Living Textbook MC610

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They were first isolated from Cephalosporium sp. in the late 1940s. The first agent, Cephalosporin C exhibited low antibacterial activity.

Adding different substrates to produce other Cephalosporins did not work.

But then using 7-ACA (7-amino cephalosporanic acid) produced enzymatically or chemically, led to the production of very useful drugs with broad spectrum and resistance to ß-lactamases.

Another approach was to synthesize compounds from Penicillins by ring expansion (the same way they are biosynthesized in the fungus).

Cephalosporins shares many of Penicillins properties, including mechanism of action, toxicity...etc. The presence of the six-member ring dihydrothiazine instead of the five-member thiazolidene ring in Penicillin will mean that the ß-lactam ring is under less stress so it will be less susceptible to act as a substrate for PBP. However the3,4 double bond coupled with a good leaving group at the 3-position will provide the driving force for the reaction.

In general, Cephalosporins are more resistant to ß-lactamases and have a broader spectrum. However Penicillins are more potent against non ß-lactamase producing bacteria. They show less allergenicity than Penicillin, where cross sensitivity occurs in about 10% of the cases. Should be especially careful with patients that develop severe reactions to Penicillin.

Structure Activity Relationship:

In many aspects similar to Penicillin, some of the highlights and differences:

    1. Changes in R-1 may cause changes in spectrum and ß-lactamase resistance, similar to Penicillins. [An electron withdrawing group will give the compound better acid stability, a bulky group close to the ring, gives it better resistance to ß-lactamases and a polar group extends its spectrum].
    2. Changes in R-2 will affect the pharmacokinetic properties of the drug:
      • Using a non-metabolized group can lead to oral activity and less metabolism.
      • 1-Methyl 5-thio tetrazole (MTT) group leads to an extended spectrum, higher potency and a longer half-life. It does however come with a price, a serious side effect, as it may cause bleeding due to hypoprothrombonemia. It will inhibit certain vitamin K-based enzymes that produce various clotting factors and can be reversed by using Vitamin K. Patients at risk for this side effect should be monitored. These compounds also inhibit aldehyde dehydrogenase, causing alcohol intolerance.

3. Addition of a methoxy group at the 7-alpha position led to compounds that are very effective against ß-lactamase producing organisms.

Cephalosporins are classified chronologically, and thus are divided into generations. The newer compounds were introduced to overcome some of the shortcomings of earlier Cephalosporins.

First Generation Cephalosporins:

They are mostly active against Gram positive bacteria, with a few exceptions.

Cefalothin and Cefapirin are used parenteral only to avoid first pass effect and degradation of the ester. May cause pain at site of injection.

Cefazolin is more active against Gram negative than Gram positive bacteria. Shows high degree of protein binding and is used parenterally.

Both Cefalexin and Cefradine are used orally as they are absorbed by active transport. They are useful in respiratory tract infections. They show low protein binding, and undergo renal excretion unchanged, thus useful in urinary tract infections. Cefradine is also used parenterally.

Cefadroxil has a wide variety of indications including RTI, UTI and skin infections. It is particularly effective against H. Influenzae. It is excreted unchanged very slowly in urine and binds extensively to serum proteins, thus has a prolonged duration of action, usually used every 12-24 hours. It may act also as an immunostimulant.

Second Generation Cephalosporins:

In general have a broader spectrum against Gram negative bacteria, but less useful against Gram positive bacteria. They have better ß-lactamase resistance and better membrane penetration.

Cefamandole is used parenterally, as it is very unstable in acidic medium. It has the MTT ring, which gives it extended spectrum and better activity. It has a formate ester on the R-1 side chain that is degraded to the active species, the free alcohol, by esterases in the blood stream.

Cefuroxime lacks an ester at the R-2 position gives it better resistance to ß-lactamases. An ester form of the drug can be used orally as it improves lipophilicity. The methoxyoxime group is in the syn-position, giving the drug better ß-lactamase resistance. It can penetrate CSF.

Ceforanide is used in parenteral preparations. It has a modified MTT ring, with the acetic acid moiety giving it a higher activity and extended spectrum. It has a higher half-life due to protein binding.

Cefonicid is used parenterally in the treatment of respiratory tract, skin, bone, urinary tract and gynecological infections. It is active against some Gram positive bacteria, such as Methicillin-sensitive staphylococci, and many streptococci, and various Gram-negative bacilli including E. coli, some and H. influenzae.

Both Cefoxitin and Cefotetan are very resistant to ß-lactamases due to the presence of the 7α-methoxy group. Cefoxitin is effective against both Gram positive and Gram negative bacteria. Cefotetan is more active against Gram positive bacteria, possesses the MTT ring and has a longer half-life. They are effective against anaerobic bacteria.

Cefaclor is indicated in a wide variety of infections such as RTI, UTI, skin infections and Gram negative infections that are resistant to Ampicillin. It has erratic oral absorption and is less stable in serum.

Cefprozil has a prolonged half-life, with excellent potency and high bioavailability. Usually dosed twice a day and indicated in most RTI and UTI.

Loracarbef can be viewed as a combination of Ampicillin (R-1) and Cefaclor (R-2) with the smaller carbon in place of a sulfur (carbapenem). It is stable, but its absorption is delayed by food.

Third Generation Cephalosporins:

They possess additional advantages, most have excellent activity against Gram negative bacteria, and are especially useful in pseudomonas infections, although usually in expense of antistaphylococci activity. They can also be used in multiresistant hospital-acquired infections.

Parenterally useful agents

Cefotaxime has excellent activity and broad spectrum. Used parenterally.

Ceftizoxime is especially effective against pseudomonas infections, not metabolized.

Ceftriaxone is also effective against pseudomonas infections, and can also pass into cerebrospinal fluid (CSF), and is useful in treatment of bacterial meningitis. It has a prolonged half-life due to protein binding, so usually dosed at once a day.

Ceftazidime shows erratic absorption due to Zwitter ion formation. It has an extensive spectrum of activity including pseudomonas and Gram positive bacteria.

Cefoperazone is used in UTI and in pseudomonas infections, with a longer duration of action. It is comparatively susceptible to ß-lactamases.

Moxolactam is a completely synthetic compound that was designed by trying to put all the positive aspects of Cephalosporins into one molecule. For example, change the sulfur to oxygen, add the carboxylic group to be more effective against Gram negative bacteria and the hydroxy group to improve blood levels and half-life. The MTT ring gives the drug exceptional Gram negative activity and a prolonged duration of action. The methoxy group gives the drug better ß-lactamase resistance. It is effective against pseudomonas infections.

Orally-active Drugs

Cefixime and Ceftibuten show excellent penetration into bacterial cell via active transport probably due to the dipeptide moiety. The ß-lactam ring is stabilized by the formation of a hydrogen bond between the carboxylic acid and the amide nitrogen. Very good oral bioavailability, excreted unchanged.

Cefpodoxime Proxitil can be used orally, as a prodrug that will be hydrolyzed in the serum to the active species. It is more effective against S. aureus than other third generation oral Cephalosporins.

Cefdinir is an orally active cephalosporin, with a relatively long action. It is used twice daily. It has better activity against Gram positive bacteria than other Cephalosporins, and shows good ß-lactamase resistance.

Cefditoren Pivoxil is used in the treatment of acute bacterial exacerbation of chronic bronchitis, pharyngitis/tonsillitis, and uncomplicated skin and skin structure infections. It is hydrolyzed after oral absorption to the free Cefditoren.

Fourth Generation Cephalosporins

They possess additional advantages; they are more resistant to ß-lactamases and are more active against Gram positive bacteria and have extended spectrum of activity for Gram negative (different from third generation Cephalosporins) including multiple drug resistance patterns (Enterobacter and Klebsiella).

Cefepime is used parenteral in a variety of infections including those caused by pseudomonas. It has a relatively prolonged duration of action.

Fifth Generation Cephalosporins

These agents are effective against MRSA. They can bind to the mutated PBP2a that leads to this resistance.

Ceftaroline is a broad spectrum antibiotics that has high affinity to the mutated PBP2a, and is thus used in MRSA infections and is effective in community-acquired pneumonia and complicated skin infections.