Antibiotics in clinical use

Beta-lactam antibiotics
Penicillins work by inhibiting peptidoglycan cross-linkage. Modifications to the penicillins have extended their antibacterial spectrum and improved absorption. Penicillins now include:

• natural penicillins (e.g. benzylpenicillin, penicillin V);
• penicillinase-resistant penicillin (e.g. flucloxacillin);
• aminopenicillins (e.g. ampicillin-like agents);
• expanded-spectrum penicillins (e.g. piperacillin);
• penicillins combined with β-lactamase inhibitors (e.g. amoxicillin and clavulanate, known as co-amoxiclav).

Oral absorption varies: benzylpenicillin (penicillin G) is unstable in the presence of gastric acid and must be given intravenously, but penicillin V is stable and can be given orally. The aminopenicillins and flucloxacillin are also absorbed orally, while the remaining agents must be given intravenously.

Penicillins are secreted by the kidney and have a short half-life. They are distributed in extracellular fluid, but do not cross the blood-brain barrier unless the meninges are inflamed.

Cephalosporins
Cephalosporins are closely related to penicillins. They are all active against Gram-positive organisms and later compounds have activity against Gram-negative bacteria including Pseudomonas.

Monobactams
The monobactams are related to penicillins and cephalosporins. They have a broad spectrum of activity, including against anaerobes. Imipenem and meropenem have antipseudomonal effects. They must be given intravenously.

Aminoglycosides
Aminoglycosides act by preventing translation of mRNA into proteins. They are given parenterally, are limited to the extracellular fluid and are excreted in the urine. Aminoglycosides are toxic to the kidney and eighth cranial nerve at amounts close to therapeutic levels, which necessitates careful monitoring of serum concentrations.

Glycopeptides
The glycopeptides (vancomycin and teicoplanin) have the following characteristics.

• They inhibit peptidoglycan cross-linking in Gram-positive organisms only.
• Resistance to them is rare but sometimes found in enterococci (glycopeptide-resistant enterococci - GRE) and in some Staphylococcus aureus.
• Administration is intravenous or intraperitoneal; they are not absorbed orally. The exception is the oral use of vancomycin to treat pseudomembranous colitis.
• They are distributed in the extracellular fluid, but do not cross the blood-brain barrier unless there is meningeal inflammation.
• Excretion is via the kidney.

Daptomycin
Daptomycin, a new agent with a long half-life, is very active against Gram-positive organisms demonstrating more rapid killing in vitro. Its mode of action is uncertain.

Quinolones

• Quinolones act by inhibiting bacterial DNA gyrase.
• The early quinolones did not attain high tissue levels and were used only for urinary tract infections.
• Fluorine modification (fluoroquinolones) has made them active against Gram-negative pathogens including Chlamydia.
• Ciprofloxacin has activity against Pseudomonas spp.
• Quinolones are well absorbed orally, are widely distributed and penetrate cells well.
• Newer agents (e.g. moxifloxacin) are active against Gram-positive pathogens, including Streptococcus pneumoniae and Mycobacterium tuberculosis.

Macrolides
The macrolides (erythromycin, azithromycin and clarithromycin) bind to the 50S ribosome, interfering with protein synthesis; they are active against Gram-positive cocci, many anaerobes (but not Bacteroides), Mycoplasma and Chlamydia. They are absorbed orally, distributed in the total body water, cross the placenta, are concentrated in macrophages, polymorphs and the liver and are excreted in the bile. Erythromycin may cause nausea. The newer macrolides (e.g. azithromycin) have more favourable pharmacokinetic and toxicity profiles.

Streptogramins
Pristinamycin is a bactericidal semisynthetic streptogramin consisting of quinupristin and dalfopristin. It acts by preventing peptide bond formation, which results in release of incomplete polypeptide chains from the donor site. It is active against a broad range of Gram-positive pathogens and some Gram-negatives, such as Moraxella, Legionella, Neisseria meningitidis and Mycoplasma. It is used mainly for the treatment of resistant Gram-positive infections (e.g. GRE and glycopeptide-intermediate S. aureus [GISA]).

Oxazolidinones
The oxazolidinones (e.g. linezolid) inhibit protein synthesis at the 50S ribosomal subunit. They are most active against Gram-positive bacteria and are used mainly for the treatment of resistant Gram-positive infections. Linezolid is well absorbed orally and concentrated in the skin.

Metronidazole
The main features of metronidazole are that it is:

• active against all anaerobic organisms;
• a receiver of electrons under anaerobic conditions, so forms toxic metabolites that damage bacterial DNA;
• also active against some species of protozoa, including Giardia, Entamoeba histolytica and Trichomonas vaginalis;
• absorbed orally and can be administered parenterally;
• widely distributed in the tissues, crossing the blood-brain barrier and penetrating into abscesses;
• metabolized in the liver and excreted in the urine;
• well tolerated, except that it cannot be taken with alcohol.

Tetracyclines

• Tetracyclines act by inhibition of protein synthesis by locking tRNA to the septal site of mRNA.
• They are active against many Gram-positive and some Gramnegative pathogens, Chlamydia, Mycoplasma, Rickettsia and treponemes, Plasmodium and Entamoeba histolytica.
• Doxycycline is absorbed orally, has a long half-life and is widely distributed; adequate therapeutic levels may be obtained by a once-daily dosage.
• The newer tetracyclines such as tigecycline are used to treat multiresistant Gram-negative infections.

Sulphonamides and trimethoprim
Sulphonamides and trimethoprim act by inhibiting the synthesis of tetrahydrofolate. They are now rarely used in the treatment of bacterial infections but have an important role in the management of Pneumocystis jiroveci and protozoan infections including malaria. Sulphonamides can be given intravenously and are well absorbed when given orally. They are widely distributed in the tissues and cross the blood-brain barrier. They are metabolized in the liver and excreted via the kidney.