Cephalosporins

Cephalosporins were discovered in 1945 by Italian pharmacologist Giuseppe Brotzu, who isolated a fungus from sewage outfall off the Sardinian coast that produced substances active against Salmonella typhi.¹ The fungus was identified as Cephalosporium acremonium (now Acremonium chrysogenum). Brotzu's work was largely ignored in Italy, but his culture was sent to Oxford University, where Edward Abraham and Guy Newton isolated cephalosporin C in 1953.² Cephalosporin C had a relatively weak antibacterial activity, but its core structure, 7-aminocephalosporanic acid (7-ACA), served as a scaffold for semisynthetic derivatives. The first clinically used cephalosporin, cephalothin, was introduced in 1964.

Cephalosporins work by binding to penicillin-binding proteins (PBPs) and inhibiting the final transpeptidation step of peptidoglycan synthesis in the bacterial cell wall, leading to cell lysis.³ They are structurally related to penicillins, but contain a six-membered dihydrothiazine ring fused to the β-lactam ring, which confers increased stability to many β-lactamases. The side chains at positions 3 and 7 of the cephem nucleus determine the antibacterial spectrum and pharmacokinetic properties.

Cephalosporins are grouped into five generations, each with an expanded spectrum against Gram-negative bacteria and increased resistance to β-lactamases. First-generation agents (e.g., cephalexin, cefazolin) are primarily active against Gram-positive cocci. Second-generation agents (e.g., cefuroxime, cefoxitin) add coverage against Haemophilus influenzae and some anaerobes. Third-generation agents (e.g., ceftriaxone, ceftazidime) have enhanced activity against Enterobacteriaceae and are used for serious infections. Fourth-generation agents (e.g., cefepime) are resistant to many AmpC β-lactamases. Fifth-generation agents (e.g., ceftaroline, ceftobiprole) are active against methicillin-resistant Staphylococcus aureus (MRSA).

Cephalosporins are used to treat a wide range of infections, including respiratory tract infections, urinary tract infections, skin and soft tissue infections, and meningitis. They are generally well tolerated, but common adverse effects include gastrointestinal disturbances, rash, and pain at injection site. Hypersensitivity reactions can occur, and cross-reactivity with penicillins is estimated at 1–3%.⁴ A unique adverse effect of some cephalosporins (e.g., cefotetan, ceftriaxone) is a disulfiram-like reaction when alcohol is consumed.

Bacterial resistance to cephalosporins is primarily mediated by β-lactamases, including extended-spectrum β-lactamases (ESBLs) and AmpC enzymes, which hydrolyze the β-lactam ring. Resistance can also arise from alterations in PBPs and reduced outer membrane permeability. The emergence of ESBL-producing Enterobacteriaceae has limited the use of third-generation cephalosporins, prompting the development of cephalosporin-β-lactamase inhibitor combinations such as ceftazidime-avibactam.⁵

Beyond the standard generations, several niche cephalosporins exist. Cefiderocol, a siderophore cephalosporin, exploits the bacterial iron transport system to enter cells, making it active against carbapenem-resistant Gram-negative bacteria.⁶ Cefaloram, an early cephalosporin, was never marketed due to toxicity. Cefmatilen is an oral cephalosporin with activity against Mycobacterium tuberculosis in vitro. Cephalosporins have also been used in agriculture and veterinary medicine, and some are used as growth promoters in livestock. The discovery of cephalosporins was serendipitous: Brotzu noticed that sewage outfall areas had fewer bacteria, leading to his isolation of the fungus.

β-lactam

A four-membered lactam ring that is the core structure of a class of antibiotics that includes penicillins, cephalosporins, and carbapenems.

Penicillin-binding protein (PBP)

Enzymes involved in bacterial cell wall synthesis that are the targets of β-lactam antibiotics.

Extended-spectrum β-lactamase (ESBL)

Enzymes that hydrolyze penicillins, cephalosporins, and aztreonam, conferring resistance to these antibiotics.

Siderophore

A molecule that binds and transports iron; cefiderocol is a cephalosporin conjugated to a siderophore to facilitate uptake.