Cephalosporin

Cephalosporins are a type of β-lactam antibiotic that come from the fungus Acremonium (once called Cephalosporium). Along with cephamycins, they form the cephem subgroup of β-lactam drugs. Their discovery happened in 1945, and they first went on sale in 1964.

Discovery

The mold that produces cephalosporin C was an aerobic fungus collected from seawater near Cagliari, Sardinia, by the Italian pharmacologist Giuseppe Brotzu in July 1945.

Chemically, cephalosporins have a six-membered dihydrothiazine ring. Changes at position 3 on the molecule usually affect how the drug behaves in the body, while changes at position 7 tend to alter its antibacterial power—though these patterns aren't absolute.

Medical uses

Doctors prescribe cephalosporins to prevent or treat infections caused by bacteria that are sensitive to them. First-generation versions work mainly against Gram-positive bacteria like Staphylococcus and Streptococcus, so they're often used for skin and soft-tissue infections and to prevent surgical infections picked up in hospitals. Later generations gain more activity against Gram-negative bacteria, but often lose some punch against Gram-positive ones.

Because their β-lactam structure differs from penicillin's, cephalosporins can sometimes be given to people allergic to penicillin. The body gets rid of the drug through urine.

Side effects

Common side effects (affecting at least 1% of patients) include diarrhea, nausea, rash, electrolyte imbalances, and pain or inflammation at the injection site. Less common reactions (0.1–1%) include vomiting, headache, dizziness, oral or vaginal yeast infections, pseudomembranous colitis, superinfection, eosinophilia, kidney toxicity, low neutrophil or platelet counts, and fever.

Allergic hypersensitivity

The often-cited 10% cross-reactivity rate between penicillins or carbapenems and cephalosporins came from a 1975 study on early cephalosporins. A "safety first" approach made that figure widely repeated and assumed to apply to all cephalosporins, leading to the common warning that they're contraindicated in anyone with a history of severe immediate allergic reactions (like hives, anaphylaxis, or interstitial nephritis) to penicillins or carbapenems.

However, newer research suggests that for many second-generation and later cephalosporins, the cross-reactivity risk is much lower, with no significant increase over first-generation drugs. The British National Formulary, which once gave blanket 10% warnings, has since the September 2008 edition advised that, when no good alternative exists, oral cefixime or cefuroxime and injectable cefotaxime, ceftazidime, and ceftriaxone can be used cautiously, while cefaclor, cefadroxil, cefalexin, and cefradine should be avoided. A 2012 review found the risk negligible with third- and fourth-generation cephalosporins, and even the risk with first-generation drugs that share similar R1 sidechains was overestimated—closer to 1%.

Some cephalosporins—including latamoxef (moxalactam), cefmenoxime, cefoperazone, cefamandole, cefmetazole, and cefotetan—can cause low prothrombin levels and a disulfiram-like reaction with alcohol. This is linked to their methylthiotetrazole side chain, which blocks vitamin K epoxide reductase (likely leading to low prothrombin) and aldehyde dehydrogenase (causing alcohol intolerance).

Drinking alcohol while taking these drugs orally or intravenously is therefore contraindicated, and severe cases can be fatal. Ceftriaxone's methylthiodioxotriazine side chain has a similar effect. Cephalosporins without these structural features are considered safe with alcohol.

Cephalosporins kill bacteria by disrupting the synthesis of peptidoglycan, the layer that gives bacterial cell walls their strength. Like other β-lactam antibiotics, they mimic the D-Ala-D-Ala end of muropeptides, binding to penicillin-binding proteins (PBPs) and irreversibly blocking the final crosslinking step of peptidoglycan assembly.

Resistance can arise when existing PBPs become less sensitive to the drug or when bacteria acquire a new PBP that β-lactams don't affect. Compared to penicillins, cephalosporins are less easily broken down by β-lactamase enzymes. Currently, some strains of Citrobacter freundii, Enterobacter cloacae, Neisseria gonorrhoeae, and Escherichia coli are resistant. Varying levels of resistance have also appeared in Morganella morganii, Proteus vulgaris, Providencia rettgeri, Pseudomonas aeruginosa, Serratia marcescens, and Klebsiella pneumoniae.

The earliest cephalosporins were called first-generation; later ones with a broader spectrum became second-generation. Each newer generation generally has stronger Gram-negative activity than the one before, though often with less Gram-positive activity. Fourth-generation cephalosporins, however, offer true broad-spectrum coverage.