Is it time to implement prolonged infusions of beta-lactam antibiotics in and beyond critical care settings?

Abstract

Sepsis affects approximately 49 million people worldwide every year.¹ An estimated 11 million people die annually from sepsis,¹ with one death every 2.8 s. In Australia, one quarter of all intensive care unit (ICU) patients have sepsis, and despite having one of the best sepsis-related survival rates in the world,² approximately one in four patients will die from sepsis.³ Sepsis also imposes a huge financial burden on society, costing the Australian healthcare system $700 million each year.⁴ Despite modern therapeutic innovations, sepsis-related mortality remains a major problem with optimised antibiotic therapy being one of the few effective strategies for treating sepsis.

Conventional intermittent dosing remains the current standard of care for beta-lactam antibiotics. However, beta-lactam antibiotics display ‘time-dependent’ bactericidal activity, which is optimised when the free drug concentration remains above the minimum inhibitory concentration (MIC) of the infecting pathogen for at least 40%–70% of the dosing interval.⁵ Prolonged infusions of beta-lactam antibiotics, either by extended infusions (infusion duration of ~50% of dosing interval) or continuous infusions, are a practical strategy to increase the time spent above the MIC. To determine the effectiveness of continuous infusions of beta-lactam antibiotics in the ICU setting, a programme of research was conducted by our group (Fig. 1),^6-8 culminating in the Beta-Lactam Infusion Group (BLING III) randomised clinical trial (RCT) and a systematic review and meta-analysis of all related sepsis RCTs involving prolonged beta-lactam antibiotic infusions in the ICU setting. Both studies were recently published in JAMA.^{9, 10} The applicability of prolonged beta-lactam antibiotic infusions outside the ICU setting is currently under debate.

The BLING III trial (n = 7202) was an international, open-label phase 3 RCT conducted in 104 ICUs across Australia, Belgium, France, Malaysia, New Zealand, Sweden and the United Kingdom.⁹ The BLING III trial compared continuous and intermittent infusions of an equivalent 24-h dose of two beta-lactam antibiotics, piperacillin-tazobactam and meropenem, on all-cause 90-day mortality in critically ill patients with sepsis. The mean age of patients was 60 years with a mean Acute Physiology and Chronic Health Evaluation (APACHE) II score of 20 (APACHE II is a disease severity classification system ranging from 0 to 71, with higher scores corresponding to more severe disease and a higher risk of mortality for ICU patients). In the 24 hours prior to randomisation, 71% of patients received inotropes and/or vasopressors. Overall, there was no statistically significant difference in all-cause day 90 mortality between the continuous infusion and intermittent infusion groups in the primary unadjusted analysis (odds ratio (OR) = 0.91, 95% confidence interval (CI): 0.81–1.01; P = 0.08). The number needed to treat for continuous beta-lactam antibiotic infusions to prevent one death was 50 patients. A statistically significant difference of −2.2% in all-cause day 90 mortality was observed in the pre-specified adjusted analysis (OR = 0.89, 95% CI: 0.89–0.99; P = 0.04) in favour of continuous infusions. Clinical cure at day 14 was higher in the continuous infusion group (56% vs 50% for the intermittent infusion group; OR = 1.26, 95% CI: 1.15–1.38; P < 0.001). There were no statistically significant differences in any of the other secondary and tertiary outcomes.

A systematic review and Bayesian meta-analysis comparing prolonged infusions of beta-lactam antibiotics with intermittent infusions in critically ill adults with sepsis and septic shock was also conducted.¹⁰ Across 18 eligible RCTs (n = 9108), the probability that prolonged beta-lactam antibiotic infusions were associated with a reduced risk of 90-day mortality compared to intermittent infusions was 99.1% (risk ratio (RR) = 0.86; 95% credible interval (CrI): 0.72–0.98). The number needed to treat for prolonged beta-lactam antibiotic infusions to prevent one death was 26 patients. Use of prolonged beta-lactam antibiotic infusions was also associated with a reduced risk of ICU mortality (RR = 0.84, 95% CrI: 0.70–0.97) and an increase in clinical cure (RR = 1.16, 95% CrI: 1.07–1.31). This evidence presents a high degree of certainty for clinicians to consider prolonged infusions of beta-lactam antibiotics as the standard of care in the management of sepsis in the ICU.

These results naturally raise the question of whether these data can be extrapolated to non-ICU settings. We suggest that key considerations for patient-specific use of prolonged infusion should include the severity of illness and practical challenges associated with administration of prolonged infusions for patients in non-ICU settings.

Pharmacokinetic/pharmacodynamic studies suggest that the difference in achievement of effective beta-lactam antibiotic exposures between intermittent and prolonged infusions is smaller in patients with a low level of illness severity and pathogens with low MIC values.¹¹ Therefore, it is plausible that the method of beta-lactam antibiotic administration may not matter as much for patients in non-critical care settings. However, the use of prolonged infusions may be beneficial for specific sub-groups of general ward patients, such as those with higher illness severity, those infected with less susceptible pathogens of deep-seated infections and those with augmented renal clearance. The application of prolonged infusions offers the advantage of enhancing beta-lactam antibiotic penetration into the interstitial fluid of infected tissues, where the antibiotic-pathogen interactions occur. Numerous pharmacokinetic/pharmacodynamic data suggest that effective beta-lactam antibiotic tissue penetration and exposure can be achieved through prolonged infusions, including in the epithelial lining fluid of pneumonia patients,^{12, 13} in bone or joint infections¹⁴ and in surgical site tissues.^{15, 16} Augmented renal clearance (defined as a creatinine clearance of >130 mL/min/1.73 m² measured by 8- to 24-h urine collection) has been associated with sub-optimal beta-lactam antibiotic exposure, particularly with intermittent infusion dosing.^{17, 18} Young, multiple-trauma, post-surgical patients with normal serum creatinine concentrations are at the highest risk for augmented renal clearance.¹⁹ The use of prolonged beta-lactam antibiotic infusions for patients with augmented renal clearance may confer clinical advantages by maintaining effective drug exposures across the dosing interval.

Continuous infusions of beta-lactam antibiotics in non-critically ill settings present logistical challenges similar to those encountered in the ICU. Relevant considerations prior to implementation include drug stability and incompatibility with other intravenous medications, the need for a dedicated intravenous portal (e.g. a peripherally inserted central catheter) and the potential impact on clinical workload. Specific practical considerations to implement continuous infusion in the ICU have been described in a recent editorial by Barton and colleagues.²⁰ In non-critical care settings, extended infusions of beta-lactam antibiotics (e.g. administration over 3–4 h) may offer a more practical alternative by addressing the feasibility limitations of continuous infusions, while still preserving the pharmacodynamic benefits of consistently maintaining effective concentrations above the MIC, although the body of evidence is more limited than for continuous infusions.¹⁰ Numerous pharmacokinetic/pharmacodynamic data²¹ and some small-scale clinical studies^22-24 have shown that extended infusions provide optimal beta-lactam antibiotic exposures and may improve patient outcomes compared to intermittent infusions.

Continuous infusions of beta-lactam antibiotics in home settings is well established, and commencement of this practice in hospital for patients anticipated to be discharged on intravenous antibiotics (e.g. those with deep-seated infections) may hold benefits from both an efficacious and practical perspective.

Prior to randomisation in the BLING III trial, 80% of enrolled patients were administered intermittent beta-lactam antibiotic infusions, with 20% administered either extended or continuous infusions. Given the recent evidence from the BLING III trial and an associated systematic review and meta-analysis,^{9, 10} these proportions will probably be reversed in the ICU setting. Although similar data are not yet available for non-ICU settings, we anticipate increased consideration of extended or continuous infusions for specific subgroups of ward patients who may benefit from sustained effective beta-lactam antibiotic exposures. We encourage further clinical and translational studies to explore beta-lactam antibiotic dosing strategies, including use of prolonged infusions, in non-ICU settings. Our hope is that the greater use of prolonged beta-lactam antibiotic administration in patients with sepsis in both ICU and non-ICU settings will translate into appreciable improvements in global sepsis outcomes.