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
1/15
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
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
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
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
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
Recall that beta-lactam antibiotics all share a common structural feature: a beta-lactam ring.
https://t.co/iWXweuG4Ct
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
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
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
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?
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
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.
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
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
More from Health
I think @SamAdlerBell in his quest to be the contrarian on Fauci gets several things wrong here. 1/
First, the failure last year actually was driven by the White House, the #Trump inner circle. Watch what's happening now, the US' scientific and public health infrastructure is creaking back to life. 2/
I think Sam underestimates the decimation of many of our health agencies over the past four years and the establishment of ideological control over them during the pandemic. 3/
I also am puzzled why Tony gets the blame for not speaking up, etc. Robert Redfield, Brett Giroir, Deb Birx, Jerome Adams, Alex Azar all could have done the same. 4/
Several of these people Bob Redfield, Brett Giroir, Alex Azar were led by craven ambition, Jerome Adams by cowardice, but I do think Deb Birx and Tony tried as institutionalists, insiders to make a difference. 5/
— Matthew Yglesias (@mattyglesias) January 30, 2021
First, the failure last year actually was driven by the White House, the #Trump inner circle. Watch what's happening now, the US' scientific and public health infrastructure is creaking back to life. 2/
I think Sam underestimates the decimation of many of our health agencies over the past four years and the establishment of ideological control over them during the pandemic. 3/
I also am puzzled why Tony gets the blame for not speaking up, etc. Robert Redfield, Brett Giroir, Deb Birx, Jerome Adams, Alex Azar all could have done the same. 4/
Several of these people Bob Redfield, Brett Giroir, Alex Azar were led by craven ambition, Jerome Adams by cowardice, but I do think Deb Birx and Tony tried as institutionalists, insiders to make a difference. 5/
this simple, counter narrative fact keeps cropping up all over the world.
hospital and ICU utilization has been and remains low this year.
it's terribly curious that so few of these monitoring tools provide historical baselines.
getting them is like pulling teeth.
we might think of this as an oversight until you see stuff like this:
this woman was arrested for filming and sharing the fact that their are empty hospitals in the UK.
that's full blown soviet. what possible honest purpose does that
this is the action of a police state and a propaganda ministry, not a well intentioned government and a public heath agency.
"we cannot let people see the truth for fear they might base their actions on real facts" is not much of a mantra for just governance.
90% full ICU sounds scary until you realize that 90-100% full is normal in flu season.
staffed ICU beds are expensive to leave empty. it's like flying with 15% of the plane empty. hospitals don't do that.
and all US hospitals are mandated to be able to flex to 120% ICU.
the US is currently at historically low ICU utilization for this time of year.
61% is "you're all going to go out of business" territory as is 66% full hospital use.
can you blame them for mining CARES act money? they'll die without it.
hospital and ICU utilization has been and remains low this year.
it's terribly curious that so few of these monitoring tools provide historical baselines.
getting them is like pulling teeth.
It took a Freedom of Information request but @Covid19DataUK acquired 2017-2019 averages for England hospitalizations.
— Yinon Weiss (@yinonw) December 31, 2020
2020 had 18% fewer hospitalizations than prior years.
All around the world, using hospital data without context of prior years is just a fear generating lie. pic.twitter.com/DJDpqhIQuw
we might think of this as an oversight until you see stuff like this:
this woman was arrested for filming and sharing the fact that their are empty hospitals in the UK.
that's full blown soviet. what possible honest purpose does that
this is the action of a police state and a propaganda ministry, not a well intentioned government and a public heath agency.
"we cannot let people see the truth for fear they might base their actions on real facts" is not much of a mantra for just governance.
90% full ICU sounds scary until you realize that 90-100% full is normal in flu season.
staffed ICU beds are expensive to leave empty. it's like flying with 15% of the plane empty. hospitals don't do that.
and all US hospitals are mandated to be able to flex to 120% ICU.
the US is currently at historically low ICU utilization for this time of year.
61% is "you're all going to go out of business" territory as is 66% full hospital use.
can you blame them for mining CARES act money? they'll die without it.
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👨💻 Last resume I sent to a startup one year ago, sharing with you to get ideas:
- Forget what you don't have, make your strength bold
- Pick one work experience and explain what you did in detail w/ bullet points
- Write it towards the role you apply
- Give social proof
/thread
"But I got no work experience..."
Make a open source lib, make a small side project for yourself, do freelance work, ask friends to work with them, no friends? Find friends on Github, and Twitter.
Bonus points:
- Show you care about the company: I used the company's brand font and gradient for in the resume for my name and "Thank You" note.
- Don't list 15 things and libraries you worked with, pick the most related ones to the role you're applying.
-🙅♂️"copy cover letter"
"I got no firends, no work"
One practical way is to reach out to conferences and offer to make their website for free. But make sure to do it good. You'll get:
- a project for portfolio
- new friends
- work experience
- learnt new stuff
- new thing for Twitter bio
If you don't even have the skills yet, why not try your chance for @LambdaSchool? No? @freeCodeCamp. Still not? Pick something from here and learn https://t.co/7NPS1zbLTi
You'll feel very overwhelmed, no escape, just acknowledge it and keep pushing.
- Forget what you don't have, make your strength bold
- Pick one work experience and explain what you did in detail w/ bullet points
- Write it towards the role you apply
- Give social proof
/thread
"But I got no work experience..."
Make a open source lib, make a small side project for yourself, do freelance work, ask friends to work with them, no friends? Find friends on Github, and Twitter.
Bonus points:
- Show you care about the company: I used the company's brand font and gradient for in the resume for my name and "Thank You" note.
- Don't list 15 things and libraries you worked with, pick the most related ones to the role you're applying.
-🙅♂️"copy cover letter"
"I got no firends, no work"
One practical way is to reach out to conferences and offer to make their website for free. But make sure to do it good. You'll get:
- a project for portfolio
- new friends
- work experience
- learnt new stuff
- new thing for Twitter bio
If you don't even have the skills yet, why not try your chance for @LambdaSchool? No? @freeCodeCamp. Still not? Pick something from here and learn https://t.co/7NPS1zbLTi
You'll feel very overwhelmed, no escape, just acknowledge it and keep pushing.
Krugman is, of course, right about this. BUT, note that universities can do a lot to revitalize declining and rural regions.
See this thing that @lymanstoneky wrote:
And see this thing that I wrote:
And see this book that @JamesFallows wrote:
And see this other thing that I wrote:
One thing I've been noticing about responses to today's column is that many people still don't get how strong the forces behind regional divergence are, and how hard to reverse 1/ https://t.co/Ft2aH1NcQt
— Paul Krugman (@paulkrugman) November 20, 2018
See this thing that @lymanstoneky wrote:
And see this thing that I wrote:
And see this book that @JamesFallows wrote:
And see this other thing that I wrote:
