ikawa K, Vardakas KZ. Clinical outcomes with extended or continuous versus short-term intravenous infusion of carbapenems and piperacillin/tazobactam: A systematic review and meta-analysis. Clin Infect Dis 2013;56:272-282.
- Vardakas KZ, Voulgaris GL, Maliaros A, et al. Prolonged versus short-term intravenous infusion of antipseudomonal β-lactams for patients with sepsis: A systematic review and meta-analysis of randomised trials. Lancet Infect Dis 2018;18:108-120.
- Dulhunty JM, Brett SJ, De Waele JJ, et al. Continuous vs intermittent β-lactam antibiotic infusions in critically ill patients with sepsis: The BLING III randomized clinical trial. JAMA 2024;June 12:e249779. doi:10.1001/jama.2024.9779. [Online ahead of print].
- Monti G, Bradic N, Marzaroli M, et al. Continuous vs intermittent meropenem administration in critically ill patients with sepsis: The MERCY randomized clinical trial. JAMA 2023;330:141-151.
- Karaba SM, Cosgrove SE, Lee JH, et al. Extended-infusion β-lactam therapy, mortality, and subsequent antibiotic resistance among hospitalized adults with gram-negative bloodstream infections. JAMA Netw Open 2024;7:e2418234.
