13th March 2024

Main classes of antibiotics

Beta-lactams

β-lactam antibiotics work by binding to transpeptidases, which are required for cross-linking of the peptidoglycan cell wall. They include several classes of groups including penicillins, cephalosporins, monobactams and carbapenems.

Penicillins

The spectrum of activity ranges from the narrow spectrum (penicillin V) to the newer semi-synthetic, extended-spectrum penicillins. β-lactamase inhibitors such as clavulanic acid and tazobactam protect the drug from being broken down, in turn, widening its coverage to β-lactamase producing bacteria. Amoxicillin and clavulanic acid combined have a wide spectrum of activity against gram negatives, positives and certain anaerobes, whereas piperacillin and tazobactam cover the same but with added antipseudomonal activity.

Adverse effects include rashes such as erythema multiforme, Steven Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The latter two are rare, acute, and potentially fatal mucocutaneous reactions with epidermal detachment. Penicillins can lead to hypersensitivity reactions causing rash, wheezing, coughing, tightness of the chest and angioedema. There is a risk of Clostridium difficile colonisation, drug-induced liver injury and anaphylaxis, which is higher in those with a history of atopy.

Cephalosporins

Cephalosporins are broad-spectrum antibiotics that are classified into five generations, with successive generations having increased gram-negative activity and the ability to cross the blood-brain barrier. As penicillins and cephalosporins both share a β-lactam ring, cross-reactivity can occur. There is around a 2% risk depending on the cephalosporin generation. With the wide spectrum of activity, there is an increased risk of C. difficile.

Glycopeptides

Glycopeptides such as vancomycin, dalbavancin and teicoplanin work by binding to transpeptidases (d-alanyl-d-alanine), which are required for cross-linking the cell wall. They have activity against gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA).

When used, there is an increased risk of nephrotoxicity, ototoxicity, thrombophlebitis and adverse skin reactions including SJS/TEN. Vancomycin has been associated with an infusion-related reaction named vancomycin flushing syndrome (VFS), leading to an erythematous rash affecting the upper body, pruritus and hypotension.

Macrolides

These drugs bind to the 50S ribosomal subunit interfering with protein synthesis. They have broad spectrum activity against gram-negative, gram-positive and mycobacteria. They are particularly useful in those with penicillin-resistant staphylococci and in pregnancy. Clindamycin, a lincosamide, is closely related to macrolides but has a narrower spectrum covering gram-positive and anaerobic bacteria.

Macrolides, except azithromycin, inhibit the CYP3A4 isoenzyme, potentiating the effects of certain drugs, including carbamazepine, ciclosporin and simvastatin. They are also known to cause gastrointestinal symptoms such as discomfort, nausea and vomiting. Other adverse effects include the unmasking or worsening of myasthenia gravis and QT prolongation. Erythromycin can cause cholestatic drug-induced liver injury, which tends to be self-limiting after cessation of the drug.

Chloramphenicol

This potent agent works through inhibiting protein synthesis by binding to the ribosomal 50S subunit. It has a wide spectrum of activity against gram-positive, gram-negative and anaerobic bacteria.

The adverse effects preclude the widespread use of this drug. It can cause bone marrow toxicity, aplastic anaemia, optic neuritis and hypersensitivity reactions. If given to premature babies and those <2 weeks of age, there is a risk of grey baby syndrome. This occurs due to immature glucuronosyltransferase and presents with the neonate having an ashen grey colour, abdominal distension, pallid cyanosis and circulatory collapse. It is also known to inhibit the CYP2C19 and CYP3A4 isoenzymes, potentiating the effects of warfarin, clopidogrel and phenytoin.

Tetracyclines

These drugs bind to the 30S ribosomal subunit, inhibiting protein synthesis and leading to activity against both gram-positive and negative bacteria. It is used to treat a wide variety of infections from respiratory, genital and many tropical diseases.

Tetracyclines are contraindicated in the latter half of pregnancy due to the risk of hepatotoxicity and in children < 12 years due to the risk of permanent teeth staining. One should be cautious of prescribing this drug in those with myasthenia gravis and systemic lupus erythematosus, as both can be exacerbated. Rarely, tetracyclines have been associated with an increased risk of idiopathic intracranial hypertension.

Aminoglycosides

Aminoglycosides bind to the 30S ribosomal subunit inhibiting protein synthesis. They include gentamicin, amikacin, tobramycin and streptomycin. These drugs have activity against gram-negative bacteria, including pseudomonas and certain gram-positive species. Blood concentration monitoring avoids both excessive and subtherapeutic levels.

The main adverse effects include nephrotoxicity, ototoxicity and acute neuromuscular blockade, particularly in those taking anaesthetic drugs or those with a history of myasthenia gravis.

Trimethoprim

This agent is a dihydrofolate reductase inhibitor which disrupts bacterial folate synthesis. It has activity against gram-positive and gram-negative bacteria. It can be combined with sulphonamide or separately with sulfamethoxazole to make co-trimoxazole, which is used to treat and prevent Pneumocystis pneumonia (PCP).

Adverse effects include bone marrow suppression, folate deficiency and SJS. Concomitant use of this agent with other dihydrofolate reductase inhibitors, such as methotrexate, leads to synergistic folate antagonism. This can cause life-threatening myelosuppression and nephrotoxicity.

Quinolones/Fluoroquinolones

These agents inhibit nucleic acid synthesis by inhibiting DNA gyrase and topoisomerase IV. Examples include ciprofloxacin and levofloxacin. They have a broad spectrum of activity against gram-positive, gram-negative and mycobacteria.

There are several notable adverse effects including prolongation of the QT interval, CNS symptoms (headache, dizziness and insomnia), and worsening or unmasking myasthenia gravis. There is a risk of tendon rupture, especially in older people and those with renal impairment. It should not be used in those with a history of tendon disorders or young children. It is known to inhibit CYP1A and CYP3A, potentiating the effects of theophylline, ciclosporin and warfarin.

Metronidazole

This drug directly inhibits bacterial DNA, causing breakage and destabilisation. It has strong activity against protozoa and anaerobic bacteria, including Clostridium.

When taken with ethanol, it has been associated with the disulfiram-like reaction resulting in nausea, blurred vision, sweating and facial flushing. Metronidazole penetrates the blood-brain barrier and can rarely lead to neurotoxicity, presenting as poor balance, reduced GCS and seizures.

Oxazolidinones

Oxazolidinones such as linezolid and tedizolid work by binding to the 23S of the 50S ribosomal subunit, which inhibits protein synthesis. It is a synthetic antibiotic with excellent gram-positive coverage, including MRSA and glycopeptide-resistant enterococci.

These drugs can cause myelosuppression and hepatotoxicity. Prolonged use of linezolid increases the risk of optic neuropathy and lactic acidosis.

An overview of the main antibiotic classes

References

• Derek G. Waller, Anthony Sampson, Andrew Hitchings, Medical Pharmacology and Therapeutics, Sixth Edition, 6th edition (Elsevier, 2021)
• Letourneau, Hooper and Hall, Beta-lactam antibiotics: Mechanisms of action and resistance and adverse effects (2023) https://www.uptodate.com/contents/beta-lactam-antibiotics-mechanisms-of-action-and-resistance-and-adverse-effects
• Richard Goering and Hazal Dockrell, Mims’ Medical Microbiology and Immunology, 6e edn: Elsevier, 2018).