Cephalosporins are a large group of beta-lactam antimicrobials used in the treatment and prophylaxis of a range of bacterial infections.

Cephalosporins exert a bactericidal action in a similar manner to penicillins. They bind to penicillin-binding proteins (PBP), an enzyme found in many bacteria that is essential for cell wall synthesis. Binding of a cephalosporin to the PBP inactivates the enzyme, making the bacteria unable to synthesise peptidoglycan, the main component of the cell wall.


All cephalosporins have a central beta-lactam ring structure. The side chains of individual agents are what give each cephalosporin its unique antibacterial, pharmacologic, and pharmacokinetic properties.

Cephalosporins are sometimes grouped into generations based on their spectrum of activity and date of introduction. However, this categorisation system is not always precise and may differ slightly between sources.

1st generation:

Cefazolin and cefalexin have a similar spectrum of activity:

  • Gram-positive
    • Active against streptococci and staphylococci (including beta–lactamase–producing staphylococci).
    • Inactive against methicillin-resistant Staphylococcus aureus (MRSA), enterococci and Listeria monocytogenes.
  • Gram-negative
    • Active against a narrow range of aerobic bacteria, including wild-type Escherichia coli and some Klebsiella species.
    • Inactive against anaerobic Gram-negative bacteria, including Bacteroides fragilis.

 2nd generation:

Cefuroxime and cefaclor:

  • Slightly broader activity against Gram-negative bacteria compared to first-generation cephalosporins.
  • More active against Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis compared to cefaclor.


  • Significant activity against anaerobic bacteria (although not as great as metronidazole)

 3rd generation:

Cefotaxime and ceftriaxone:

  • Broad spectrum
  • No activity against Pseudomonas aeruginosa
  • Less active against staphylococci compared to cefazolin
  • Inactive against MRSA
  • Anti-staphylococcal activity is dose-dependent (sometimes co-administered with flucloxacillin)
  • No clinically useful activity against enterococci
  • Can be used for meningitis as they achieve therapeutic concentrations in the cerebrospinal fluid in the presence of meningeal inflammation


  • Extended-spectrum
  • Active against most Enterobacteriaceae and P. aeruginosa.
  • Also available in combination with avibactam, a beta-lactamase inhibitor. This further extends the spectrum of ceftazidime to include organisms that produce beta-lactamase.

4th generation:


  • Extended-spectrum
  • Active against most Enterobacteriaceae and P. aeruginosa
  • Greater Gram-positive activity compared to ceftazidime.

 5th generation:


  • Good activity against aerobic Gram-positive bacteria
  • Only cephalosporin that is active against MRSA
  • Active against vancomycin-intermediate S. aureus (VISA) and heterogeneous VISA (hVISA)
  • Active against penicillin-intermediate and penicillin‑resistant S. pneumoniae.
  • Variable activity against Gram-negative and anaerobic bacteria
  • Inactive against Pseudomonas spp.


  • Activity against P. aeruginosa and E. coli
  • Only available in combination with tazobactam, a potent and irreversible inhibitor of class A broad-spectrum and extended-spectrum beta-lactamases and class C cephalosporinases.
  • Inactive against bacteria that produce Klebsiella pneumoniae carbapenemases (KPCs), metallo–beta-lactamases or OXA-carbapenemases.



Many cephalosporins are available in parenteral formulations that can be given intravenously (IV) or intramuscularly (IM). Cephalosporins not approved for IM use are cefuroxime, ceftaroline, ceftolozane, and ceftazidime when formulated with avibactam. The IM route is often avoided for cefazolin, cefoxitin, and cefotaxime, as it can be painful.

Mixing cephalosporins with other drugs should be avoided due to a large number of physical incompatibilities.


Only cefalexin, cefuroxime, and cefaclor are available for oral administration. Cefalexin can be given without regard to food. Optimal absorption of cefuroxime occurs when administered after a light meal. While cefaclor is well absorbed orally, total absorption is increased when given within one hour after a meal.

Cefuroxime oral liquid has been discontinued in Australia. However, the Therapeutic Goods Administration (TGA) has approved the import and supply of an internationally registered cefuroxime oral liquid under Section 19A of the Therapeutic Goods Act. This approval is currently valid until end June 2025. Cefalexin and cefaclor are both still available in an oral liquid in addition to capsule/tablet presentations.

An overview of the use of cephalosporins via oral and parenteral routes is shown in Table 1.

Table 1. Administration of cephalosporins

Drug Oral Parenteral Usual dosing interval

1st generation

Cefazolin x 6-8 hourly
Cefalexin x 6-12 hourly

2nd generation

Cefoxitin x 8 hourly (severe infections: 4 hourly)
Cefuroxime 12 hourly
Cefaclor x 8-hourly (controlled release: 12-hourly)

3rd generation

Ceftazidime x 8-12 hourly
Ceftriaxone x Daily (Meningitis: 12 hourly)
Cefotaxime x 6-12 hourly

4th generation

Cefepime x 12 hourly

5th generation

Ceftaroline x 8-12 hourly
Ceftolozane x 8 hourly


Resistance to cephalosporins can occur by different mechanisms, including changes to the PBP or the production of beta-lactamase enzymes.

As an example, S. aureus can develop resistance to cephalosporins by changing the structure of its PBP. This prevents the beta-lactam ring of the cephalosporin from inactivating the protein. Altered PBPs are found in MRSA, and most cephalosporins are ineffective against MRSA. Ceftaroline is unique in that it inhibits the altered PBP produced by MRSA.

Beta-lactamase is an enzyme some bacteria produce that inactivates beta-lactam antibiotics by cleaving the beta-lactam ring. Cephalosporins are less susceptible to these enzymes than other beta-lactam antibiotics (such as penicillins); however, this is still an important resistance mechanism.

Cephalosporin and beta-lactamase inhibitor combinations are available, e.g. ceftazidime + avibactam, ceftolozane + tazobactam. This extends the spectrum of the cephalosporin to cover bacteria that produce beta-lactamase.


Cephalosporins can induce IgE-mediated allergic reactions. Symptoms can include urticaria, angioedema, rhinitis, and bronchospasm. Immediate reactions to cephalosporins have been reported to occur in up to 3% of the population, while anaphylactic reactions are rare, with a reported incidence of 0.0001–0.1%.

For some time, cross-reactivity between penicillin and cephalosporins was thought to be common (i.e. around 10%). However, much of the cross-reactivity found in early studies is now known to be related to penicillin contamination of the cephalosporin preparations tested.

Studies demonstrate that it is the side chains that are responsible for beta-lactam allergies rather than the beta-lactam ring itself. Penicillins have an R1 side chain, while cephalosporins have an R1 and R2. The R1 side chain is thought to be the major factor in cross-reactivity between penicillins and cephalosporins. Some penicillins and cephalosporins have the same or similar side chains, which makes cross-reactivity more likely.

The following antibiotics have the same or similar side chains:

  • Ampicillin + amoxicillin + cefalexin + cefaclor;
  • Penicillin G + cefoxitin;
  • Cefotaxime + cefalotin;
  • Cefuroxime + cefoxitin.

Cefazolin has a unique side chain which confers a very low risk of cross-reactivity with penicillins.

More recent evidence suggests that the rate of cross-reactivity between penicillins and cephalosporins is much lower than originally thought. It is now thought that less than 2% of patients with a confirmed penicillin allergy have a cephalosporin allergy. In many cases, a cephalosporin can be safely administered to a patient with a reported penicillin allergy. However, consideration of the severity of the reaction and the specific penicillin involved should occur. E.g. an allergy to ampicillin or amoxicillin makes a reaction to cefalexin or cefaclor more likely due to the side chain similarity.

Adverse effects

Cephalosporins are generally well-tolerated. The most common adverse reactions include nausea, vomiting, diarrhoea, and pain and inflammation at the injection site.

Superinfection can occur, including Candida and Enterococcus spp. This is more likely to occur during prolonged treatment and when agents with a broader spectrum of activity are used. Clostridioides difficile-associated disease has also been reported, particularly with broad-spectrum cephalosporins. C. difficile is the most common cause of infectious diarrhoea in the healthcare setting, and its incidence has increased over the past decade. While any antibiotic may theoretically increase the risk of C. difficile-associated disease, studies suggest that the first-generation cephalosporin cefalexin carries a low risk.

Neurotoxicity is rarely reported. This may be characterised by encephalopathy, myoclonus, and/or seizures. One study suggests that these effects may be most common with cefepime, followed by ceftriaxone and ceftazidime. Factors that may increase the risk of central nervous system effects include older age (>65 years), renal impairment, history of CNS disease, and other medications. The majority of these reactions occurred following IV administration. Attention should be paid to the rate of IV administration, particularly if the patient has renal impairment or high doses are used.



  1. Buckley AM, Moura IB, Altringham J, Ewin D, Clark E, Bentley K, et al. The use of first-generation cephalosporin antibiotics, cefalexin and cefradine, is not associated with induction of simulated Clostridioides difficile infection. J Antimicrob Chemother. 2021; 77(1), 148-54.
  2. Chaudhry SB, Veve MP, Wagner JL. Cephalosporins: A Focus on Side Chains and β-Lactam Cross-Reactivity. Pharmacy (Basel). 2019; 7(3): 103.
  3. D’Errico S, Frati P, Zanon M, Valentinuz E, Manetti F, Scopetti M, et al. Cephalosporins’ cross-reactivity and the high degree of required knowledge. Case report and review of the literature. Antibiotics. 2020; 9(5): 209.
  4. Devchand M, Trubiano JA. Penicillin allergy: a practical approach to assessment and prescribing. Aust Prescr. 2019; 42(6): 192-9.
  5. Jeimy S, Ben-Shoshan M, Abrams EM, Ellis AK, Connors L, Wong T. Practical guide for evaluation and management of beta-lactam allergy: position statement from the Canadian Society of Allergy and Clinical Immunology. Allergy, Asthma & Clinical Immunology 2020; 16: 95.
  6. Rossi S (ed). Australian Medicines Handbook. Adelaide: AMH; 2024.

Subscribe Knowledge Centre Updates

Enter your details to receive Knowledge Centre updates