Introduction

Here, we offer an overview of the pharmacology of antimicrobial agents – specifically, those drugs deployed in the treatment of bacterial infections (see Pharmacology of Antifungal Drugs for an overview of antifungal drugs). There are many and varied classes of antibacterial drugs, some of which we have covered in other articles. Now, though, we bring all these threads together, as well as including other antimicrobial agents we haven’t yet covered. At the end of this article, you’ll find principles of antimicrobial therapy, as there are numerous clinical factors worth considering before prescribing any of these drugs. You’ll also find links to specific pages should you require more information about any one particular class.

Pharmacology of Antimicrobial Agents

When studying the pharmacology of antimicrobial agents, you’ll notice just how many classes and drugs we’re talking about. It’s quite an extensive range, and can be intimidating for many students having to commit much of this information to memory. We recommend focussing on the very basics – understanding the mechanism, the differences between various classes, and why they are used in the way they are – before dealing with anything more advanced.

In this section, we’ll go through the antimicrobial pharmacology of the following classes:

  1. Beta-lactam antibacterials (penicillins, cephalosporins, monobactams, carbapenems)
  2. Drugs affecting bacterial DNA (fluoroquinolones, metronidazole, nitrofurantoin)
  3. Drugs affecting protein synthesis (macrolides, aminoglycosides, tetracyclines, lincosamides, streptogramins, oxazolidinones)
  4. Drugs affecting bacterial metabolism (sulphonamides, trimethoprim)
  5. Drugs used for TB (rifampicin, isoniazid, pyrazinamide, ethambutol)
  6. Drugs used for leprosy (dapsone, clofazimine)

Our study of antimicrobial pharmacology is not intended to be exhaustive, but it does provide a convenient overview upon which the student can build their knowledge further. We’ll begin at once, with the beta-lactam antibacterials – one of the most prominent such classes.

  1. Beta-lactam antibacterials

There are four main classes of beta-lactam antibacterials:

…examples of which can be found in the infographic below. What unites all four classes is the presence of a beta-lactam ring – a structural component that plays an important role in their antibacterial capacity. It’s this ring that is the target of a frontal assault by enzymes called beta-lactamases, which seek to destroy the integrity of this ring and – by extension – eliminate any antibacterial power the drug happens to possess.

Many of these drugs are structurally designed to be resistant to beta-lactamase inactivation. Other drugs, such as amoxicillin, are combined with beta-lactamase inhibitors – such as clavulanic acid, the latter compound being responsible for protecting the beta-lactam ring against the unbridled vandalism caused by beta-lactamase. Below are infographics detailing the specifics of penicillins, cephalosporins, monobactams, and carbapenems.

Penicillins

Cephalosporins

Monobactams

Carbapenems

Before we finish up with the beta-lactam antibacterials, it’s worth mentioning some other drugs which work by disrupting the bacterial cell wall. These drugs include the glycopeptides and polymyxins. Polymyxins include the drug colistin, a drug which alters the cell membrane permeability – resulting in lysis of the bacteria. Polymyxins are bactericidal against Gram negative bacteria, including pseudomonas species.

Colistin is poorly absorbed from the gut, and is therefore commonly administered either topically or by inhalation. Colistin is eliminated unchanged by the kidney and has a half-life of around 6 hours. Unwanted effects with colistin include nephrotoxicity and renal impairment, neurotoxicity (dizziness, paraesthesia, and confusion), and bronchospasm or sore throat. This medicine is not, however, available in the US (only UK at the moment).

For more information on polymyxins and glycopeptides, see the infographics below:

Polypeptides

Glycopeptides

  1. Drugs affecting Bacterial DNA

When studying the pharmacology of antimicrobial agents, you’ll find that just about every main cellular avenue has been exploited – and this is no less true of bacterial DNA. There are numerous antibacterial members of this category, including:

Fluoroquinolones, for example, inhibit replication of bacterial DNA – doing so by blocking the activity of bacterial DNA gyrase and topoisomerase; enzymes essential to DNA replication and repair processes. Examples of fluoroquinolones include ciprofloxacin, moxifloxacin, and norfloxacin. More information about the fluoroquinolones can be found in the infographic below.

Quinolones

Nitrofurans

Metronidazole is not bactericidal in itself, but does become bactericidal when it’s reduced to an intermediate compound; a compound that terminally interferes with DNA synthesis, while also degrading existing bacterial DNA. Metronidazole (and tinidazole) are almost exclusively effective against anaerobes and protozoa (as these organisms contain the enzyme that converts metronidazole to its more active component).

Unwanted effects with metronidazole include nausea, vomiting, metallic taste, alcohol intolerance, and rash. Nitrofurantoin, too, must be activated – a process of reduction by the enzyme nitrofurantoin reductase. Nitrofurantoin is used in the treatment of bladder infections. It is mostly active against Gram positive cocci and E. coli. Unwanted effects include gastrointestinal disturbances, discoloured brown urine, and pulmonary toxicity.

  1. Drugs affecting Protein Synthesis

Antibacterial agents have also been designed to disturb bacterial protein synthesis. Members of this class are quite varied, and include:

The bacterial ribosome – the site from which proteins are synthesised – is made up of many different components. Each of the listed antibacterial agents above affects the ribosome to different, sometimes similar, degrees. For example, macrolides bind reversible to the 50S subunit, whereas aminoglycosides bind irreversibly to the 30S ribosomal subunit. Tetracyclines, on the other hand, bind reversibly to the 30S ribosomal subunit.

Bear these mechanistic differences in mind as you study this class of antimicrobial agents. There are some pharmacology of antimicrobial agents we haven’t yet covered in other articles – such as fusidic acid. This drug is mostly used against Gram positive bacteria, particularly for skin infections. It inhibits translocation of peptidyl-tRNA when it forms a complex with ribosomes. Fusidic acid may cause thrombophlebitis when given as an IV infusion.

Linezolid is a member of the oxazolidinedione class of antibacterial drugs. It is active against non-replicating bacteria – which works by inhibiting the ribosomal 50S subunit, preventing the initiation of tRNA transcription. It is active against Gram positive organisms: MRSA and vancomycin-resistant Enterococcus faecium, for example. It has a half-life of 5 hours. Unwanted effects include headache, nausea, taste disturbances, and diarrhoea.

Let’s take a look at some pharmacological infographics of the remaining classes:

Macrolides

Aminoglycosides

Tetracyclines

Lincosamides

Streptogramins

  1. Drugs affecting Bacterial Metabolism

So what do we mean by bacterial metabolism? Quite simply it refers to those metabolic processes that sustain bacterial cells – such as folate metabolism. There are two main classes of antimicrobial agents in this class: sulphonamides and trimethoprim. Both drugs focus on folate synthesis for their mechanism of action, not least because folate is an essential nutrient for bacterial cell growth and is used to develop purines for DNA production.

Trimethoprim inhibits dihydrofolate reductase – an enzyme responsible for converting dihydrofolate to tetrahydrofolate. Trimethoprim is often combined with sulfamethoxazole (co-trimoxazole) to prevent bacterial folate synthesis. Trimethoprim has bacteriostatic activity against both Gram positive and Gram negative organisms. Unwanted effects include nausea, vomiting, diarrhoea, rash, bone marrow suppression, and folate deficiency.

See below for more information on sulphonamides.

Sulfonamides

  1. Drugs used for TB

The next class in our pharmacology of antimicrobial agents are anti-tubercular drugs – which includes:

  • Rifampicin
  • Isoniazid
  • Pyrazinamide
  • Ethambutol

Rifampicin inhibits DNA-dependent RNA polymerase – inhibiting transcription, which is bactericidal in effect. It has a broad spectrum of activity, though resistance develops rapidly. Oral absorption of rifampicin is quite good (an intravenous formulation is also available). It is metabolised in the liver and has a half-life of approximately 3.5 hours. Unwanted effects with rifampicin include nausea, anorexia, pseudomembranous colitis, and orange colouration of tears and urine.

Isoniazid is particularly important in the treatment of Mycobacterium tuberculosis. It is a prodrug, which becomes active once it encounters catalase-peroxidase activity within cells. It inhibits the synthesis of long-chain mycolic acids and is bactericidal in effect (dividing organisms only). Oral absorption is reduced by food. The half-life of isoniazid is between 0.5-2 hours – depending on whether the patient is a slow or rapid acetylator. Unwanted effects include nausea, vomiting, constipation, peripheral neuropathy (high doses), aplastic anaemia, and hepatitis.

Pyrazinamide, like isoniazid, is a prodrug – bactericidal only in actively replicating cells. The active product – pyrazinoic acid – lowers intracellular bacterial pH and eliminates an essential enzyme in fatty acid synthesis; the product of whose effects leads to the death of the cell. Oral absorption of pyrazinamide is quite good, and it is mostly metabolised by the liver. It has a relatively long half-life of around 10 hours. Unwanted effects of pyrazinamide include hepatotoxicity, nausea, vomiting, arthralgia, and sideroblastic anaemia.

Ethambutol completes the line-up; a drug that functions as an arabinose analogue. As such, ethambutol inhibits arabinosyl transferase, an enzyme essential to the integrity of the Mycobacterial cell wall. Oral absorption remains good, and the drug is primarily eliminated unchanged in the urine. Ethambutol, like isoniazid, also has a long half-life – around 10 hours. Unwanted effects include optic neuritis (dose related red/green colour blindness), and peripheral neuritis.

The last class in our pharmacology of antimicrobial agents deals with leprosy, a condition which – according to the World Health Organization – still causes up to 250,000 new cases each year.

  1. Drugs used for Leprosy

Leprosy is mostly caused by the bacterium Mycobacterium leprae. As well as the drugs listed below, rifampicin is also used in the treatment of this condition. The two other drugs levelled against leprosy are:

  • Dapsone
  • Clofazimine

If you think back to the sulphonamides, they were used to disrupt bacterial metabolism – or, more specifically, folate synthesis. Dapsone, too, operates by this means. Dapsone may also be used, however, in the treatment of pneumocystis pneumonia and dermatitis herpetiformis. Clofazimine is a dye that binds to the guanine bases of DNA – inhibiting bacterial proliferation. It is given orally and has a very long half-life – 10 days. Unwanted effects include gastrointestinal upset, brown-black skin discolouration, and acne.

Learn more about drugs used for leprosy below…

Leprostatic Drugs

Principles of Antibacterial Therapy

That’s about it for the pharmacology of antimicrobial agents. Again, be sure to check out the pharmacology of antifungal drugs if you haven’t yet already. Before we finish up, there’s just one more thing to review – principles of antibacterial therapy. These are the principles that guide, if not determine, the prescribing process of antibacterial drugs. The infographic below does not attempt to be exhaustive, but it gives some idea as to what therapeutic considerations should be bore in mind.

Principles of Antibacterial Therapy I

Principles of Antibacterial Therapy II

And so we reach the end. If you’d like to test your knowledge of the pharmacology of antimicrobial agents – whether it’s macrolides, quinolones, or aminoglycosides – do be sure to check out our topical quizzes which cover everything you need to know.

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