Cephalosporins

01Drug classification

The first cephalosporin came from a mould, Cephalosporium, found near a sewage outlet off the coast of Sardinia. Changes to its two side chains gave drug after drug, grouped in four generations by what they reach, and an advanced generation for the newer drugs that fit none of them.

02Pharmacokinetics

Several can be taken by mouth: cefalexin, cefadroxil and cefaclor are almost fully absorbed, cefuroxime axetil, cefixime and cefpodoxime only about half. The rest are injected. Ceftriaxone, cefotaxime, ceftazidime and cefepime reach the cerebrospinal fluid well enough to treat meningitis.

Most leave through the kidneys, so their doses are cut in kidney failure, and probenecid slows their tubular secretion as it does the penicillins'. Ceftriaxone is the main exception: it is cleared in bile and urine, needs no dose change in kidney failure unless the liver fails too, and its long half-life, about eight hours against an hour or two for most cephalosporins, allows one dose a day. Cefazolin, too, lasts longer than most.

03Pharmacodynamics

Cephalosporins bind the PBPs and stop the wall's cross-links, as the penicillins do (the β-lactam overview has how), and kill in the same time-dependent way, needing longer above the MIC than a penicillin. Their two side chains make them stable to many β-lactamases, staphylococcal penicillinase among them, and set the spectrum of each generation: from the first to the third, activity against gram-positives falls and against gram-negatives rises. Ceftaroline and ceftobiprole bind PBP2a, the PBP that lets MRSA resist the other β-lactams.

Against resistant gram-negatives

Newer drugs pair a cephalosporin with a β-lactamase inhibitor, or change how it gets in:

• ceftazidime–avibactam, which also reaches bacteria with ESBLs and with KPC, AmpC and OXA-48 enzymes, but not those with metallo-β-lactamases such as NDM;
• ceftolozane–tazobactam, mostly for multidrug-resistant Pseudomonas;
• cefepime–enmetazobactam, authorised in the EU in 2024: enmetazobactam blocks ESBLs, but not reliably KPC, and no metallo-β-lactamase or OXA-48 enzyme, though cefepime itself withstands AmpC and OXA-48;
• cefiderocol, a siderophore cephalosporin: it binds iron and is carried into gram-negatives by their own iron transporters, a "Trojan horse" that gets past lost porins. It is stable to many β-lactamases, carbapenemases among them, and is kept for infections that resist almost everything else.

04Clinical indications

05Adverse drug reactions

Cephalosporins are well tolerated, and share the allergy and C. difficile risk of all β-lactams. Their own reactions come from a few drugs.

• Life-threatening
  Anaphylaxis, as with any β-lactam, though rarely.
• Serious
  Hives and swelling, immediate allergic reactions and among the commonest; the drug is stopped.
• Mild
  Rash, among the reactions most often reported with ceftriaxone, mostly a delayed maculopapular rash. A rash with fever, blisters, a sore mouth or eyes, or peeling skin is treated as a severe reaction.
• Life-threatening
  Severe skin reactions, rarely: Stevens–Johnson syndrome, toxic epidermal necrolysis and DRESS (drug reaction with eosinophilia and systemic symptoms).
• Life-threatening
  Ceftriaxone in newborns. It pushes bilirubin off albumin, so a jaundiced newborn could develop kernicterus. In infants under 28 days old given intravenous calcium, ceftriaxone–calcium crystals can precipitate in the lungs and kidneys, sometimes fatally.
• Serious
  C. difficile colitis. Third-generation cephalosporins are among the antibiotics most often behind it.
• Serious
  Cefepime neurotoxicity. Mostly when the kidneys clear it poorly and the dose isn't cut to match, though sometimes with normal kidneys, cefepime can cause encephalopathy, myoclonus, seizures and non-convulsive status epilepticus, typically a few days into treatment. It usually clears within days of stopping the drug; dialysis helps in severe cases. An early meta-analysis found more deaths with cefepime than with other β-lactams, but a larger analysis did not confirm it.
• Serious
  The N-methylthiotetrazole side chain (cefotetan, cefoperazone, cefamandole, cefmetazole). It interferes with vitamin K, causing hypoprothrombinaemia and bleeding, and with warfarin, raising its effect. It also blocks aldehyde dehydrogenase, so alcohol brings on a disulfiram-like reaction of flushing, nausea and palpitations.
• Life-threatening
  Immune haemolytic anaemia, most often with cefotetan and ceftriaxone. It can be sudden and severe, and has killed adults and children, so the drug is stopped at once.
• Serious
  Ceftriaxone in bile. It binds calcium in the gallbladder into a sludge that looks like stones on ultrasound, biliary pseudolithiasis. About one adult in five on ceftriaxone develops it, a third of them with symptoms that can mimic cholecystitis, more with high doses, long courses, fasting or kidney failure. It usually goes away once the drug is stopped; when it causes symptoms it is managed without surgery, and stopping ceftriaxone is considered. In children on high doses it can also form stones in the urinary tract, which clear when it is stopped.

on ceftriaxone develop biliary pseudolithiasis, a third of them with symptoms

1 in 5adultson ceftriaxone develop biliary pseudolithiasis, a third of them with symptoms

with penicillins, set mostly by the R1 side chain

2%cross-reactivitywith penicillins, set mostly by the R1 side chain

06Side effects

• Mild
  Diarrhoea, nausea, vomiting and abdominal pain, the commonest complaints. Diarrhoea is among the reactions most often reported with ceftriaxone and cefalexin.
• Mild
  Pain at the injection site, and phlebitis along the vein. Ceftriaxone for injection into muscle is dissolved in lidocaine to ease it.
• Mild
  Thrush, such as a vaginal yeast infection.

07Contraindications

• Contraindicated
  An allergy to any cephalosporin.
• Contraindicated
  A severe reaction, such as anaphylaxis, to another β-lactam, in ceftriaxone's licence (cefalexin's asks only for care in penicillin allergy). Allergy guidance is less strict (below).
• Contraindicated
  Ceftriaxone in newborns at risk: premature babies up to a postmenstrual age of 41 weeks (gestational age plus age since birth), and those born at term, up to 28 days old, who are jaundiced, have a raised bilirubin, low albumin or acidosis, or need intravenous calcium.
• Contraindicated
  Ceftriaxone dissolved in lidocaine, into a vein. That solution is for muscle only, and lidocaine's own contraindications apply.
• Caution
  Ceftriaxone with intravenous calcium, after 28 days of age. The two are never mixed or given at the same time, even through separate lines, and fluids with calcium, such as Ringer's or Hartmann's, are not used to dissolve it. They can follow each other through lines at different sites, or through one line changed or flushed well between them. Calcium by mouth, and ceftriaxone into a muscle, have not been found to interact.
• Caution
  Alcohol with the N-methylthiotetrazole drugs, such as cefotetan. The patient doesn't drink during the course or for about three days after it, because of the disulfiram-like reaction.
• Caution
  Warfarin. Ceftriaxone can raise its effect and the risk of bleeding, so the INR is checked often.
• Caution
  Kidney failure. Most doses are cut to match, cefepime's above all. Ceftriaxone needs no change unless the liver fails too, and is kept to 2 g a day when the kidneys have almost failed.
• Caution
  A penicillin allergy that wasn't severe. A cephalosporin with a different R1 side chain is usually tolerated; one with the same or a similar side chain, such as cefalexin after ampicillin, is the one to avoid.

08Pregnancy and lactation

• Compatible
  Pregnancy. Most studies of cephalosporins in pregnancy show no harm to the baby, and no extra monitoring for birth defects is needed. An occasional link with heart defects after use early in pregnancy is not borne out by most studies. Their licences are more cautious, ceftriaxone's above all in the first trimester.
• Compatible
  Gonorrhoea in pregnancy. It is treated with ceftriaxone, one dose into muscle, as outside pregnancy.
• Compatible
  Breastfeeding. Ceftriaxone, like most cephalosporins, passes into milk in amounts too small to matter, and the baby absorbs little of it. Rarely the baby gets diarrhoea or thrush. Their licences are more cautious, asking for care, or for the benefit to mother and baby to be weighed.