3rd August 2023

Antimicrobials

Antibacterial Drugs

This section will focus on antibacterial drugs, or antibiotics, which form most of the curriculum for antimicrobials for MRCP examinations.

The most common and important classes of antibacterials are discussed in separate sections, with background information on their mechanism of action, the spectrum of activity, and important side effects, interactions and monitoring requirements about each class.

Each NHS trust will have individual local guidelines for antibiotic prescribing based on bacterial resistance patterns in the area. However, the questions in the MRCP exams are based on national guidance, which has been used to reference this text.

The following table demonstrates the spectrum of activity for commonly used antibiotics; an understanding of which can help guide prescribing and can be used as an overview for this section.

Table 1: Spectrum of activity of common antibiotics

Beta-lactams

Mechanism of action

Beta-lactams are bactericidal, meaning they directly kill bacteria, and work by disrupting bacterial cell wall synthesis. There are several different types of beta-lactam antibiotics, which are discussed in turn below.

Spectrum of activity

Penicillins

The first class of antibiotics first synthesised, which remain amongst the most commonly prescribed in healthcare today.

Benzylpenicillin (penicillin G)

• Narrow spectrum, with most activity against gram positive organisms, particularly Streptococci species
• Some activity against gram negative organisms, most importantly Neisseria and Leptospira species
• Also active against Treponema species
• Given IM or IV

Phenoxymethylpenicillin (penicillin V)

• Similar spectrum to benzylpenicillin, but given orally.

Amoxicillin

• A broader spectrum antibiotic that is commonly used to treat both gram positive and some gram negative organisms

Flucloxacillin

• Treats gram positive organisms and is the antibiotic of choice for Staphylococcus aureus.
• Especially used in skin and soft tissue infections

Co-amoxiclav (amoxicillin/clavulanic acid)

• Clavulanic acid is a beta lactamase inhibitor, which, when used in combination with amoxicillin, broadens the spectrum.
• Co-amoxiclav is used to treat a range of gram positive, gram negative, and anaerobic bacteria. It is a common first line antibiotic for many sources of infection, including sepsis of unknown origin.

Tazocin (piperacillin/tazobactam)

• Tazocin is a broad spectrum antibiotic that treats gram positive, gram negative, and anaerobic bacteria.
• Importantly, it has activity against Pseudomonas aeruginosa
• Generally first line for hospital-acquired infections and neutropenic sepsis

Cephalosporins

A category of beta-lactams, of which there exist several ‘generations’ with slightly different spectrums of actions.
Cross-react with penicillins (10%), and so therefore, should be avoided in severe penicillin allergy.

First generation:

• e.g. cefalexin
• Mainly active against Gram positive organisms

Second generation:

• e.g. cefuroxime
• Enhanced Gram negative activity compared to first generation

Third generation:

• e.g. ceftriaxone, cefotaxime
• Enhanced Gram negative activity compared to second generation, but not as good with Gram positive organisms, especially Staphylococcus aureus
• Ceftazidime in particular, has good activity against Pseudomonas species
• Reduced cross-reactivity with penicillin (2-3%) compared to first and second generation

Fourth generation:

• e.g. cefepime
• Broad spectrum –active against Gram positive and negative bacteria to a greater degree than cefotaxime (third generation)
• Active against Pseudomonas species

Fifth generation:

• e.g. ceftaroline
• Similar spectrum to cefotaxime (third generation) but has an extended activity against Gram positive organisms, including MRSA and multi-drug resistant Streptococcus pneumoniae, and hence reserved for these infections to decrease drug resistance

Carbapenems

Have a broad spectrum of activity against Gram positive, Gram negative and anaerobic bacteria. Less cross-reactivity with penicillin than cephalosporins (1% rather than 10%), so it may be safer to give in penicillin allergy.

Examples include imipenem, meropenem and ertapenem; the latter is not active against Pseudomonas aeruginosa, which separates it from other carbapenems.

Generally reserved for severe infections. Imipenem and meropenem are used for complicated hospital-acquired pneumonias, intra-abdominal, skin and soft tissue, and urinary tract infections. Ertapenem treats abdominal and gynaecological infections, community-acquired pneumonia, and skin and soft tissue infections in diabetics.

Carbapenems are not active against MRSA.

Important side effects, interactions and monitoring

Penicillins

Penicillin allergy is common and can range from mild skin reactions to life-threatening anaphylaxis. Side effects caused by penicillin are often mistakenly interpreted as an allergic reaction. It is important to establish the nature of symptoms to determine whether or not the reaction represents a true allergy. It is also crucial to clarify the severity of any allergic reactions, as this affects decision-making over whether cephalosporins would be safe to administer.
A common reaction with ampicillin and amoxicillin is a maculopapular rash, often mistaken for an allergic reaction. This rash generally manifests in patients with glandular fever or, more rarely, leukaemia or cytomegalovirus function. Broad spectrum penicillins are therefore contraindicated in patients presenting with sore throats, in case this is due to glandular fever, which triggers this reaction.

Caution should be taken when prescribing high doses in patients with renal failure, as accumulation may lead to encephalopathy. Interstitial nephritis may also be seen as a rare but important side effect of penicillins.

Penicillins do not require any special monitoring.

Cephalosporins

Hypersensitivity reactions are the most important side effect of cephalosporins. First and second generation cephalosporins have a cross-sensitivity with penicillin of 10% and 2-3% with third generation patients. Cephalosporins should therefore be avoided in penicillin-allergic patients, but if there are no suitable alternatives, then cefixime, cefotaxime, ceftazidime, ceftriaxone and cefuroxime may be used with caution. Caution should be taken when prescribing high doses in patients with renal failure, as accumulation may lead to encephalopathy.

Cephalosporins do not require any special monitoring.

Carbapenems

Common side effects of all meropenems include GI upset, headache, skin reactions and thrombophlebitis. Carbapenems are known to lower the seizure threshold (especially imipenem), so they should be used cautiously in people with seizure disorders and the elderly. Meropenem has less seizure-inducing potential and can be used to treat central nervous system infections.

Meropenem requires monitoring of LFTs, as it can cause hepatotoxicity. Dose reductions are necessary for all carbapenem antibiotics for renal impairment.

Imipenem is given in combination with the enzyme inhibitor cilastatin. This is because this enzyme can partially inactivate the kidney’s imipenem, reducing its effectiveness.

Glycopeptides

Mechanism of action

Bactericidal drugs work by inhibiting bacterial cell wall synthesis.

Spectrum of activity

Glycopeptides are active against aerobic and anaerobic Gram positive bacteria, including MRSA. Staphylococcus aureus and enterococci resistant to glycopeptides are increasingly emerging, making antibiotic stewardship of these drugs especially important. They are generally reserved for severe infections, especially useful in skin and soft tissue infections, joint and bone infections, endocarditis, and complicated infections where other antibiotics have failed. There are two key drugs in the class –vancomycin and teicoplanin. Teicoplanin has a longer duration, so following the loading dose can be given once daily.

Important side effects, interactions and monitoring

Fever and skin reactions are common side effects. In particular, intravenous vancomycin is commonly associated with ‘red man syndrome’, a hyperactivity reaction characterised by a diffuse erythematous rash, which may mimic an allergic reaction. Teicoplainin is associated with ototoxicity; if tinnitus or hearing impairment develops, it should be discontinued.

Vancomycin and teicoplanin require serum monitoring, including on the second day of treatment and pre-dose. Each hospital trust will have its own specific guidance, which should be referred to.

Both glycopeptides may cause nephrotoxicity, and monitoring renal function is a requirement.

Macrolides

Mechanism of action

Bacteriostatic drugs inhibit bacterial growth by binding to the 50s subunit of the bacterial ribosome, rather than directly killing the bacteria.

Spectrum of activity

Macrolides have a similar spectrum of activity to many penicillins, so they are a common alternative agent for patients allergic to penicillin.

Common indications include respiratory tract infections (including atypical pneumonia(, skin and soft tissue infections, and gastroenteritis caused by Campylobacter species.

The three most commonly used macrolides are erythromycin, clarithromycin and azithromycin. Claithromycin is derived from erythromycin and has a broader spectrum of activity. Azithromycin has not as good Gram positive activity but better Gram negative activity. It has a long half life, so it’s amenable to once daily dosing.

Important side effects, interactions and monitoring

GI upset is a common side effect, especially with erythromycin and clarithromycin; this is dose-dependent, so it may be avoided by giving lower doses when possible. This is also a therapeutic effect of erythromycin, which can treat vomiting caused by gastric stasis.

Macrolides are also known to be QT interval prolongers.

Tetracyclines

Mechanism of action

Bacteriostatic drugs inhibit bacterial growth by binding to the 30s subunit of the bacterial ribosome, preventing the translation of RNA into proteins. They are not bactericidal – like beta-lactams – and do not directly kill bacteria.

Spectrum of activity

A broad spectrum antibiotic, which covers both Gram positive and negative bacteria, can also be used to treat intracellular organisms. Due to increasing drug resistance, they are less popular than in previous years. They are still indicated in treating chlamydia, rickettsia brucella and Lyme disease. They are also used in genital infections, acne, and respiratory tract infections, especially exacerbations of chronic bronchitis, due to their activity against Haemophilus influenzae, a commonly associated pathogen.

Examples include doxycycline, minocycline, and tigecycline. They are all very similar, with doxycycline generally the macrolide of choice.

Important side effects, interactions and monitoring

Tetracyclines do not require routine monitoring. They should be used cautiously in those with hepatic and renal impairment but without precise contraindications.

A key side effect is photosensitivity; tetracycline use increases the risk of sunburn under exposure to UV light.

Tetracyclines are contraindicated in pregnant and breastfeeding women. This is because of the well-documented phenomenon of permanent discolouration of the teeth of foetuses and babies who are exposed. They are also contraindicated in children under the age of 8 for the same reason. This is known as “tetracycline teeth” – an example image below.

Tetracyclines are also associated with a risk of worsening muscle weakness in myasthenia gravis and exacerbating the symptoms of systemic lupus erythematosus. So they should be used with caution in these patients.

Examples of tooth staining – “tetracycline teeth”.

Image Source: Wikimedia Commons (2019). Examples of tooth staining, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Examples_of_tooth_staining.jpg (Accessed: 25 September 2022).

Aminoglycosides

Mechanism of action

Like tetracyclines inhibit bacterial growth by binding to the 30s subunit of the bacterial ribosome, preventing the translation of RNA into proteins, but unlike tetracyclines, they are bactericidal, directly killing bacteria.

The mechanism of action is also concentration-dependent, meaning the higher doses of antibiotic given, the more effective against bacteria they are.

Spectrum of activity

Has some activity against Gram positive bacteria but is best known for its broad spectrum against Gram negative bacteria, and due to its effectiveness is generally used to treat severe infections. They are most effective against rapidly-multiplying bacteria, hence why they are effective in severe infections. However, they are not effective against anaerobes.

Examples include gentamicin (the most commonly used), tobramycin, amikacin, streptomycin and neomycin. Gentamicin, tobramycin, and amikacin also have activity against Pseudomonas aeruginosa. Aminoglycosides cannot be absorbed enterally and hence are generally given intravenously.

Important side effects, interactions and monitoring

Gentamicin generally has hospital-specific guidelines for administration and monitoring. It is increasingly given on a once-daily regime. Serum monitoring is essential to adjust the dose and avoid toxicity, especially in elderly patients or those with renal impairment.

The most important side effects of gentamicin to be aware of, is nephrotoxicity and ototoxicity, with the former necessitating regular monitoring of renal function.

Quinolones

Mechanism of action

Bactericidal antibiotics inhibit DNA topoisomerase and gyrase enzymes to prevent DNA replication. Nearly all quinolone antibiotics have a fluorine atom attached and hence are known as fluoroquinolones.

Spectrum of activity

The two most commonly used are ciprofloxacin and levofloxacin. Ciprofloxacin has activity against both Gram positive and negative bacteria; although not anaerobic organisms, and is limited in treating infection caused by Streptococcus pneumoniae and Enterococcus faecalis. It is also active against some mycobacteria. Ciprofloxacin is often used for GI tract infections (including typhoid fever), bone and joint infections, gonorrhoea, and sepsis caused by sensitive organisms. Levofloxacin has better Gram positive activity than ciprofloxacin and can treat atypical infections. Many Staphylococci are resistant to quinolones and therefore have no use in MRSA infections.

Important side effects, interactions and monitoring

QT interval prolongers, so best avoided if patients are taking other drugs, which may also prolong the QT interval. Not recommended for pregnant women. Dose reductions are required in patients with renal impairment, and local guidelines should be consulted.

Others

Other important antibiotics to be aware of are summarised in the table below.

Table 2: Miscellaneous antibacterial drugs

Special circumstances

When prescribing any medication, consideration should be given to individual patient factors that may influence the drug’s pharmacokinetics.

The most important of these situations are prescribing in renal impairment, hepatic impairment, and pregnant and breastfeeding women. Drugs may either be contradicted, or dose reductions may be required.

Detailed information on prescribing in these circumstances can be found in the British National Formulary (BNF) for each drug.

Antiviral Drugs

Antiviral drugs do not directly affect viruses but work by limiting the replication of a virus within a host organism. Not every viral infection necessitates treatment with antivirals. The most common indications are HIV infection (e.g. antiretrovirals), herpes virus infections (e.g. aciclovir), influenza viruses (e.g. oseltamivir) and hepatitis B and C (e.g. tenofovir, interferon-α).

As antivirals are not a topic which features heavily on the MRCP examination, this section focuses on the self-assessment questions – further information and references can be found in the explanations provided. The BNF treatment summaries cited below are also a useful resource. More background can also be found in the Viral Infections topic.

Antifungal Drugs

This topic is not a particular focus of the MRCP curriculum, so this section emphasises the self-assessment questions. Further information on the topic can be found in the explanations provided for these questions. More background can also be found in the Fungal Infections topic.

Antiparasitic Drugs

This topic is not a particular focus of the MRCP curriculum, so this section emphasises the self-assessment questions. Further information on the topic can be found in the explanations provided for these questions. More background can also be found in the Parasitic Infections topic.