β-lactam antibiotics: overview

01Drug classification

The β-lactam ring is a cyclic amide under strain, which makes its carbonyl reactive: this is what the PBP's serine attacks. In three of the families it is fused to a second ring, and the side chains hung on the two rings decide each drug's spectrum, its stability to β-lactamases and, for cephalosporins, much of its pharmacokinetics.

The R1 side chain matters again in allergy: it, more than the shared ring, decides which β-lactams cross-react. Each family's own topic lists more of its drugs.

02Pharmacokinetics

β-Lactams are water-soluble and spread through the fluid outside cells. They reach most tissues, the pleura, joints and urine well, but get into cells poorly. Into the cerebrospinal fluid they reach useful levels only when the meninges are inflamed, so meningitis is treated with high doses of the ones that cross best.

Most leave in the urine, filtered by the glomeruli and secreted by the tubules. Probenecid competes for that tubular secretion and raises their levels, and doses of most β-lactams are cut in kidney failure. The exceptions are cleared partly in bile: ceftriaxone, nafcillin and oxacillin among them. Most penicillins have half-lives under an hour, so they are given several times a day.

03Pharmacodynamics

How they kill

Outside the plasma membrane, most bacteria build a wall of peptidoglycan: chains of two alternating sugars, N-acetylglucosamine and N-acetylmuramic acid, each muramic acid carrying a short peptide that, as it is made, ends in two D-alanines. Peptides on neighbouring chains are cross-linked into one mesh round the cell, which holds its shape against the pressure of the water inside.

1. 1

   Units are made inside

   In the cytoplasm, each building block is assembled: the two sugars and the peptide ending in D-Ala-D-Ala.
2. 2

   Carried across the membrane

   A lipid carrier, bactoprenol, takes each unit across the plasma membrane. Bacitracin stops the carrier being recycled.
3. 3

   Joined into chains

   Outside the membrane, glycosyltransferases add each unit to the end of a growing sugar chain. Glycopeptides such as vancomycin bind the D-Ala-D-Ala end and block this step and the next.
4. 4

   Cross-linked by PBPs

   Transpeptidases, the PBPs, join a peptide to its neighbour, cutting off the last D-alanine. β-Lactams block them here.

The β-lactam ring looks to a PBP like the D-Ala-D-Ala end of its substrate. The enzyme's active-site serine opens the ring and is left acylated, a stable, inactive complex. New wall goes up without cross-links while the bacterium's own autolysins go on cutting the old wall to make room for growth, and the cell lyses. The last step is often taught as the drug inactivating an inhibitor of the autolysins. That holds in pneumococci, whose lipoteichoic acids hold back their main autolysin until penicillin sets it free; in other bacteria it is not settled whether anything sets the autolysins off or they simply carry on with their usual work. Enterococci are the exception: a β-lactam alone holds them back rather than kills them.

Time above the MIC

Because they kill by time above the MIC, a β-lactam does better given more often, or infused over hours, than given as larger, rarer doses. About half the dosing interval above the MIC is the classic aim for a penicillin; cephalosporins need longer above it, carbapenems less. Their effect also stops soon after the level falls below the MIC, because most have little or no post-antibiotic effect, which is one more reason not to let the gaps between doses grow long.

Gram-positive and gram-negative

A gram-positive bacterium has a thick wall of many layers of peptidoglycan, open to the drug. A gram-negative one has a thin wall under a second, outer membrane, which a β-lactam must cross through porins, water-filled protein channels. Between the outer and plasma membranes lies the periplasm, a gel that holds the thin wall, where the PBPs work and where a gram-negative keeps its β-lactamases, concentrated just where the drug has to pass.

LearnRevise

3D model

E. coli, a rod-shaped prokaryote, shown twice: as a model of the whole cell, which you can turn, and in a longitudinal section, a slice along its length. Its envelope has three layers: the outer membrane, a thin cell wall, and the plasma membrane. Inside, with no nucleus, a tangle of DNA, the nucleoid, fills the middle of the cytoplasm, with small rings of DNA, plasmids, and many ribosomes round it. Outside, short fimbriae cover the cell, and long wavy flagella rise all over it, each turned by a motor in the envelope, and stream back from it. Arrow keys turn it, plus and minus zoom, and Home brings back the first view.

Longitudinal section

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1. 1Flagellum
2. 2Fimbriae
3. 3Outer membrane
4. 4Cell wall
5. 5Plasma membrane
6. 6Cytoplasm
7. 7Nucleoid
8. 8Plasmids
9. 9Ribosomes

Drag to turn it, pinch or scroll to zoom, and tap a part to read what it does.

E. coli, a prokaryote about 2 µm long, has no nucleus and no membrane-bound organelles: its one circular chromosome lies in the nucleoid, a region of the cytoplasm with no membrane round it. Its envelope is the plasma membrane, a thin wall of peptidoglycan and, outside that, the outer membrane of a gram-negative bacterium. Flagella, turned by motors in the envelope, drive it along, and fimbriae let it stick to surfaces and cells.

Simplified: not to scale: the envelope drawn thicker, and the flagella and fimbriae shorter than they are; the chromosome far shorter than it is: stretched out, it would be about 1.1 mm long, over 500 times the cell’s length; far fewer ribosomes than a real cell has; the flagella drawn apart, though while it swims they turn together in one bundle; in the model, the fimbriae shown only round its outline, where they stand out from it; the wall in carbohydrate’s colour, though its cross-links are peptides; the outer membrane drawn like the plasma membrane, though its outer layer holds lipopolysaccharide; ribosomes in RNA’s colour, though they are part protein.

10 sources

1. Clark MA, Douglas M, Choi J. Biology 2e. OpenStax; 2018. 4.2 Prokaryotic Cells.
2. Clark MA, Douglas M, Choi J. Biology 2e. OpenStax; 2018. 4.3 Eukaryotic Cells.
3. Parker N, Schneegurt M, Thi Tu AH, et al. Microbiology. OpenStax; 2016. 3.3 Unique Characteristics of Prokaryotic Cells.
4. Parker N, Schneegurt M, Thi Tu AH, et al. Microbiology. OpenStax; 2016. 3.4 Unique Characteristics of Eukaryotic Cells.
5. Parker N, Schneegurt M, Thi Tu AH, et al. Microbiology. OpenStax; 2016. 14.3 Mechanisms of Antibacterial Drugs.
6. Parker N, Schneegurt M, Thi Tu AH, et al. Microbiology. OpenStax; 2016. 9.2 Oxygen Requirements for Microbial Growth.
7. Parker N, Schneegurt M, Thi Tu AH, et al. Microbiology. OpenStax; 2016. 15.2 How Pathogens Cause Disease.
8. Clark MA, Douglas M, Choi J. Biology 2e. OpenStax; 2018. 7.4 Oxidative Phosphorylation.
9. Clark MA, Douglas M, Choi J. Biology 2e. OpenStax; 2018. 14.2 DNA Structure and Sequencing.
10. Escherichia coli. Wikipedia, citing Encyclopaedia Britannica and Kubitschek HE, J Bacteriol 1990.

The outer membrane is one reason gram-negatives are harder to reach, and some drugs are built to pass it: cefepime, for one, carries a positive charge beside its negative one, which lets it through the porins faster than other cephalosporins. It is also why the glycopeptides, far larger molecules, reach only gram-positives.

How bacteria resist

• β-Lactamases, the main way, above all in gram-negatives. They open the ring before it reaches the PBP. Gram-positives such as Staphylococcus aureus release theirs outside the cell; gram-negatives keep theirs in the periplasm. Their genes often travel on plasmids, between species.
• PBPs they bind poorly. The mecA gene of methicillin-resistant S. aureus (MRSA) codes for PBP2a, which goes on cross-linking the wall when the other PBPs are blocked. Penicillin-resistant pneumococci have altered PBPs too. In gram-positives, this is the main way.
• Less getting in. A gram-negative can make fewer porins, or change them, so less drug reaches the periplasm.
• Efflux pumps, which push the drug back out across the outer membrane.

The β-lactamases fall into four classes by their structure. Classes A, C and D have a serine in the active site; class B, the metallo-β-lactamases, use zinc.

β-Lactamase inhibitors

A β-lactamase inhibitor binds the enzyme in the drug's place and inactivates it, so the partner reaches its PBP. Clavulanic acid, sulbactam, tazobactam and enmetazobactam are β-lactams themselves, with little antibacterial activity of their own; avibactam, relebactam and vaborbactam are not β-lactams.

None of them blocks the metallo-β-lactamases. Clavulanate, sulbactam, tazobactam and enmetazobactam don't block AmpC usefully, nor the carbapenemases.

04Clinical indications

β-Lactams are among the most used antibiotics, and the family is chosen by the bacteria it has to reach. The topics after this one give each family's uses in full.

Where killing is needed against enterococci, as in enterococcal endocarditis, a β-lactam is given with a partner and the two kill together: ampicillin with gentamicin, or ampicillin with ceftriaxone (two β-lactams that block different PBPs).

05Adverse drug reactions

β-Lactams are among the safest antibiotics, which is why so many are given. Their adverse reactions are mostly those of the whole class, and allergy comes first.

• Life-threatening
  Anaphylaxis. The gravest of the immediate, IgE-mediated reactions, which usually start within an hour of a dose. It is rare, in about 4 to 15 patients in 100,000.
• Serious
  Other immediate reactions: urticaria, angioedema and bronchospasm, IgE-mediated too and as quick to come on. Swelling of the throat or bronchospasm can be the start of anaphylaxis, and is treated as anaphylaxis.
• Life-threatening
  Severe skin reactions, such as Stevens–Johnson syndrome and toxic epidermal necrolysis. Delayed, T-cell reactions, and rare.
• Mild
  Delayed rashes, mostly maculopapular. T-cell reactions that come hours to weeks later, usually after some days, and can begin after the course has ended. A rash with fever, blisters, a sore mouth or eyes, or peeling skin is treated as a severe reaction.
• Serious
  Clostridioides difficile colitis. β-Lactams disturb the gut's bacteria, and C. difficile can take their place.
• Serious
  Neurotoxicity at high doses, especially when the kidneys clear the drug slowly: confusion, myoclonus and seizures, most with penicillin G, cefepime and imipenem.
• Serious
  Blood and kidney. β-Lactams can cause immune haemolytic anaemia, rarely fatal with ceftriaxone, and neutropenia, mostly on long, high-dose courses, so the blood count is checked on a long course. They can also cause interstitial nephritis.

Allergy and cross-reactivity

Cross-reactivity between penicillins and cephalosporins is lower than once thought. Early cephalosporins were contaminated with penicillin, which gave the old figure of 10%; it is now put at about 2%, lower still with carbapenems, and it follows the R1 side chain more than the shared ring. A penicillin and a cephalosporin with the same or a similar side chain, such as ampicillin and cefalexin, are the ones to avoid together. Aztreonam rarely cross-reacts with the other β-lactams; the clear exception is ceftazidime, which has the same side chain.

report a penicillin allergy

10%of patientsreport a penicillin allergy

were not allergic when tested, in one series of inpatients

95%of themwere not allergic when tested, in one series of inpatients

between penicillins and cephalosporins, set mostly by the R1 side chain

2%cross-reactivitybetween penicillins and cephalosporins, set mostly by the R1 side chain

06Side effects

At usual doses, what patients notice most comes from the gut, whose bacteria every β-lactam disturbs.

• Mild
  Diarrhoea, the commonest. Diarrhoea that is severe or bloody, or goes on, may be C. difficile (above).
• Mild
  Nausea, and less often vomiting.
• Mild
  Thrush, in the mouth or the vagina, for the same reason as the diarrhoea, most often with the broader drugs, such as co-amoxiclav.

07Contraindications

• Contraindicated
  An allergy to the drug's own family. A patient allergic to a penicillin is given no penicillin. One allergic to a cephalosporin is given no cephalosporin by its licence, though an allergist may allow one with a different side chain.
• Contraindicated
  Anaphylaxis or a severe skin reaction to any β-lactam. After anaphylaxis, the licences of the penicillins, cephalosporins and carbapenems rule out the other β-lactams too, and the carbapenems' and aztreonam–avibactam's do after a severe skin reaction as well; plain aztreonam's asks only for care. In practice an allergist decides which other β-lactams, if any, are safe: cross-reactivity follows the side chain, and after a severe skin reaction that may be none.
• Caution
  A penicillin allergy label, without a severe reaction. Most labelled patients aren't allergic, so the label is checked first. A cephalosporin with a different side chain, or a carbapenem, is usually tolerated.
• Caution
  Kidney failure. The doses of most β-lactams are cut, or they build up toward neurotoxicity. The exceptions are those cleared partly in bile, such as ceftriaxone.
• Avoid
  Valproate, with a carbapenem. Carbapenems cut valproate levels by 60 to 100% within about two days, and raising the valproate dose may not make up for it. Another antibiotic is chosen, or, if a carbapenem is needed, another anticonvulsant is added.
• Caution
  Methotrexate, with a penicillin. Penicillins slow its excretion and can make it toxic, so its levels are watched.
• Caution
  Warfarin. Amoxicillin and ceftriaxone can raise the INR, so it is checked when the antibiotic starts and when it stops.

08Pregnancy and lactation

Penicillins and cephalosporins are among the antibiotics of choice in pregnancy, which many other antibiotics are not, and are used in breastfeeding too.

• Compatible
  Penicillins in pregnancy. Penicillin V, amoxicillin and co-amoxiclav are commonly prescribed, with no concern that they harm the baby, and no extra monitoring needed afterwards. The broader ones, such as piperacillin–tazobactam, have fewer data.
• Compatible
  Cephalosporins in pregnancy. Most studies show no harm to the baby. An occasional link with heart defects after use early in pregnancy is not borne out by most studies.
• Avoid
  Co-amoxiclav when the membranes rupture before term. Given to prevent infection after preterm prelabour rupture of the membranes, it was linked to necrotising enterocolitis in the newborn, so another antibiotic is used.
• Caution
  Carbapenems in pregnancy. There are few human data. Animal studies of meropenem and ertapenem show no harm, but imipenem–cilastatin increased embryo loss in monkeys. They are kept for serious infections that need them, and meropenem's licence prefers to avoid it, as a precaution.
• Avoid
  Aztreonam in pregnancy. There are few human data, though animal studies show no harm. Its licence lists pregnancy as a contraindication, yet allows it when clearly needed, so another drug is used if one will do.
• Compatible
  Breastfeeding. β-Lactams pass into milk in small amounts, and those given only by injection, such as ceftriaxone and the carbapenems, are barely absorbed from the baby's gut. The baby may get diarrhoea or thrush, and rarely a rash.