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Why can cefepime cause neurological toxicity?

And why is renal failure the main risk factor for this complication?

The answer requires us to learn about cefepime's structure and why it unexpectedly binds to a certain CNS receptor.

#MedTwitter #Tweetorial

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Let's establish a few facts about cefepime:

🔺4th generation cephalosporin antibiotic
🔺Excretion = exclusively in the urine (mostly as unchanged drug)
🔺Readily crosses the blood-brain barrier (so it easily accesses the brain)

https://t.co/rjYG1BfGPR
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The first report of cefepime neurotoxicity was in 1999.

A patient w/ renal failure received high doses of cefepime and then developed encephalopathy, tremors, myoclonic jerks, and tonic-clonic seizures.

✅All symptoms resolved after hemodialysis.

https://t.co/u7JLVitQpp
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Cefepime neurotoxicity is surprisingly common, occurring in up to 15% of treated critically ill patients (w/ symptoms varying from encephalopathy to seizures).

💡The main risk factors = renal failure and lack of dose adjustment for renal function.

https://t.co/nxbnzSq8AR
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What about cefepime induces neurotoxicity?

One clue is that it's not the only antibiotic that causes neurotoxicity, particularly seizures.

This actually is a class effect w/ other beta-lactam antibiotics (including penicillins and carbapenems).

https://t.co/Lf4BhON9IY
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Recall that beta-lactam antibiotics all share a common structural feature: a beta-lactam ring.

https://t.co/iWXweuG4Ct
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A 1971 study in cats implicated beta-lactam rings as the source of neurotoxicity.

High doses of penicillin were used to induce seizures.

🔑But pre-incubation w/ the enzyme beta-lactamase (disrupts the beta-lactam ring) blocked all seizure activity.

https://t.co/M3lDiXm88N
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So why can beta-lactam antibiotics like cefepime cause neurotoxicity?

It turns that they block the binding of the inhibitory neurotransmitter gamma aminobutyric acid (GABA) to its receptor.     

🔑Cephalosporins block GABA particularly effectively.

https://t.co/Eo0OlTduOE
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The GABA receptor has two subtypes (A and B), and the A subtype functions as a ligand-gated Cl⁻ ion channel.

Cefepime binds to the GABA-A receptor and blocks Cl⁻ influx, which correlates with its ability to induce seizure activity.

https://t.co/l2f9QHHEEW
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We've established that cefepime blocks GABA.

This induces neuro-excitation leading to seizures and other neurotoxic manifestations such as tremors and encephalopathy.

💡But why is there such a strong link with renal failure?
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An obvious explanation would be that, since cefepime is renally cleared, elevated serum and CNS drug levels build up.

This is supported by the observation that cefepime and other cephalosporins block GABA in a concentration-dependent manner.

https://t.co/l2f9QHHEEW
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But increased drug levels might not be the only reason that patients w/ renal failure are predisposed to neurotoxicity.

The milieu around neurons seems to matter as well.
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This experiment in rat brain slices simulated a "renal" milieu by using a hyperkalemic medium around neurons.

⚡️Exposure to higher potassium levels significantly increased the ability of cefepime to induce epileptiform discharges.

https://t.co/vb3p4xXdTm
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Let's ask one final question.

Why can cefepime (and other beta-lactam antibiotics) block the GABA receptor?

Exactly why hasn't been well-studied but it likely reflects sufficient structural similarity w/ GABA.

https://t.co/KN7I6ACXvb
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🧠Cefepime induces neurotoxicity by blocking the GABA receptor, similar to other beta-lactam antibiotics
🧠This results from structural similarities between GABA and the beta-lactam ring
🧠Renal failure = main risk factor b/c of ⬆️ drug levels +/- hyperkalemia

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IMPORTANCE, ADVANTAGES AND CHARACTERISTICS OF BHAGWAT PURAN

It was Ved Vyas who edited the eighteen thousand shlokas of Bhagwat. This book destroys all your sins. It has twelve parts which are like kalpvraksh.

In the first skandh, the importance of Vedvyas


and characters of Pandavas are described by the dialogues between Suutji and Shaunakji. Then there is the story of Parikshit.
Next there is a Brahm Narad dialogue describing the avtaar of Bhagwan. Then the characteristics of Puraan are mentioned.

It also discusses the evolution of universe.(
https://t.co/2aK1AZSC79 )

Next is the portrayal of Vidur and his dialogue with Maitreyji. Then there is a mention of Creation of universe by Brahma and the preachings of Sankhya by Kapil Muni.


In the next section we find the portrayal of Sati, Dhruv, Pruthu, and the story of ancient King, Bahirshi.
In the next section we find the character of King Priyavrat and his sons, different types of loks in this universe, and description of Narak. ( https://t.co/gmDTkLktKS )


In the sixth part we find the portrayal of Ajaamil ( https://t.co/LdVSSNspa2 ), Daksh and the birth of Marudgans( https://t.co/tecNidVckj )

In the seventh section we find the story of Prahlad and the description of Varnashram dharma. This section is based on karma vaasna.
राम-रावण युद्ध समाप्त हो चुका था। जगत को त्रास देने वाला रावण अपने कुटुम्ब सहित नष्ट हो चुका था।श्रीराम का राज्याभिषेक हुआ और अयोध्या नरेश श्री राम के नेतृत्व में चारों दिशाओं में शन्ति थी।
अंगद को विदा करते समय राम रो पड़े थे ।हनुमान को विदा करने की शक्ति तो राम में थी ही नहीं ।


माता सीता भी हनुमान को पुत्रवत मानती थी। अत: हनुमान अयोध्या में ही रह गए ।राम दिनभर दरबार में, शासन व्यवस्था में व्यस्त रहते थे। संध्या को जब शासकीय कार्यों में छूट मिलती तो गुरु और माताओं का कुशल-मंगल पूछ अपने कक्ष में जाते थे। परंतु हनुमान जी हमेशा उनके पीछे-पीछे ही रहते थे ।


उनकी उपस्थिति में ही सारा परिवार बहुत देर तक जी भर बातें करता ।फिर भरत को ध्यान आया कि भैया-भाभी को भी एकांत मिलना चाहिए ।उर्मिला को देख भी उनके मन में हूक उठती थी कि इस पतिव्रता को भी अपने पति का सानिध्य चाहिए ।

एक दिन भरत ने हनुमान जी से कहा,"हे पवनपुत्र! सीता भाभी को राम भैया के साथ एकांत में रहने का भी अधिकार प्राप्त है ।क्या आपको उनके माथे पर सिन्दूर नहीं दिखता?इसलिए संध्या पश्चात आप राम भैया को कृप्या अकेला छोड़ दिया करें "।
ये सुनकर हनुमान आश्चर्यचकित रह गए और सीता माता के पास गए ।


माता से हनुमान ने पूछा,"माता आप अपने माथे पर सिन्दूर क्यों लगाती हैं।" यह सुनकर सीता माता बोलीं,"स्त्री अपने माथे पर सिन्दूर लगाती है तो उसके पति की आयु में वृद्धि होती है और वह स्वस्थ रहते हैं "। फिर हनुमान जी प्रभु राम के पास गए ।