Cephalosporin generations
How cephalosporins are grouped into generations 1 to 5, what each covers, and the gaps they all share: enterococci, Listeria and atypicals.
Cephalosporins are β-lactams with a six-membered dihydrothiazine ring; like penicillins they block the penicillin-binding proteins. They are grouped into «generations» roughly in the order they appeared. As a rule, moving from the first to the third generation adds gram-negative activity and loses some staphylococcal activity; the fourth generation combines both, and the fifth adds MRSA. Some newer drugs (cefiderocol, combinations with avibactam or tazobactam) were made for resistant gram-negative bacteria and do not fit the scheme neatly.
First generation
Cefazolin (intravenous) and cefalexin or cefadroxil (oral) are very active against methicillin-susceptible Staphylococcus aureus and streptococci, with some activity against E. coli, Klebsiella and Proteus. Cefazolin is the usual choice for antibiotic prophylaxis before most surgery and an alternative to antistaphylococcal penicillins for serious MSSA infections. They penetrate the cerebrospinal fluid poorly, so they are not used for meningitis.
Second generation
Cefuroxime (oral and intravenous) and cefaclor add Haemophilus influenzae and Moraxella and are used for sinusitis, otitis media and some respiratory infections. The cephamycins cefoxitin and cefotetan are grouped here; a methoxy group protects them from many β-lactamases and gives them activity against gut anaerobes, so they serve in gynaecological and abdominal infections and for colorectal surgery prophylaxis.
Third generation
Ceftriaxone and cefotaxime are strongly active against streptococci (including many penicillin-resistant pneumococci), H. influenzae, Neisseria and most community Enterobacterales, and they reach the brain well: they are mainstays for meningitis, community pneumonia, pyelonephritis and gonorrhoea. Ceftriaxone is also cleared in bile and can form biliary sludge; in newborns cefotaxime is preferred because ceftriaxone displaces bilirubin and can precipitate with intravenous calcium. Cefixime, cefpodoxime and cefdinir are oral members. Ceftazidime stands apart: weaker against gram-positives but active against Pseudomonas aeruginosa. Bacteria that make ESBLs or inducible AmpC β-lactamases can destroy third-generation cephalosporins.
Fourth generation
Cefepime combines good gram-positive activity with cover of Pseudomonas and of Enterobacter species with AmpC enzymes. It is used for febrile neutropenia and hospital-acquired pneumonia. At high levels, above all when kidney function is reduced and the dose is not adjusted, it can cause encephalopathy and non-convulsive seizures.
Fifth generation and anti-MRSA cephalosporins
Ceftaroline and ceftobiprole bind PBP2a, the altered penicillin-binding protein that makes MRSA resistant to almost every other β-lactam. Ceftaroline is used for skin infections and community pneumonia; ceftobiprole also covers Pseudomonas. They do not cover ESBL producers reliably.
Newer agents for resistant gram-negative bacteria
- Ceftazidime–avibactam: avibactam blocks ESBL, AmpC and KPC carbapenemases, but not metallo-β-lactamases
- Ceftolozane–tazobactam: for multidrug-resistant Pseudomonas
- Cefiderocol: a siderophore cephalosporin that enters bacteria through their iron transporters; active against many carbapenem-resistant gram-negatives
- These are WHO Reserve antibiotics, kept for confirmed or strongly suspected resistant infections
Shared safety points
- Allergy: rash is the most common reaction and anaphylaxis can occur; cross-reaction with penicillins is less frequent than once thought and depends mostly on similar side chains
- Clostridioides difficile diarrhoea, as with any broad-spectrum antibiotic
- Cefotetan carries a group that can cause bleeding (low prothrombin) and a disulfiram-like reaction with alcohol
- Most are cleared by the kidneys and need dose adjustment in kidney failure; ceftriaxone is the main exception
Test yourself
Think of the answer, then tap the question to see it.
Which cephalosporin generation is the usual choice for surgical prophylaxis, and which drug?
The first generation: cefazolin.
Which third-generation cephalosporin covers Pseudomonas aeruginosa?
Ceftazidime; the others in its generation, such as ceftriaxone, do not.
Why is cefotaxime preferred to ceftriaxone in newborns?
Ceftriaxone can displace bilirubin and can precipitate with intravenous calcium; cefotaxime avoids both problems.
Which cephalosporins are active against MRSA, and why?
Ceftaroline and ceftobiprole, because they bind PBP2a, the altered penicillin-binding protein of MRSA.
Which organisms are not covered by any cephalosporin?
Enterococci, Listeria monocytogenes and the atypical pathogens such as Mycoplasma and Legionella.
Example drugs
- Cefazolin
- Cefalexin
- Cefuroxime
- Cefaclor
- Cefoxitin
- Cefotetan
- Ceftriaxone
- Cefotaxime
- Cefixime
- Cefpodoxime
- Cefdinir
- Ceftazidime
- Cefepime
- Ceftaroline
- Ceftobiprole
- Ceftazidime + avibactam
- Ceftolozane + tazobactam
- Cefiderocol
Connections
Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.
Sources: Cefazolin Injection: MedlinePlus Drug Information (MedlinePlus (U.S. National Library of Medicine), 2026); DailyMed - CEFTRIAXONE injection, powder, for solution (DailyMed (U.S. National Library of Medicine), 2026); DailyMed - CEFEPIME- cefepime hydrochloride injection, powder, for solution (DailyMed (U.S. National Library of Medicine), 2026); Ceftaroline Injection: MedlinePlus Drug Information (MedlinePlus (U.S. National Library of Medicine), 2026).
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Representative model, for educational purposes only.