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Does Achieving Better β-lactam Pharmacokinetic Targets Translate to Better Clinical Outcomes in Septic Patients?

Sepsis and septic shock are life-threatening conditions that require prompt and effective treatment. β-lactam antibiotics, such as penicillins and cephalosporins, are commonly employed in these scenarios due to their broad-spectrum antibacterial activity. However, the method of administration can significantly impact their effectiveness. The Surviving Sepsis Campaign guidelines recommend that adults with sepsis or septic shock should receive prolonged infusion of β-lactams (after an initial bolus) rather than conventional intermittent infusion. This recommendation is based on moderate-quality evidence and is classified as weak.


Pharmacokinetics and Pharmacodynamics

Up to 40% of ICU patients treated with β-lactam antibiotics may not maintain drug concentrations above the minimum inhibitory concentration (MIC) during 50% to 100% of the dosing intervals. This issue is exacerbated in sepsis due to various physiological changes, such as increased cardiac output, leading to increased drug clearance, and leaky capillaries necessitating intravenous volume resuscitation, which increases the volume of distribution. In the early phases of sepsis, these changes often result in lower plasma concentrations of the antibiotic. Later, kidney or hepatic failure can decrease drug clearance, leading to higher plasma concentrations.

Pharmacokinetic Changes of Abx in Sepsis

Continuous vs. Intermittent Infusion

Administering β-lactams via prolonged or continuous infusion can sustain drug concentrations throughout the dosing interval, leading to a longer time above the MIC and improved bacterial eradication. The question remains: does achieving better pharmacokinetic targets translate to better clinical outcomes?



Clinical Evidence

Over the past two decades, numerous randomized clinical trials (RCTs) have explored this question. An early trial in France (2005) compared continuous infusion and intermittent dosing of cefepime in critically ill patients, finding no differences in clinical outcomes but longer times above the MIC with continuous infusion. Multiple meta-analyses incorporating this and other trials have reported reduced short-term mortality with continuous β-lactam infusion.

The MERCY trial, published in 2023, observed a non-significant 2% reduction in absolute 28-day mortality with continuous infusion of meropenem. Despite this, uncertainties about long-term outcomes and antimicrobial resistance necessitate further investigation to define the clinical benefits of prolonged infusions clearly.


Recent Contributions

Two major new contributions in JAMA bolster the evidence for continuous β-lactam infusion. The BLING III trial, a large-scale, well-conducted study, compared continuous and intermittent infusions in critically ill sepsis patients across 104 ICUs in seven countries. While the primary outcome (90-day mortality) showed no statistically significant difference, there was a trend toward lower mortality with continuous infusion.

A subsequent meta-analysis, incorporating the BLING III trial, evaluated the effectiveness of prolonged versus intermittent infusions of β-lactam antibiotics in critically ill sepsis patients. This meta-analysis included 18 randomized controlled trials with a total of 9,108 patients, of which the BLING III trial represented 77.1%. The results demonstrated a reduced risk of all-cause 90-day mortality (RR 0.86) and ICU mortality (RR 0.84), along with an increased clinical cure rate (RR 1.16) for prolonged infusions. No significant differences were found in microbiological cure, adverse events, or ICU stay duration between the two groups. Additionally, a Bayesian meta-analysis of these trials indicated a 99% posterior probability that continuous infusions reduced 90-day mortality.


Which beta-lactam dosing regimen do you use for your septic patients in the ICU?

  • Intermittent infusion

  • Continuous infusion



Conclusion

Continuous infusion of β-lactam antibiotics holds promise for better outcomes in sepsis treatment, particularly in maintaining optimal drug levels and improving clinical outcomes. However, individual patient factors, specific antibiotics, and potential logistical challenges must be considered. Ongoing research and tailored treatment strategies are essential to maximize the benefits of this approach in sepsis management.



REFERENCES

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  1. Dulhunty  JM, Brett  SJ, De Waele  JJ,  et al; BLING III Study Investigators.  Continuous vs intermittent β-lactam antibiotic infusions in critically ill patients with sepsis: the BLING III randomized clinical trial.   JAMA. Published June 12, 2024. doi:10.1001/jama.2024.9779

  2. 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. Published June 12, 2024. doi:10.1001/jama.2024.9803

  3. Georges  B, Conil  JM, Cougot  P,  et al.  Cefepime in critically ill patients: continuous infusion vs an intermittent dosing regimen.   Int J Clin Pharmacol Ther. 2005;43(8):360-369. doi:10.5414/CPP43360

  4. Monti  G, Bradic  N, Marzaroli  M,  et al; MERCY Investigators.  Continuous vs intermittent meropenem administration in critically ill patients with sepsis: the MERCY randomized clinical trial.   JAMA. 2023;330(2):141-151. doi:10.1001/jama.2023.10598





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