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Cell wall synthesis inhibitors: Cephalosporins

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Cell wall synthesis inhibitors: Cephalosporins

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Cell wall synthesis inhibitors: Cephalosporins

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are second generation cephalosporins that are used to treat gram negative bacilli, such as Enterobacter aerogenes.

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A 4-year-old boy comes to the emergency department with his mother because he has a high fever, stiff neck and photophobia. His mother says that he started being very restless4 hours ago and was very sensitive to light. He did not have any nausea or vomiting. His temperature is 38.1°C (100.7°F), pulse is 115/min, respirations are 16/min, and blood pressure is 135/75 mm Hg. Physical examination shows a petechial non-blanching rash on his left arm. The rash is present on his torso and legs as well. Neurological examination shows a positive Babinski sign. A lumbar puncture reveals an opening pressure of 200 mmHg, an elevated white blood cell count with a predominance of neutrophils, and a glucose of 35 mg/dl. Gram staining revealed pink staining organism growing in pairs. Which of the following is the most appropriate pharmacotherapy?

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Transcript

Content Reviewers:

Yifan Xiao, MD

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.

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.

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!

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.

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! 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!

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.

Sources
  1. "Katzung & Trevor's Pharmacology Examination and Board Review,12th Edition" McGraw-Hill Education / Medical (2018)
  2. "Rang and Dale's Pharmacology" Elsevier (2019)
  3. "Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th Edition" McGraw-Hill Education / Medical (2017)
  4. "Penicillin-Binding Proteins of Gram-Negative Bacteria" Clinical Infectious Diseases (1988)
  5. "Methicillin-resistant Staphylococcus aureus: A consensus review of the microbiology, pathogenesis, and epidemiology with implications for prevention and management" The American Journal of Medicine (1993)
  6. "A Comparison of Ceftriaxone and Cefuroxime for the Treatment of Bacterial Meningitis in Children" New England Journal of Medicine (1990)
  7. "Third-generation cephalosporins" Medical Clinics of North America (1995)
  8. "Summary of Ceftaroline Fosamil Clinical Trial Studies and Clinical Safety" Clinical Infectious Diseases (2012)