Is neurotoxicity caused by cefepime common?

The incidence of cefepime-induced neurotoxicity (CIN) has varied from 1% to 15%.1 Potential clinical manifestations of CIN include delirium, impaired level of consciousness, disorientation/agitation, myoclonus, non-convulsive status epilepticus, seizures, and aphasia.1  Many of these signs and symptoms (eg, delirium) are common among hospitalized patients.

Although renal dysfunction and inadequately adjusted dosages are often cited as risk factors, one-half of patients develop suspected CIN despite apparently proper adjustment for renal function.In addition,  several case reports of CIN have involved patients with normal renal function. 2  A study of 1120 patients receiving cefepime found epileptiform discharges in 14 cases, most having normal renal function.3 Of interest, in the same study, the prevalence of epileptiform discharges was 6-fold higher than that of meropenem!

Proposed mechanisms for CIN include its avidity for central nervous system GABA-A receptors (higher than that of many beta-lactam antibiotics) combined with its high concentration in brain tissue.1 Renal impairment, decreased protein binding, and increased organic acid accumulation can increase transfer of cefepime across the blood brain barrier from an expected 10% to up to 45% of its serum concentration, further contributing to its neurotoxicity.4

 

References

  1. Appa AA, Jain R, Rakita RM, et al. Characterizing cefepime neurotoxicity: a systematic review. Open Forum Infectious Diseases 2017 Oct 10;4(4):ofx170. doi: 10.1093/ofid/ofx170. eCollection 2017 Fall. https://www.ncbi.nlm.nih.gov/pubmed/29071284
  2. Meillier A, Rahimian D. Cefepime-induced encephalopathy with normal renal function. Oxford Medical Case Reports, 2016;6, 118-120. https://academic.oup.com/omcr/article/2016/6/118/2362353
  3. Naeije G, Lorent S, Vincent JL, et al. Continuous epileptiform discharges in patients treated with cefpime or meropenem Arch Neurol 2011;68:1303-7. https://www.ncbi.nlm.nih.gov/pubmed/21987544
  4. Payne LE, Gaganon DJ, Riker RR, et al. Cefepime-induced neurotoxicity: a systematic review. Critical Care 017;21:276. https://www.ncbi.nlm.nih.gov/pubmed/29137682

 

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Is neurotoxicity caused by cefepime common?

My elderly patient is scheduled to undergo elective surgery? Is there an objective “stress test for the brain” that may predict postoperative delirium?

Possibly, in the near future! Although the pathophysiology of postoperative delirium (POD) is not fully understood, a recently proposed conceptual model of delirium may provide a basis for preoperative neurophysiologic testing1.

According to this model, delirium is a “consequence of the breakdown in brain network dynamics” precipitated by insults or stressors (eg, surgery) in persons with low brain resilience ie, low connectivity between brain regions and/or deficient neuroplasticity (the ability of brain to reorganize itself by forming new neural connections).  

As expected,  patients with strong baseline connectivity and optimal neuroplasticity would not be expected to have POD, whereas those with weakened connectivity (eg baseline cognitive dysfunction) and/or suboptimal neuroplasticity (eg due to aging) may be at higher risk. Transcranial magnetic stimulation (TMS)  is considered a powerful tool that measures the connectivity and plasticity of the brain through induced perturbation.  When applied in repetitive trains, TMS produces changes in cortical excitability that can be measured using electromyography and EEG,  and is thought to have the ability to assess neuroplasticity 2. If proven effective in predicting POD, it could revolutionize preoperative risk assessment in the elderly! Stay tuned!

 

Reference

  1. Shafi MM, Santarnecchi E, Fong TG, et al. Advancing the neurophysiological understanding of delirium. J Am Geriatr Soc 2017. DOI:10.1111/jgs.14748.
  2. Pascual-Leone A, Freitas C, Oberman L, et al. Characterizing brain cortical plasticity and network dynamics across the age-span in health and disease with TMS-EEG and TMS-fMRI. Brain Topogr 2011, 24:302-15.
My elderly patient is scheduled to undergo elective surgery? Is there an objective “stress test for the brain” that may predict postoperative delirium?