Medical School, Notes, Pharmacy

Cephalosporins: The Smart Antibiotics

Cephalosporins are class of Beta-lactam antibiotics as the structure of cephalosporins contain beta lactam rings. Along with that they have dihydrothiazine ring and an acetyl side chain.

Like Penicillin, cephalosporin also has a fungal origin (fungus Acremonium) and thus will be associated with hypersensitivity reactions. Originally, they were discovered from a fungus and then later semi-synthetic forms were developed. Cephalosporin has wider spectrum of activity than Penicillin.

Cephalosporin basically disrupts the synthesis of peptidoglycan layer forming the bacterial cell wall. As they break the cell wall structure formation ultimately will cause the loss of cell integrity for the bacteria and bacteria will die.

Classification of Cephalosporins

There are five generations of cephalosporin. They are:

a. 1st Generation
b. 2nd Generation
c. 3rd generation
d. 4th generation
e. 5th generation

1st and 2nd generations show moderate spectrum. 3rd, 4th, and 5th generations show broad spectrum.

1st Generation Cephalosporins

Cefazolin was kind of common in first generation. But they have no anaerobic coverage. Although they were very effective against gram positive bacteria (Streptococcus pneumonia, Staphylococcus aureus). These were broadly used against skin infections. They were also effective against regular gram negatives bacteria such as, E.coli, Proteus and Klebsiella.
This generations includes; Cefadroxil, Cephalexin, Cephadrine, Cefazolin, Cefalothin, Cefaloridine, Cephapirin.
In oral preparation Cephalexin, Cefadroxil, and Cephadrine are common. In parenteral prepaation Cefazolin, Cephapirin are common.

2nd Generation Cephalosporins

This generation has anaerobic coverage and a little bit better gram-negative coverage. They also have Anti-Haemophilus activity. That’s why they were used against anaerobic bacterial intra-abdominal infections. They were still same against gram positive bacteria as first generation.
This generations includes; Cefoxitin, Cefprozil, Cefotitan, Cefmetazole, Cefuroxime, Ceflacor etc.

3rd generation Cephalosporins

Cefexime and Ceftriaxone were very common of this generation. They have no anaerobic coverage. In terms of Gram positive, they were very good in Streptococcus pneumonia but not as good coverage in terms of Staphylococcus aureus. Other than that, in terms of Gram negative, they have good coverage with Neisseria gonorrhoeae, Enterobacteriaceae, Pseudomonas and Serratia. Ceftazidime works against Pseudomonas and lung infections (Community-acquired pneumonia).
This generations also includes; Cefexime, Ceftazidime, Cefotaxime, Ceftizoxime, Cefdopoxime, Ceftriaxone, Cefoperazone, Ceftibuten, Cefdinir, Moxalactam.

4th generation Cephalosporins

This generation has no anaerobic coverage. But they took the strength of first generation for gram positives added the great gram-negative coverage of the third generation and made them strong. They also work against Pseudomonas. They got excellent coverage that’s why we are using these for very serious infections i.e., for fever of unknown origin.
Common drugs of this generation are Cefepime, Cefpirole etc.

5th generation Cephalosporins

The latest generation of cephalosporins are valuable anti-infective agents, with potent activity against multidrug-resistant bacteria, and it also provides a positive balance between benefits and side effects. This generations’ cephalosporins used to treat “Methicillin-resistant Staphylococcus aureus (MRSA)” infections, that are resistant to other antibiotics.
5th generation cephalosporins includes; Ceftibiprole, Ceftaroline, Ceftolozan etc. Ceftolozane is combined with tazobactam which is a beta-lactamase inhibitor.
In terms of Ceftalozane, they took the structure of Ceftazidime and made it better along with tazobactam. So, we can say that Ceftolozane is the most potent anti- Pseudomonas cephalosporin that we currently have. On the other hand, Ceftaroline is the only cephalosporin that can treat MRSA (Methicillin-resistant Staphylococcus aureus). It has good anaerobic coverage.

A Quick Look of Cephalosporin Antibiotics







Everything Else




Cefadroxil, Cefazolin, Cefalothin, Cefaloridine, Cephapirin. Cephalexin, Cephadrine.

Cefoxitin, Cefprozil, Cefotitan, Cefmetazole

Ceftriaxone, Cefoperazone, Ceftibuten Cefexime, Ceftazidime, Cefotaxime


Ceftibiprole, Ceftaroline

At a glance, we can see that, the cephalosporins are effective against both gram positive and gram-negative bacteria. Although effectivity against gram negative bacteria was reduced earlier in the first and second generation. But the more we are moving from the first generation to fifth generation, the more the cephalosporins are becoming effective against the gram-negative bacteria and the chance of killing gram positive bacteria is remaining kind of constant. Also, there are 3 cephalosporins which are anti- Pseudomonas medications: Ceftazidime, Cefepime, Ceftalozane.

Mechanism of Action

All generation of cephalosporins are bactericidal. The mechanism of action of cephalosporin is same as penicillin. It inhibits the cell wall synthesis of bacteria. As we know that, both gram positive and negative bacteria possess peptidoglycan cell wall layer. In gram positive bacteria the layer is thick and in gram negative bacteria it is thin.
However, the peptidoglycan layer is synthesized by crosslinking of NAM (N-acetyl muramic acid) and NAG (N-acetylglucosamine). Cephalosporin blocks the crosslinking of NAG and NAM by inhibiting transpeptidase enzyme (Cephalosporin binding protein) by the presence of beta lactam ring. No crosslinking means no peptidoglycan synthesis. No peptidoglycan synthesis means no cell wall integrity. That ultimately causes the bacteria cell lysis and the cell will die.

Some bacteria can develop beta-lactamase enzyme that can degrade the beta lactam ring. So, beta lactamase inhibitors are combined with cephalosporin to exert synergistic effect that will inhibit the beta lactamase enzyme and cephalosporin can exert its pharmacological action. Some beta lactamase inhibitors are: Clavulanic acid, Sulbactam, Tazobactam, Avibactam, and Vaborbactam.


Mechanisms of bacterial resistance to the cephalosporins are the same as the penicillins. Although they are not susceptible to hydrolysis by the staphylococcal penicillinase, cephalosporins may be susceptible to ESBLs.

Medical uses

1. Respiratory tract infection, Urinary tract infection, and Soft tissue infections
2. Cefazolin is used to treat surgical prophylaxis
3. Ceftriaxone is used to treat Gonorrhea
4. 3rd generation Cephalosporins is used to treat Meningitis, and Nosocomial infections.
5. Typhoid can be also treated with Cephalosporins
6. Mixed aerobic-anaerobic infection in cancer can be treated with 3rd generation cephalosporins.
7. Ceftaroline is used to treat MRSA infections.
8. Pseudomonas and lung infections are treated with Ceftazidime, Cefepime, and Ceftalozane.
9. Dental infections: Alternate to penicillin;
a. 1st generation cephalosporins: Cephalexin, Cephadroxil effective against gram positive, and aerobic bacteria. Alternate to amoxicillin for prophylaxis.
b. 2nd generation cephalosporins effective against oral anaerobes.

Side Effects

1. Stomach upset
2. Nausea
3. Vomiting
4. Diarrhea
5. Yeast infection or oral thrush
6. Dizziness

Caution in pregnancy

Cephalosporin in pregnancy might increase the likelihood of a specific birth defect in the baby. One study found that the use of cephalosporin antibiotic in early pregnancy may be linked to heart defects in babies.