What Are Cephalosporins and Generations?

Cephalosporins Are Antibiotics Used to Treat Infection


Cephalosporins are one of the most widely prescribed class of medications in the world.  Chances are that you have encountered these antibiotics even if you are unfamiliar with the name.  For example, among other things, Keflex (cefalexin) is used to treat skin infections.  And Rocephin (ceftriaxone) is used to treat pneumonia.

What are cephalosporins?

Cephalosporins were first discovered in a sewer water off the coast of Sardinia in 1945.

  By 1964, the first cephalosporin was first prescribed.

Cephalosporins are structurally similar to other antibiotics.  Like penicillins, cephalosporins have a beta-lactam ring attached to a dihyrdothiazole ring.  Hanging off this dihyrdothiazole ring are various side chains, the composition of which makes for different cephalosporins with different pharmacology and antimicrobial activity.

Cephalosporins have 3 different mechanisms of action:

  • Cephalosporins bind to specific penicillin-binding proteins.
  • Cephalosporins inhibit cell wall synthesis.
  • Cephalosporins are activated autolytic (self-destructive) enzymes in the bacterial cell wall.

Cephalosporins are divided into 5 generations.  However, different cephalosporins in the same generation are sometimes chemically unrelated and have different spectra of activity (think cephamycins).

A generalization taught to many health care professionals is that with subsequent generations of cephalosporins, gram-positive coverage decreases while gram-negative coverage increases.


One to 3 percent of all people are allergic to cephalosporins.  In reality, however, this number is probably higher because people with penicillin allergies are often not prescribed cephalosporins. 

First-Generation Cephalosporins

First-generation cephalosporins come in oral and intravenous forms.

  They are active against viridans streptococci, group A hemolytic streptococci, staphylococcus aureus, E. coli, Klebsiella and Proteus bacteria.  Like all other cephalosporins, first-generation cephalosporins don't work on enterococci.

Examples of first-generation cephalosporins include the following:

  • cephalexin (Keflex)
  • cephradine
  • cefadroxil
  • cefazolin (intravenous and intramuscular) 

In general, first-generation cephalosporins can be used to fight skin and other soft-tissue infections, respiratory tract infections, and urinary tract infections.  Intravenous first-generation cephalosporin can be used as prophylaxis after clean surgical procedures.  Of particular note, the prevalence of MRSA has diminished the efficacy of first-generation cephalosporins as means of prophylaxis and treatment.

Second-Generation Cephalosporins

In general, second-generation cephalosporins are more active against gram-negative organisms, making them more useful in many clinical situations.  For example, second-generation cephalosporins are active against strains of Proteus and Klebsiella.

  Second-generation cephalosporins also combat H. influenza--a cause of pneumonia, sepsis, and meningitis.  Nevertheless, first-generation cephalosporins are generally still better at treating gram-positive infections.

Examples of second-generation cephalosporins include the following:

  • cefoxitin (cephamycin)
  • cefotetan (cephamycin)
  • cefuroxime (oral and intravenous)
  • cefprozil

Clinical uses of second-generation cephalosporins:

  • sinusitis
  • otitis media (ear infection)
  • mixed anaerobic infections including peritonitis and diverticulitis
  • prophylaxis after colorectal surgery

Second-generation cephalosporins have no activity against Pseudomonas aeruginosa.

Third-Generation Cephalosporins

A major advantage of third- and fourth-generation antibiotics is significantly expanded coverage against gram-negative bacteria.  Furthermore, the third-generation cephalosporin ceftazidime is active against Pseudomonas aeruginosa, a bacteria that can cause skin infections in people with normal immune systems (think under-chlorinated hot tubs or pools), and pneumonia, blood infections and so forth in those with weakened immune systems (think post-surgical and hospitalized patients).

There are several third-generation cephalosporins.  Discussing them all would be outside the scope of this article.  Thus, I will focus on ceftriaxone (Rocephin) which has numerous uses including:

  • lower respiratory tract infections
  • skin and soft tissue infections
  • uncomplicated gonorrhea
  • urinary tract infections
  • otitis media
  • pelvic inflammatory disease
  • surgical prophylaxis
  • bacteria septicemia (blood infection)
  • meningitis
  • bone infections
  • joint infections
  • intra-abdominal infections

Fourth-generation cephalosporin

Cefepime is the only available (FDA-approved) fourth-generation cephalosporin.  Like the third-generation cephalosporin ceftazidime, cefepime is active against Pseudomonas aeruginosa.  Furthermore, cefepime is more active against enterobacter and citrobacter bacteria.  Finally, cefepime has gram-positive coverage comparable with ceftriaxone.

Here are some clinical uses for cefepime:

  • moderate to severe pneumonia
  • severe urinary tract infection
  • skin and soft tissue infections
  • complicated intra-abdominal infections

Fifth-generation cephalosporin

In 2010, the FDA approved Ceftaroline (Teflaro), the only fifth- or advanced-generation cephalosporin. Like cefepime, ceftaroline is a "big-gun" antibiotic that should be reserved for serious infection.  Specifically, it's active against multidrug-resistant infections like MRSA (methicillin-resistant S. aureus) and VRSA (vancomycin-resistant S. aureus).  This drug is also injectable and prescribed to fight community-acquired pneumonia and serious skin and soft tissue infections.  Fortunately, ceftaroline is safe and hs little ability to induce resistance.

As you can now appreciate, cephalosporins are a remarkably diverse class of antibiotics with broad coverage.  However, as with most antibiotics, resistance is a concern for many clinicians, epidemiologists, public health officials, patients and so forth.  Bacterial resistance is partially due to physicians overprescription; nevertheless, we, as patients, can also help combat the development of resistance.  For example, you shouldn't always expect or demand that your prescriber gives you antibiotics to treat an infection which may very well be viral in nature.  (Antibiotics are ineffective against viruses).  Furthermore, when prescribed antibiotics, it's imperative that you finish the entire course even if you "feel better."

Selected Sources

Guglielmo B. Anti-Infective Chemotherapeutic & Antibiotic Agents. In: Papadakis MA, McPhee SJ, Rabow MW. eds. Current Medical Diagnosis & Treatment 2015. New York, NY: McGraw-Hill; 2014. Accessed March 19, 2015.

Article titled "Diagnosis and Management of Immediate Hypersensitivity Reactions to Cephalosporins" by MH Kim and JM Lee from Asthma, Allergy & Immunology Research published in 2014.

Presentation titled "Use and Importance of Cephalosporins in Human Medicine" by JH Powers at the FDA.

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