Cell wall synthesis inhibitors: Cephalosporins

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Introduction0:00–0:29

Cephalosporins are antibiotics which got their name from a mold known as cephalosporium, from which they were originally extracted.
They belong to the pharmacological group of beta-lactam antibiotics. What all beta-lactams have in common is a beta-lactam ring in their structure, which gives them their name, and also the mechanism of action - which is the inhibition of cell wall synthesis in bacteria.

Physiology0:29–1:57

So, our body is made out of eukaryotic cells. Bacterias belong to a different type of cells, called the prokaryotes.
From the outside to inside, they have a slimy capsule made out of polysaccharides. Then, there’s a cell wall in most prokaryotes.
A cell wall is a structural layer, which encapsulates bacteria, and offers structural support and protection, like a suit of armor.
It also offers some filtering capabilities, as not everything can pass freely through it. Finally, on the inside, there’s a pretty standard cell membrane.
Should something happen to this wall, say, if its synthesis mysteriously stopped, its owner’s life expectancy will turn to that of a snowflake in Sahara.
And that’s exactly what we’re hoping to do. Bacterial cell walls are made of a substance called peptidoglycan, or murein.
Peptidoglycan is a very strong, crystal lattice resembling three-dimensional structure, composed out of long using “strands” of amino polysaccharides, running in parallel.
These are made of made out segments of N-acetylglucosamine, or NAG, and N-acetylmuramic acid, or NAM, in an alternating pattern - so, NAG, NAM, NAG, NAM, and so on, like a pearl necklace.
These strands are also cross linked by short, four to five amino acids long, or tetrapeptide chains, protruding from NAM subunits.
Those pentapeptides reach out and link to pentapeptide chains from the neighboring strands, for structural stability, a sub-process known as transpeptidation.
All of this is made possible by enzymes called DD-transpeptidases, that are also better known as penicillin binding proteins, or PBPs.
These enzymes are highly specialized to grab and hold two pentapeptide ends and fuse them together, creating a stable link between the two polysaccharide strands, essentially creating peptidoglycan.
If you imagine the enzyme as a “lock”, then the pentapeptide chain would be a key, so it fits perfectly in, and allows the enzyme to do its work.

Mechanism of Action1:57–2:34

In essence, all beta lactam antibiotics, like the cephalosporins, somewhat resemble the tetrapeptide chains. Inside the bacteria, PBP enzymes will mistakenly bind to the beta lactams antibiotic molecule instead of a tetrapeptide and stick inside the PBP forever, like chewing gum in a keyhole, permanently disabling it.
As more and more of PBPs get disabled, the crosslinking fails to occur, and the wall becomes weak and unstable. If the affected bacteria attempts to divide, their cell wall will collapse, killing them in the process!

Antibiotic Resistance2:34–4:00

Now, some bacteria have developed resistance to beta lactam antibiotics. The most notable is the notorious staphylococcus aureus, which evolved an enzyme called beta lactamases or penicillinases that breaks down the beta lactam ring within the antibiotic, rendering it ineffective.
In response, we started adding beta lactamase inhibitors, such as clavulanic acid, that would binding to beta lactamases and inactivate them, like the gum into the keyhole.
Another approach was to create newer kinds of beta lactam antibiotics like methicillin, which had a large side chain that wouldn’t “fit” into the keyhole of the beta lactamase.
They did work quite well, until some staphylococcus aureus developed PBP site mutations that changed the shape of the keyhole.
So even if beta lactamase enzymes can’t break down these antibiotics, they won’t fit into the PBP enzyme and thus won’t work.
We call these bacteria methicillin resistant staphylococcus aureus, or MRSA. This poses a huge problem, as it makes MRSA virtually untreatable by beta lactam antibiotics.
To treat MRSA, we resort to so-called reserve antibiotics belonging to the glycopeptide antibiotics, like vancomycin and teicoplanin.
But, even that might come to an end, as MRSA is also developing vancomycin resistance, becoming VRSA. Cephalosporins are a very versatile group of antibiotics, and new members of the family get discovered all the time.

Classification4:00–4:38

Cephalosporins are usually classified into loose “generations”, depending on their usage profile - or simply put, what they’re effective against.
It is important to know that generations are not “age” related. There are currently 5 generations of cephalosporins; the 1st generation has the narrowest spectrum and mainly used to treat gram positive bacteria, and generally, each successive generation expands the spectrum to treats a wider variety of bacteria.
Now, we want to make a simple and fun mnemonic that’ll help you efficiently memorize and retain all these crazy pharm facts!

Memory Palace4:38–5:08

So let’s imagine an apartment complex with 3 rooms in a row. The first room is pretty dilapidated and the tenants represent the 1st and 2nd gen.
The 2nd room is just average, and the tenants represent 3rd and 4th gen which are broad spectrum. The 5th gen gets the fanciest room since it’s broad spectrum and it could treat MRSA!

First Generation Cephalosporins5:08–5:45

So, the 1st gen cephalosporins, like cephalexin and cefazolin, are useful against gram positive bacteria. They are effective against streptococci and staphylococci that cause skin infections, and they are also taken prophylactically to prevent infections from surgical procedures.
However, they are only effective against staphylococci that have not yet “evolved” beta lactamases. They are also effective against a few gram negative bacteria that cause urinary tract infections like proteus mirabilis, escherichia coli, and klebsiella pneumoniae.

Memory Palace5:45–6:38

Now let’s go back to our apartment complex mnemonic. On one side of the dilapidated room we have the 1st gen cephalosporins represented by Alexander the great (cephalexin), playing the violin (cefazolin).
Since he’s horrible at it, there’s a lot of people in here complaining, which represent the bacteria. First, we have a protester holding up a protest sign (proteus), next is an annoyed border collie for E.coli, then there’s a very angry person carrying a large club (klebsiella).
All three of them are waiting by the bathroom because they cause urinary tract infections. The final person is a surgeon, representing surgical prophylaxis, and his scratching himself all over because he has skin infections.

Second Generation Cephalosporins6:38–7:25

Next, are the 2nd generation cephalosporins which include cefaclor, cefprozil, cefuroxime, cefotetan, and cefoxitin. These medications are like an upgrade over 1st generation cephalosporins.
First, they are more resistant to beta lactamase. Second, they have comparable effectiveness for treating gram positive bugs, and they cover more gram negative bugs.
These include haemophilus influenzae, serratia marcescens, enterobacter aerogenes, and some neisseria species. In addition, cefotetan and cefoxitin are the only cephalosporins that can treat anaerobic bacteria such as bacteroides fragilis which cause peritonitis.

Memory Palace7:25–8:42

Going back to the mnemonic. We will put the 2nd gen cephalosporins on the other side of the dilapidated room.
These medications will be represented by a falcon (cefaclor) wearing a furry coat (cefuroxime), eating a giant pretzel (cefprozil).
He's got a pet fox (cefoxitin) which is peeking out from a giant teacup (cefotetan). For the bugs, remember 2nd gen can treat all the bacteria covered by the 1st gen plus a few more.
So, on the floor, there’s a tiny, vampire bat for haemophilus, since hemo means blood and philus means like. Let’s also add in a tiny Loch Ness monster for Neisseria.
The two of them are fighting over a sausage which represent enterobacter, since “entero,” means intestine, which is what sausages are made of.
To divide it up they are using a saw for serratia, since serrated means sawlike. Finally, cefoxitin and cefotetan are the only cephalosporins used against anaerobic bacteria, so let’s use a fishbowl full of water to represent a low oxygen environment.
We can put an angry bacteria on steroids in there for bacteroides. This is what’s scaring the fox and causing him to hide in the teacup!

Third Generation Cephalosporins8:42–9:40

Moving on to the 3rd generation cephalosporins which include cefixime, ceftriaxone, cefotaxime, and ceftazidime. These are broad spectrum antibiotics with improves anti-gram-negative activity at the cost of decreased efficiency against gram positive bacteria.
These cephalosporins can cross the blood-brain barrier, making them first line treatment for bacterial meningitis, which can be caused by haemophilus influenzae, pneumococci, meningococci, and neisseria species.
Nowadays, 3rd gen. cephalosporins are also the antibiotic of choice against penicillin-resistant Neisseria gonorrhoeae.
In addition, ceftazidime is effective in treating pseudomonas aeruginosa, a bacteria so hardcore resilient, it swims laps in hand disinfectant just to wake up.
Ceftriaxone is effective in treating borrelia burgdorferi which causes lyme disease. Back to the mnemonic.

Memory Palace9:40–10:50

We are in the 2nd room now, and the medications in here are broad spectrum. Let’s put a lot of books in here because the medications in this room can get to the brain, kind of like knowledge!
For the 3rd gen medications, we have a mechanic living here to represent cefixime. His working on fixing a taxi representing cefotaxime.
The taxi’s in for repair because there’s an ax with three heads stuck in the windshield for ceftriaxone. The mechanic was paid with a giant dime for ceftazidime!
To help you remember what this class of medication treats, we can use the mechanic’s old memorabilia from high school. On a shelf, there’s his high school football helmet with a flame logo on it to represent meningitis, and below it, is the gong he played in band representing gonorrhea.
Now, ceftazidime is special since it’s the only 3rd gen cephalosporin that could treat pseudomonas so, if you flip the dime over, it has the face of the Mona Lisa.
Ceftriaxone can be used to treat lyme disease, which is spread by ticks, so let’s have the triangular ax smash a giant tick against the windshield.

Fourth Generation Cephalosporins10:50–11:41

Next, are the 4th generation cephalosporins which are an upgrade over the 3rd gen, and have an even wider spectrum of activity.
The main medication in this class is cefepime, which is just as effective against gram-negative bacteria as the 3rd gen cephalosporins, plus it’s also comparable to 1st gen when it comes to gram positive infections.
It’s also effective against pseudomonas, and it also crosses the blood-brain barrier! Cefepime is often used to treat the same infections as the 3rd gen like meningitis.
It’s also more resistant to beta lactamases than any other cephalosporin so they are often used to treat nosocomial bacterial infections, or infections originating from the hospital.
However, cefepime is still ineffective against MRSA just like the other cephalosporins. Back to the mnemonic, the main 4th gen cephalosporin in the US is cefepime, which will be represented by a primate, so we’ll use a gorilla.

Memory Palace11:41–12:05

It shares the room with the mechanic so it can be used to treat many of the same infections as the 3rd gen. Like ceftazidime, it’s also effective against pseudomonas, so let’s have him paint a picture of the Mona Lisa, except she’s in a hospital bed to represent nosocomial infections.

Fifth Generation Cephalosporins12:05–12:24

Finally we get to the fifth generation of cephalosporins, and the main medication in this class is ceftaroline. This is also a broad spectrum antibiotic but it doesn’t cross the blood brain barrier.
This medication is very important, since it’s the only cephalosporin that can treat MRSA! For the mnemonic, let’s move to the last, and nicest room.

Memory Palace12:24–12:44

5th gen is so amazing, it gets the room all for itself! Let’s have a kid jumping on a trampoline to represent ceftaroline.
He is super rich so he bought the Mars rover representing MRSA. Adverse drug reactions related to cephalosporins are usually mild and unspecific, including diarrhea, nausea, rash, and tenderness at the injection site.

Side effects & Contraindications12:44–13:18

These medications can cause disulfiram-like reaction; if alcohol is consumed while taking cephalosporin the person may experience nausea, flushing, and rapid heartbeat.
There’s also a small likelihood of cross reactivity between penicillin and cephalosporin, so if someone took penicillin, they can develop an allergy to both penicillin and cephalosporin.

Memory Palace13:18–13:35

As the last part of the mnemonic let’s put an emergency exit at the back of the apartment complex. Blocking the door, are 2 pens forming a cross to represent cross-reactivity with penicillin.
In front of the door are a few empty beer bottles to represent disulfiram reaction. All right, as a quick recap.

Review13:35–14:32

Cephalosporins are bactericidal antibiotics and members of the beta lactam antibiotic family which inhibit cell wall synthesis.
There are 5 generations of cephalosporins. 1st gen medications are mainly used to treat gram positive infections, UTIs, caused by a few gram negative bacteria, and as prophylaxis before surgery.
2nd gen can treat a wider variety of gram negative bacteria, and some are effective against anaerobes. Generation 3 and 4 are wide spectrum and crosses the blood brain barrier, making them first line treat for bacterial meningitis.
Ceftazidime from the 3rd gen and cefepime from the 4th gen are also effective against pseudomonas. Gen 5 is also wide spectrum but does not cross the blood brain barrier.
It’s the only class of cephalosporins effective against MRSA. But wait, there's more: Here's a mind map with all of the mnemonics from the video.

Mind Map14:32–14:49

Go ahead and pause the video so you can test yourself to see what you remember. Stay tuned for the answers at the end.