Carbapenems and monobactams. Glycopeptides

01Drug classification

Three groups act on the same wall. The carbapenems and the monobactam are β-lactams; the glycopeptides and the other cell wall inhibitors are not.

How the carbapenems differ

Carbapenems descend from thienamycin, made by the soil bacterium Streptomyces cattleya. Their five-membered second ring has a carbon where penicillins have sulfur, and where penicillins and cephalosporins carry an acylamino side chain on the β-lactam ring, carbapenems carry a hydroxyethyl group, and their ring junction is trans where penicillins' is cis, which puts that group on the opposite face. That group helps keep β-lactamases off the ring, one reason carbapenems reach so much.

The glycopeptides, fosfomycin and bacitracin

Vancomycin was isolated in 1953 from Amycolatopsis orientalis, a bacterium found in a soil sample; teicoplanin, from Actinoplanes teichomyceticus, followed some 30 years later. Vancomycin is a chain of seven amino acids cross-linked into a rigid cup, with sugars attached. Teicoplanin is a lipoglycopeptide: its fatty tail anchors it in the bacterial membrane beside lipid II, and it is used outside the US. The newer lipoglycopeptides, telavancin, dalbavancin and oritavancin, carry side chains that add potency and, for the last two, a half-life of one to two weeks.

Fosfomycin, described in 1969 from Streptomyces fradiae, is a small molecule that looks like phosphoenolpyruvate, one of the wall's first raw materials, and is related to no other antibiotic class. Bacitracin is a mix of cyclic peptides, named, with her surname misspelled, after Margaret Treacy, the girl from whose leg wound its Bacillus was grown in 1943.

02Pharmacokinetics

No carbapenem is absorbed by mouth. Like other β-lactams, they leave mostly through the kidneys, and their doses are cut in kidney failure. Dehydropeptidase I, on the brush border of the proximal tubule, breaks imipenem down, so it is given with cilastatin, which blocks the enzyme; meropenem and ertapenem are stable to it. Carbapenems are thought to block the enzyme (acylpeptide hydrolase) that turns valproate glucuronide back into valproate, so valproate is cleared several times faster and its levels fall fast, often below the therapeutic range.

Aztreonam is given intravenously or intramuscularly, and by inhalation for Pseudomonas in the lungs of people with cystic fibrosis.

Glycopeptides are poorly absorbed from the gut, so they are given by injection, except when the target is in the gut: by mouth, vancomycin stays in the lumen. Teicoplanin can be given intravenously or intramuscularly, once a day after loading doses. Dalbavancin and oritavancin have half-lives long enough for one or two doses to treat a skin infection.

Fosfomycin by mouth is fosfomycin trometamol, a 3 g sachet taken once on an empty stomach. It leaves unchanged in the urine, which it keeps above the MIC of most E. coli for a day or more, so one dose treats cystitis. Intravenously, as fosfomycin disodium, it reaches most tissues, bone and the cerebrospinal fluid among them, but each gram brings about 14 mmol of sodium.

Bacitracin is used only on the skin and in the eye, from which little is absorbed.

Dosing vancomycin by levels

Vancomycin leaves through the kidneys and builds up when they fail. Too little fails to cure, too much harms the kidney, so its dose is adjusted to blood levels. Dosing now often aims for a 24-hour area under the curve of 400 to 600 mg·h/L, estimated from one or two levels, rather than the trough of 15 to 20 mg/L once used; dosing by AUC is linked to less kidney injury.

the target 24-hour AUC of vancomycin in serious MRSA infection

400 to 600mg·h/Lthe target 24-hour AUC of vancomycin in serious MRSA infection

valproate is cleared with a carbapenem, in one model

4.5times fastervalproate is cleared with a carbapenem, in one model

03Pharmacodynamics

Carbapenems

Carbapenems bind the PBPs as every β-lactam does. They cover most gram-positives, gram-negatives and anaerobes: streptococci, MSSA, E. faecalis (imipenem best), Enterobacterales including those with ESBLs or AmpC, Pseudomonas, Acinetobacter and Bacteroides. They don't reach MRSA, Enterococcus faecium, Stenotrophomonas maltophilia or the atypical bacteria.

Gram-negatives resist carbapenems with carbapenemases (KPC in class A, the metallo-β-lactamases NDM, VIM and IMP in class B, OXA-48 in class D), often together with fewer porins: Pseudomonas aeruginosa that loses its OprD porin resists imipenem. Efflux pumps and altered PBPs add to it. Newer combinations restore some activity: meropenem–vaborbactam and imipenem–relebactam against KPC, ceftazidime–avibactam against KPC and OXA-48. None of these inhibitors blocks the metallo-β-lactamases.

Aztreonam

Aztreonam binds PBP3 of aerobic gram-negatives, which makes them grow into filaments and burst. It reaches Enterobacterales, Pseudomonas aeruginosa, H. influenzae and Neisseria, and does nothing for gram-positives or anaerobes.

It is stable to metallo-β-lactamases, but broken by ESBLs, AmpC and KPC, which the same bacteria often carry. Aztreonam–avibactam, approved in the EU in 2024 and the US in 2025, protects it from those. Where it isn't available, ceftazidime–avibactam given together with aztreonam does the same.

Glycopeptides

A glycopeptide binds the D-Ala-D-Ala end of lipid II, the building block on its way into the wall, by a set of hydrogen bonds. Sitting on the substrate, it blocks the glycosyltransferases from adding the unit to the chain and the transpeptidases from cross-linking it. β-Lactams block the enzyme; glycopeptides hide its substrate.

Their size keeps them out of gram-negatives: they can't cross the outer membrane to reach lipid II. They kill staphylococci and streptococci slowly, and only hold back enterococci.

Enterococci with the vanA or vanB gene clusters build their precursors to end in D-alanyl-D-lactate instead. One hydrogen bond is lost and an oxygen now repels the drug, so vancomycin binds about 1000 times less well: these are vancomycin-resistant enterococci (VRE). vanA can pass from enterococci to S. aureus, but vancomycin-resistant S. aureus remains rare. Vancomycin-intermediate S. aureus (VISA) resists in another way, with a thickened wall that holds the drug back. Teicoplanin still acts on enterococci with vanB, and oritavancin binds D-Ala-D-Lac as well, and acts on some VRE.

Fosfomycin and bacitracin

Fosfomycin works in the cytoplasm, at the first step of the wall. It enters through the bacterium's own sugar-phosphate transporters and, looking like phosphoenolpyruvate, binds MurA (enolpyruvyl transferase) for good, so the first building block, UDP-N-acetylmuramic acid, can't be made. It kills, and reaches E. coli, ESBL producers among them, Enterococcus faecalis and S. aureus, MRSA included. Bacteria quickly become resistant by losing those transporters, which is why it is given alone only for cystitis and with another antibiotic for anything more serious; its unique target means no cross-resistance with other classes.

Bacitracin works at the membrane: it binds the lipid carrier, bactoprenol, as a pyrophosphate, so the carrier can't be freed to fetch the next unit (the β-lactam overview's steps show where). It reaches gram-positives, staphylococci and streptococci, and is often combined with polymyxin B and neomycin, which reach gram-negatives.

04Clinical indications

Aztreonam is the β-lactam for aerobic gram-negative infections in patients with a severe β-lactam allergy; inhaled, it treats Pseudomonas in the lungs in cystic fibrosis, and with avibactam, Enterobacterales that make metallo-β-lactamases. Teicoplanin treats serious gram-positive infections of the skin, bones and joints, lungs, urinary tract and heart valves, and by mouth C. difficile.

Fosfomycin by mouth, one 3 g dose, treats uncomplicated cystitis in women and in girls over 12, and two doses cover a biopsy of the prostate through the rectum. It is not used for pyelonephritis, or for urinary infections in men, which count as complicated, and in the UK it is a second choice for cystitis, after nitrofurantoin or trimethoprim; in the EU, since 2020, intravenous fosfomycin is kept for serious infections when other antibiotics aren't suitable. Bacitracin treats minor infections of the skin and eye.

05Adverse drug reactions

Carbapenems and aztreonam share the β-lactams' reactions, and cross-reactivity between carbapenems and penicillins is rare. The glycopeptides' are their own.

• Life-threatening
  Anaphylaxis to a carbapenem, aztreonam or fosfomycin, rarely; with the first two, as with any β-lactam.
• Serious
  Seizures, with imipenem above all. At high doses it lowers the seizure threshold, especially in patients with lesions of the central nervous system or kidney failure. Meropenem does so less; ertapenem can too, mostly in older patients with brain disease or poor kidneys.
• Serious
  C. difficile colitis, with carbapenems as with other broad antibiotics, and with fosfomycin.
• Serious
  Kidney injury with vancomycin, its main risk: more likely with high levels, long courses, other drugs that harm the kidney such as aminoglycosides, and when it is given with piperacillin–tazobactam. Teicoplanin can harm the kidney too, though less often.
• Serious
  Hearing damage, rarely, with vancomycin and teicoplanin: more likely with deafness already, too high doses or another drug that harms the ear. It can be lasting.
• Serious
  Neutropenia with long courses of vancomycin.
• Life-threatening
  Severe drug rashes, rarely. Vancomycin is the antibiotic behind up to 40% of cases of DRESS, drug reaction with eosinophilia and systemic symptoms, and after one it is never given again.
• Mild
  The vancomycin infusion reaction, once called red man syndrome: flushing and itching of the face, neck and upper body, sometimes with low blood pressure, during or soon after a fast infusion. Vancomycin releases histamine from mast cells directly; it is not an IgE allergy. Slowing the infusion, with antihistamines if needed, usually prevents it. Teicoplanin causes it rarely, even at the first dose.
• Serious
  Salt and potassium with intravenous fosfomycin. Its sodium load can raise the sodium and overload the circulation, in heart failure above all, and it can lower the potassium, so both are checked.
• Serious
  Kidney injury from bacitracin given into the body, which is why it is used only on the skin and eye; in 2020 bacitracin for injection was withdrawn in the US, for its harm to the kidney and anaphylaxis.
• Mild
  Contact allergy to bacitracin, an itchy dermatitis where it is applied, among the commoner allergies to an ointment.
• Life-threatening
  Anaphylaxis to bacitracin, rarely, even from an ointment or a wound wash.

06Side effects

• Mild
  Diarrhoea and nausea, with carbapenems. With ertapenem they are among the commonest, in about 5 and 3 patients in 100.
• Mild
  Trouble at the infused vein, phlebitis among it: with ertapenem in about 5 patients in 100, and with vancomycin too.
• Mild
  Diarrhoea, nausea, indigestion and headache after fosfomycin by mouth, the commonest complaints, with dizziness, abdominal pain and vulvovaginitis.

07Contraindications

• Contraindicated
  An allergy to any carbapenem, or, in the licence, a severe reaction such as anaphylaxis or a severe skin reaction to another β-lactam. Allergy guidance is less strict: after a penicillin or cephalosporin allergy, a carbapenem is given without testing, unless the reaction was a severe skin or organ reaction.
• Avoid
  A carbapenem with valproate. Valproate levels fall by 60 to 100% within about two days, which can bring back seizures, and raising the valproate dose doesn't reliably make up for it; the licence calls the combination unmanageable. Another antibiotic is the usual answer. If a carbapenem can't be avoided, another antiepileptic is added and kept for about a week after the carbapenem stops.
• Caution
  Imipenem with epilepsy, a brain lesion or kidney failure, because of the seizures. Meropenem lowers the threshold less.
• Contraindicated
  An allergy to aztreonam. Allergy guidance allows the other β-lactams, ceftazidime apart.
• Avoid
  Aztreonam after an allergy to ceftazidime, which has the same R1 side chain.
• Caution
  Aztreonam in a severe allergy to a penicillin, a carbapenem or a cephalosporin other than ceftazidime. It does not cross-react with them, so it is the β-lactam for these patients, and allergy guidance gives it without testing. Its licence asks for care, and aztreonam–avibactam's is stricter, ruling it out after a severe reaction to any other β-lactam.
• Contraindicated
  An allergy to the glycopeptide itself. A vancomycin infusion reaction is not an allergy, and doesn't rule out vancomycin or teicoplanin.
• Contraindicated
  A severe skin reaction to vancomycin before, such as DRESS or toxic epidermal necrolysis. It is never given again.
• Contraindicated
  Vancomycin into a muscle, which risks necrosis where it is injected.
• Caution
  The vancomycin infusion. It is given diluted, at no more than 10 mg a minute and over an hour at least, to prevent the infusion reaction. Around anaesthesia it is best given before induction, at 5 mg/mL or less, with the heart monitored.
• Caution
  Vancomycin with other drugs that harm the kidney or the ear, such as aminoglycosides, loop diuretics, amphotericin B and cisplatin, or with piperacillin–tazobactam, which raises the risk of kidney injury when the two are given together. Levels, kidney function and, on long courses, hearing are watched.
• Caution
  Teicoplanin after an allergy to vancomycin. Cross-reactions, fatal anaphylaxis among them, can happen.
• Contraindicated
  An allergy to fosfomycin or bacitracin.
• Avoid
  Fosfomycin by mouth in severe kidney failure (creatinine clearance under 10 mL/min), when it isn't recommended.
• Avoid
  Metoclopramide with fosfomycin by mouth, which lowers its levels.
• Caution
  Intravenous fosfomycin with heart failure, high blood pressure or oedema, because of its sodium; the salt in the diet is cut and the sodium and potassium watched.
• Contraindicated
  Bacitracin into the body. It is for the skin and eye only.

08Pregnancy and lactation

• Caution
  Carbapenems in pregnancy. There are few human data. Animal studies of meropenem and ertapenem show no harm; imipenem–cilastatin raised embryo loss in pregnant monkeys, though it caused no birth defects. A carbapenem is given when a serious infection needs one; meropenem's licence prefers to avoid it, as a precaution.
• Avoid
  Aztreonam in pregnancy. It crosses the placenta; there are few human data, and animal studies show no harm. Its own licence lists pregnancy as a contraindication, yet also allows it when clearly needed, and aztreonam–avibactam's allows it when clearly indicated. So another drug is used if one will do.
• Caution
  Vancomycin in pregnancy. Given when clearly needed, with its blood levels watched closely to limit any harm to the fetus. Animal studies at several times the human dose showed none.
• Avoid
  Teicoplanin in pregnancy. There are few human data, and in rats high doses raised stillbirths and newborn deaths. Harm to the fetus's inner ear and kidneys can't be ruled out, so it is not used unless clearly necessary.
• Compatible
  Fosfomycin by mouth in pregnancy. One dose for cystitis is possible, and in France it is the first choice until the culture is back, though UK practice doesn't list it. Studies of its use early in pregnancy found no rise in birth defects; there are fewer data later on. Its licence is more cautious, allowing it only if clearly necessary.
• Avoid
  Intravenous fosfomycin in pregnancy, given only when better-suited drugs can't be.
• Compatible
  Bacitracin on the skin, in pregnancy and breastfeeding: so little is absorbed that it is unlikely to reach the baby in amounts that matter.
• Compatible
  Breastfeeding. Carbapenems, aztreonam and vancomycin pass into milk in amounts too small to matter, and teicoplanin, measured in one mother's milk, does too; so does fosfomycin. All are hardly absorbed from the baby's gut, except perhaps in premature and newborn babies. Their licences are more cautious: ertapenem's and aztreonam's say not to breastfeed during treatment, and the others' to weigh it.