Mechanism of action

Penicillins are bactericidal. Structurally they possess a thiazolidine ring connected to a β-lactam ring. The side chain from the β-lactam ring determines the unique pharmacological properties of the different penicillins.

Penicillins bind to penicillin-binding proteins on susceptible microorganisms. This interaction results in inhibition of peptide cross-linking within the microbial cell wall, and indirect activation of autolytic enzymes. The combined result is lysis (see Fig. 11.2).

Spectrum of activity

Penicillins exhibit considerable diversity in their spectrum of activity (Fig. 11.3).

Fig. 11.3 Drugs of choice and alternatives for selected common bacterial pathogens

Benzylpenicillin is active against aerobic Gram-positive and Gram-negative cocci and many anaerobic organisms. Many staphylococci are now resistant to benzylpenicillin. Flucloxacillin is used against penicillin-resistant staphylococci as it is not inactivated by their β-lactamase. Phenoxymethylpenicillin is similar to benzylpenicillin but less active. Amoxicillin and ampicillin are broad-spectrum penicillins.

Route of administration

Benzylpenicillin must be administered parenterally as it is inactivated when given orally. Phenoxymethylpenicillin, flucloxacillin, amoxicillin and ampicillin are active when given orally. Consult the British National Formulary (BNF) for parenteral routes.

Contraindications

Known hypersensitivity to penicillins or cephalosporins.

Adverse effects

Generally very specific and safe antibiotics. Hypersensitivity reactions are the main adverse effect, including rashes (common) and anaphylaxis (rare). Neurotoxicity occurs at excessively high cerebrospinal fluid (CSF) concentrations. Diarrhoea is common, owing to disturbance of normal colonic flora.

Therapeutic notes

Resistance to penicillins is often due to production of β-lactamase by some microorganisms, which hydrolyses the β-lactam ring. This resistance gene is located in a plasmid and is transferable. Flucloxacillin is resistant to β-lactamase.

Mechanism of action

Cephalosporins are bactericidal. They are β-lactam-containing antibiotics and inhibit bacterial cell wall synthesis in a manner similar to the penicillins. Structurally cephalosporins possess a dihydrothiazine ring connected to the β-lactam ring that makes them more resistant to hydrolysis by β-lactamases than are the penicillins.

Spectrum of activity

The cephalosporins are broad-spectrum antibiotics that are second-choice agents for many infections (see Fig. 11.3).

Route of administration

Oral, intravenous, intramuscular. Consult the BNF.

Contraindications

Known hypersensitivity to cephalosporins or penicillins.

Adverse effects

Side-effects of the cephalosporins include hypersensitivity reactions, which occur in a similar and cross-reacting fashion to the penicillins. Diarrhoea is common, owing to disturbance of normal colonic flora. Nausea and vomiting may also occur.

Therapeutic notes

The cephalosporins can be inactivated by the β-lactamase enzyme, though the later-generation drugs are more resistant to hydrolysis.

Mechanism of action

Glycopeptides are bactericidal. They inhibit peptidoglycan synthesis, with possible effects on RNA synthesis (see Fig. 11.2).

Spectrum of activity

Vancomycin is active only against aerobic and anaerobic Gram-positive bacteria. Glycopeptides are reserved for resistant staphylococcal infections and Clostridium difficile in antibiotic-associated pseudomembranous colitis (see Fig. 11.3).

Route of administration

Glycopeptides are usually administered intravenously as they are not well absorbed orally. Oral administration is reserved for when a local gastrointestinal tract effect is required, e.g. in colitis.

Adverse effects

Side-effects of glycopeptides include ototoxicity and nephrotoxicity at high plasma levels, and fever, rashes and local phlebitis at the site of infection.

Therapeutic notes

Acquired resistance to vancomycin is rare, but reports of vancomycin-resistant enterococci are becoming more common.

Mechanism of action

Folate is an essential co-factor in the synthesis of purines and hence of DNA. Bacteria, unlike mammals, must synthesize their own folate from para-aminobenzoic acid (Fig. 11.2). This pathway can be inhibited at two points: the sulphonamides inhibit dihydrofolate synthetase, and are bacteriostatic while trimethoprim inhibits dihydrofolate reductase and are bacteriostatic.

Spectrum of activity

The sulphonamides are used for ‘simple’ urinary tract infections (UTIs). Trimethoprim and co-trimoxazole (trimethoprim and sulfamethoxazole) are used for UTIs and respiratory tract infections (see Fig. 11.3).

Route of administration

Oral, intravenous.

Contraindications

Pregnant women – as there is a theoretical teratogenic risk with antifolates. Neonates – as bilirubin displacement can damage the neonatal brain (kernicterus).

Adverse effects

Nausea, vomiting and hypersensitivity reactions, e.g. rashes, fever, Stevens–Johnson syndrome. The sulphonamides are relatively insoluble and can cause crystalluria, while trimethoprim can cause myelosuppression/agranulocytosis.

Therapeutic notes

Antifolates are often used in combined preparations as they have synergistic effects. Resistance is common and is due to the production of enzymes that have reduced affinity for the drugs. Resistance can be acquired on plasmids in Gram-negative bacteria.

Mechanism of action

Quinolones are bactericidal. They act by inhibiting prokaryotic DNA gyrase. This enzyme packages DNA into supercoils and is essential for DNA replication and repair (see Fig. 11.2).

Spectrum of activity

Ciprofloxacin has a broad spectrum of activity, while nalidixic acid is more narrowly active against Gram-negative organisms (see Fig. 11.3).

Route of administration

Oral, intravenous. Ciprofloxacin is so well absorbed orally that intravenous administration is rarely required unless the patient is unable to tolerate oral medication.

Contraindications

Quinolones should not be given with theophylline as theophylline toxicity may be precipitated.

Adverse effects

Gastrointestinal upset. Rarely, hypersensitivity and central nervous system (CNS) disturbances occur.

Mechanism of action

Aminoglycosides are bactericidal. They bind irreversibly to the 30S portion of the bacterial ribosome. This inhibits the translation of mRNA to protein and causes more frequent misreading of the prokaryotic genetic code (see Fig. 11.4).

Spectrum of activity

Aminoglycosides have a broad spectrum of activity but with low activity against anaerobes, streptococci and pneumococci (see Fig. 11.3). Streptomycin is used against Mycobacterium tuberculosis (p. 174).

Route of administration

Parenteral only.

Contraindications

Acute neuromuscular blockade can occur if an aminoglycoside is used in combination with anaesthesia or other neuromuscular blockers.

Adverse effects

Dose-related ototoxicity and nephrotoxicity at high plasma levels.

Therapeutic notes

Resistance to aminoglycosides is increasing and is primarily due to plasmid-borne genes encoding degradative enzymes.

Mechanism of action

Tetracyclines are bacteriostatic. They work by selective uptake into bacterial cells due to active bacterial transport systems not possessed by mammalian cells. The tetracycline then binds reversibly to the 30S subunit of the bacterial ribosome, interfering with the attachment of tRNA to the mRNA ribosome complex (see Fig. 11.4).

Spectrum of activity

Tetracyclines have broad-spectrum activity against Gram-positive and Gram-negative bacteria, as well as intracellular pathogens (see Fig. 11.3).

Route of administration

Oral, intravenous. Oral absorption is incomplete and can be impaired by calcium (e.g. milk), and magnesium or aluminium salts (e.g. antacids).

Contraindications

Tetracyclines should not be given to children or pregnant women.

Adverse effects

Gastrointestinal disturbances which are common after oral administration. In children, tetracyclines depress bone growth, and produce permanent discolouration of teeth.

Therapeutic notes

Resistance to tetracyclines is slow to develop, but is now widespread. In the majority of cases, resistance is due to decreased uptake of the drug, and is plasmid borne.

Mechanism of action

Chloramphenicol is both bactericidal and bacteriostatic, depending on the bacterial species. It reversibly binds to the 50S subunit of the bacterial ribosome, inhibiting the formation of peptide bonds (see Fig. 11.4).

Spectrum of activity

Chloramphenicol has a broad spectrum of activity against many Gram-positive cocci and Gram-negative organisms (see Fig. 11.3). Because of its toxicity, it is reserved for life-threatening infections, especially typhoid fever and meningitis.

Route of administration

Oral, intravenous.

Contraindications

Chloramphenicol should not be given to pregnant women or neonates.

Adverse effects

Myelosuppression, reversible anaemia. Neutropenia and thrombocytopenia may occur during chronic administration. Fatal aplastic anaemia is rare.

Neonates cannot metabolize chloramphenicol and ‘grey baby syndrome’ may develop, which comprises pallor, abdominal distension, vomiting and collapse.

Therapeutic notes

Resistance to chloramphenicol is due to a plasmid-borne gene encoding an enzyme that inactivates the drug by acetylation. Blood monitoring is necessary.

Mechanism of action

Macrolides are bacteriostatic/bactericidal. They reversibly bind to the 50S subunit of the bacterial ribosome, preventing the translocation movement of the ribosome along mRNA (see Fig. 11.3).

Spectrum of activity

Erythromycin is effective against most Gram-positive bacteria and spirochaetes. Clarithromycin is active against Haemophilus influenzae, Mycobacterium avium cellulare and Helicobacter pylori.

Route of administration

Oral, intravenous.

Adverse effects

Side-effects of erythromycin include gastrointestinal disturbance, which is common after oral administration. Liver damage and jaundice can occur after chronic administration.

Therapeutic notes

Resistance to erythromycin results from a mutation of the binding site on the 50S subunit. Erythromycin has a similar spectrum of activity to penicillin and is an effective alternative in penicillin-sensitive patients. Azithromycin can be given as a one-off dose for uncomplicated chlamydial infections of the genital tract.

Mechanism of action

Fusidic acid is a steroid that prevents binding of tRNA to the ribosome (Fig. 11.4).

Spectrum of activity

Fusidic acid has a narrow spectrum of activity, particularly against Gram-positive bacteria (see Fig. 11.3).

Route of administration

Oral, intravenous.

Adverse effects

Gastrointestinal disturbance. Skin eruptions and jaundice may occur.

Therapeutic notes

Resistance to fusidic acid can occur via mutation or by plasmid-borne mechanisms.

Mechanism of action

Similar to the macrolides.

Spectrum of activity

Clindamycin is active against Gram-positive cocci, including penicillin-resistant staphylococci, and many anaerobes.

Route of administration

Oral, parenteral.

Adverse effects

Antibiotic-associated (pseudomembranous) colitis; greater risk than for other antibiotics.

Therapeutic notes

Clindamycin is used for staphylococcal joint and bone infections.

Mechanism of action

Metronidazole is bactericidal. It is metabolized to an intermediate that inhibits bacterial DNA synthesis and degrades existing DNA. Its selectivity is due to the fact that the intermediate toxic metabolite is not produced in mammalian cells.

Spectrum of activity

Metronidazole is antiprotozoal (p. 183) and has antibacterial activity against anaerobic bacteria (see Fig. 11.3).

Route of administration

Oral, rectal, intravenous, topical.

Contraindications

Metronidazole should not be given to pregnant women.

Adverse effects

Mild headache, gastrointestinal disturbance. Adverse drug reactions occur with alcohol.

Therapeutic notes

Acquired resistance to metronidazole is rare. Tinidazole is similar to metronidazole but has a longer duration of action.

Mechanism of action

The mechanism of action of nitrofurantoin is uncertain though it possibly interferes with bacterial DNA metabolism.

Spectrum of activity

Nitrofurantoin is active against Gram-positive bacteria and Escherichia coli (see Fig. 11.3).

Route of administration

Oral; it reaches high therapeutic concentrations in the urine.

Adverse effects

Gastrointestinal disturbance. Pulmonary complications can occur with chronic therapy.

Therapeutic notes

Rarely, chromosomal resistance to nitrofurantoin can occur.

Mechanism of action

Bacitracin is a natural antibiotic, isolated from Bacillus subtilis, that inhibits bacterial cell wall formation.

Spectrum of activity

Bacitracin is similar in its spectrum of activity to penicillin (see Fig. 11.3).

Route of administration

Topical.

Adverse effects

Well tolerated when used topically. Serious nephrotoxicity can occur if it is used systemically

Therapeutic notes

Bacitracin is much less likely to cause hypersensitivity reactions than penicillin. Acquired resistance is rare.

Mechanism of action

Polymyxins are bactericidal. They are peptides that interact with phospholipids on the outer plasma cell membranes of Gram-negative bacteria, disrupting their structure. This disruption destroys the bacteria’s osmotic barrier, leading to lysis (Fig. 11.2).

Spectrum of activity

Polymyxins are active only against Gram-negative bacteria including Pseudomonas aeruginosa (see Fig. 11.3).

Route of administration

Intravenous, intramuscular, inhalation. Oral polymyxins are given to sterilise the bowel in neutropenic patients.

Adverse effects

Perioral and peripheral, paraesthesia, vertigo, nephrotoxicity, neurotoxicity

Therapeutic notes

Resistance to polymyxins is rare.