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Background <p>Spondylodiscitis is a severe infection associated with considerable morbidity and mortality. The prevalence of gram-negative infections is on the rise, posing significant therapeutic challenges. Cefepime/enmetazobactam constitutes a novel antibiotic combination that offers broad-spectrum activity against resistant gram-negative organisms. However, its pharmacokinetic profile within spinal tissues remains unknown.</p> Objectives <p>To dynamically assess unbound steady-state concentrations of cefepime/enmetazobactam in healthy vertebral cancellous bone, intervertebral disc, and paravertebral muscle after both short-term and continuous infusions.</p> Methods <p>16 pigs were randomised to receive either short-term infusion (3 doses of 2&#xa0;g/0.5&#xa0;g cefepime/enmetazobactam administered over 2&#xa0;h, repeated every 8&#xa0;h) or continuous infusion (1&#xa0;g/0.25&#xa0;g loading dose administered over 15&#xa0;min, followed by 6&#xa0;g/1.5&#xa0;g administered over 15&#xa0;h and 45&#xa0;min). Steady state was assumed during the third dosing interval (16–24&#xa0;h). Microdialysis was employed to sample interstitial fluid from spondylodiscitis-relevant tissues: vertebral cancellous bone, intervertebral disc and paravertebral muscle, at steady state for 8&#xa0;h. The unbound concentrations of cefepime and enmetazobactam were quantified by LC–MS/MS. The primary endpoint was to determine the time above relevant MIC (T &gt; MIC) for cefepime (0.125, 4, 8, and 32 mg/L) and the time above relevant concentration threshold (T &gt; Ct) for enmetazobactam (2 and 8 mg/L).</p> Results <p>For both cefepime and enmetazobactam, there were no differences in T &gt; MIC and T &gt; Ct when comparing dosing regimens, applying the conventional targets of MIC 0.125, 4, and 8 mg/L, and Ct of 2 mg/L. Only when applying the aggressive targets of MIC 32 mg/L and Ct 8 mg/L did continuous infusion yield longer T &gt; MIC and T &gt; Ct compared with short-term infusion in both the vertebral cancellous bone and intervertebral disc.</p> Conclusion <p>Both cefepime and enmetazobactam consistently reached theoretically effective unbound steady-state tissue levels in relevant target tissues for spondylodiscitis, irrespective of the dosing regimen.</p>

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Cefepime/enmetazobactam steady-state concentrations in spondylodiscitis-relevant tissues: an experimental porcine study

  • 期刊论文

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  • 发表日期：

    2026年5月20日

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  • Maria Bech Damsgaard Nielsen,
  • Mads Kristian Duborg Mikkelsen,
  • Kresten Wendell Rickers,
  • Haisheng Li,
  • Christoph Crocoll,
  • Michal Poborsky,
  • Nis Pedersen Jørgensen,
  • Alex Soriano,
  • Maiken Stilling,
  • Mats Bue

摘要

Background

Spondylodiscitis is a severe infection associated with considerable morbidity and mortality. The prevalence of gram-negative infections is on the rise, posing significant therapeutic challenges. Cefepime/enmetazobactam constitutes a novel antibiotic combination that offers broad-spectrum activity against resistant gram-negative organisms. However, its pharmacokinetic profile within spinal tissues remains unknown.

Objectives

To dynamically assess unbound steady-state concentrations of cefepime/enmetazobactam in healthy vertebral cancellous bone, intervertebral disc, and paravertebral muscle after both short-term and continuous infusions.

Methods

16 pigs were randomised to receive either short-term infusion (3 doses of 2 g/0.5 g cefepime/enmetazobactam administered over 2 h, repeated every 8 h) or continuous infusion (1 g/0.25 g loading dose administered over 15 min, followed by 6 g/1.5 g administered over 15 h and 45 min). Steady state was assumed during the third dosing interval (16–24 h). Microdialysis was employed to sample interstitial fluid from spondylodiscitis-relevant tissues: vertebral cancellous bone, intervertebral disc and paravertebral muscle, at steady state for 8 h. The unbound concentrations of cefepime and enmetazobactam were quantified by LC–MS/MS. The primary endpoint was to determine the time above relevant MIC (T > MIC) for cefepime (0.125, 4, 8, and 32 mg/L) and the time above relevant concentration threshold (T > Ct) for enmetazobactam (2 and 8 mg/L).

Results

For both cefepime and enmetazobactam, there were no differences in T > MIC and T > Ct when comparing dosing regimens, applying the conventional targets of MIC 0.125, 4, and 8 mg/L, and Ct of 2 mg/L. Only when applying the aggressive targets of MIC 32 mg/L and Ct 8 mg/L did continuous infusion yield longer T > MIC and T > Ct compared with short-term infusion in both the vertebral cancellous bone and intervertebral disc.

Conclusion

Both cefepime and enmetazobactam consistently reached theoretically effective unbound steady-state tissue levels in relevant target tissues for spondylodiscitis, irrespective of the dosing regimen.