Different Generations of Cephalosporin Medication

Cephalosporins are one of the most widely prescribed classes of medications in the world. Chances are you have encountered these antibiotics even if you are unfamiliar with the name. For example, among other things, Keflex (cephalexin) is used to treat skin infections and infections of the bone, respiratory tract, urinary tract, and middle ear. Additionally, Rocephin (ceftriaxone) is used to treat pneumonia.

Different antibiotics spread out
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What Are Cephalosporins?

Cephalosporins were first discovered in sewer water off the coast of Sardinia in 1945. By 1964, the first cephalosporin was 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 three different mechanisms of action. They are:

  • Binding to specific penicillin-binding proteins.
  • Inhibition of cell wall synthesis.
  • Activation of autolytic (self-destructive) enzymes in the bacterial cell wall.

Cephalosporins are divided into five 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 healthcare professionals is that with subsequent generations of cephalosporins, gram-positive coverage decreases while gram-negative coverage increases.  

One to 3% 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:

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 cephalosporins can be used as prophylaxis after clean surgical procedures.

The prevalence of MRSA has diminished the efficacy of first-generation cephalosporins as a 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
  • Cefotetan
  • Cefuroxime (tablet and injection)
  • Cefprozil

Second-generation cephalosporins treat the following:

  • 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 (such as after exposure to an under-chlorinated hot tub or pool) as well as pneumonia, blood infections, and so forth in those with weakened immune systems. P. aeruginosa most commonly occurs in patients who have been hospitalized one week or longer). The infections can be highly complicated and life-threatening.

There are several third-generation cephalosporins. Discussing them all would be outside the scope of this article. Let's instead 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 Citrobacterr 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 potent 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 has little ability to induce resistance.

A Word From Verywell

As you can now appreciate, cephalosporins are a remarkably diverse class of antibiotics with broad coverage. However, as with most antibiotics, antibiotic resistance is a concern for many clinicians, epidemiologists, public health officials, and patients.

Bacterial resistance is partially due to physicians' overprescription; nevertheless, we 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."

3 Sources
Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
  1. Abraham EP. Cephalosporins 1945-1986. Drugs. 1987;34 Suppl 2:1-14.doi:10.2165/00003495-198700342-00003

  2. Kapoor G, Saigal S, Elongavan A. Action and resistance mechanisms of antibiotics: A guide for clinicians. J Anaesthesiol Clin Pharmacol. 2017;33(3):300–305. doi:10.4103/joacp.JOACP_349_15

  3. Kwak YG, Choi SH, Kim T, et al. Clinical Guidelines for the Antibiotic Treatment for Community-Acquired Skin and Soft Tissue InfectionInfect Chemother. 2017;49(4):301–325. doi:10.3947/ic.2017.49.4.301

Additional Reading
  • Dickson SD, Salazar KC. Diagnosis and management of immediate hypersensitivity reactions to cephalosporins. Clin Rev Allergy Immunol. 2013;45(1):131-42. doi:10.1007/s12016-013-8367-x

  • Powers JH. "Use and Importance of Cephalosporins in Human Medicine" Presentation. FDA.

  • 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

By Naveed Saleh, MD, MS
Naveed Saleh, MD, MS, is a medical writer and editor covering new treatments and trending health news.