Part of the TeachMe Series
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Original Author(s): Charlotte Smith
Last updated: 7th August 2020
Revisions: 7

Original Author(s): Charlotte Smith
Last updated: 7th August 2020
Revisions: 7

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Penicillins

Mechanism

Penicillins competitively inhibit penicillin-binding proteins such as the enzyme DD-transpeptidase. This catalyses the cross-linking of peptidoglycans in bacterial cell walls.

Inhibition of this process weakens the cell walls, allowing an influx of water into the cell, which leads to cell swelling and then cell lysis.

Figure 1 – Penicillin mechanism of action

Their antimicrobial activity results from the presence of a ß-lactam ring in their chemical structure. However, some bacteria can produce the ß-lactamase enzyme, which breaks down the ß-lactam ring in the penicillin, resulting in resistance.

Coverage

Example Drugs Organisms covered/Clinical Indication
Benzylpenicillin and

Phenoxymethylpenicillin (Penicillin V)

Streptococcal infections e.g. tonsillitis, pneumonia, endocarditis and skin infections

Clostridial infections e.g. tetanus

Meningococcal infections e.g. meningitis

Amoxicillin/Co-Amoxiclav Gram-positive or Gram-negative pneumonia

E. coli UTI

Intra-abdominal sepsis

H. pylori eradication

Flucloxacillin Streptococcal infections including skin and soft tissue, osteomyelitis and septic arthritis
Tazocin Used for only very severe infections, especially where there is a broad spectrum of potential causative organisms, including Pseudomonas.

It is used to treat sepsis of almost all causes, in particular respiratory, urinary, skin, soft-tissue and intra-abdominal infections.


Common Side Effects

  • GI upset, including antibiotic-associated C. difficile infection.
  • A degree of allergy to penicillin is very common, affecting up to 10% of the population.

Cephalosporins and Carbapenems

These antibiotics are grouped together due to their similar structural properties and mechanisms of action.

Mechanism

Like penicillins, these antibiotics get their antimicrobial effect from the presence of a ß-lactam ring in their structure; they inhibit the cross-linking of peptidoglycans in bacterial cell walls.

Examples

  • Cephalosporins – Cefotaxime, Cetriaxone, Cefuroxime.
  • Carbapenems – Meropenem is the major example.

Coverage

Cephalosporins and Carbapenems are broad-spectrum, but as they have evolved, cephalosporins have become more suited for use against Gram-negative bacteria.

As both these types of antibiotic have a high chance of leading to bacterial resistance, they are usually reserved for very serious infections.

Common Side Effects

  • Simple GI upset
  • Antibiotic-associated colitis
  • Hypersensitivity reactions. As their structure and mechanism is similar to penicillin, there may be cross-reactivity in penicillin-allergic patients, thus extreme caution must be taken.

Cautions/Contraindications

  • Use with extreme caution in those with penicillin allergy
  • Use with caution in those at high risk of C. difficile
  • Use with caution in renal impairment

Glycopeptides

Mechanism

Similar to but distinct from penicillins, glycopeptides prevent the formation of cross links in the peptidoglycan cell wall. While penicillins irreversibly and competitively inhibit DD-transpeptidase, glycopeptides bind to the proteins in the cell wall themselves to prevent DD-transpeptidase from binding.

As shown in the below figure, resistance can occur when the last amino acid residue on the cross link changes from alanine to D-lactate.

Figure 2 – Vancomycin mechanism of action

Examples and coverage

  • Vancomycin – used orally for severe C. difficile infections, or intravenously for severe soft tissue/bone/joint infections as gram-positive cover.
  • Teicoplanin – used IV for gram-positive cover, either as treatment or commonly as surgical prophylaxis in penicillin allergic patients.

Cautions

Vancomycin accumulates in renal disease, and so dosing is done according to the patient’s weight and creatinine clearance (not eGFR).

Monitoring

Pre-dose (trough) levels are taken before the third or fourth dose, and the dosing regimen is adjusted accordingly depending on the serum level.

Aminoglycosides

Mechanism

Inhibit bacterial protein synthesis by binding to the 30S subunit of the ribosome.

Examples

Gentamicin is the most commonly used example, but others include neomycin and tobramycin.

Coverage

Aminoglycosides tend to be used for severe infections, especially those caused by Pseudomonas. They are also often combined with penicillins or metronidazole where the causative organism of severe infection is unknown.

Common Side Effects

  • Nephrotoxicity, especially if combined with other nephrotoxic drugs
  • Ototoxicity – usually only if used long-term. Symptoms can include tinnitus, hearing loss or vertigo, and these may be irreversible.

Interactions

  • Loop diuretics such as Furosemide – high risk of otoxocity
  • Vancomycin – risk of nephrotoxicity and ototoxicity

Monitoring

A plasma drug concentration level must be taken 18 – 24 hours after the first dose. It’s also important to monitor the renal function regularly.

Macrolides

Mechanism

Inhibit bacterial protein synthesis by binding to the 50S subunit of the ribosome, preventing ribosomal translocation and therefore protein elongation.

Examples

Clarithromycin, Erythromycin, Azithromycin

Coverage

Macrolides are usually used for respiratory, skin and soft tissue infections in those with a penicillin allergy. They are also used in H. pylori eradication (along with a PPI + amoxicillin or metronidazole – this is known as “triple therapy”)

Common Side Effects

  • GI irritation/upset common if given orally – macrolides are pro-kinetic and can be used therapeutically in gastroparesis.
  • Prolonged QT interval.
  • Ototoxicity.

Interactions

  • Macrolides are CYP450 inhibitors (except Azithromycin) so increase the concentration of drugs metabolised by CYP450 enzymes – this increases the bleeding risk with warfarin, for example. CYP450 inhibitors in turn decrease the efficacy of macrolides.
  • Macrolides should also not be given with other drugs that prolong the QT interval.

Cautions/Contraindications

Use with caution in severe renal or hepatic impairment

Quinolones

Mechanism

Inhibit bacterial DNA duplication through inhibition of topoisomerases, which interfere with DNA unwinding and therefore transcription and translation.

Examples

Ciprofloxacin is the most commonly used quinolone, but others include levofloxacin and ofloxacin.

Coverage

The quinolone group of antibiotics are used mainly for Gram-negative infections. They should be reserved for 2nd or 3rd-line treatment only as there is increasing resistance to these antibiotics, and they also commonly cause C. difficile.

However, it is worth noting that Ciprofloxacin is the only antibiotic available in oral form which is active against Pseudomonas aeruginosa, necessitating its use in certain infections.

Key Side Effects

  • GI upset
  • Prolonged QT interval
  • High risk of C. difficile

Interactions

  • Should not be used with other drugs that prolong the QT interval

Administration

Equal bioavailability oral and IV, so only needed intravenously in those who cannot swallow or are nil by mouth.

Metronidazole

Mechanism

Once in its reduced form, metronidazole inhibits bacterial DNA synthesis. As metronidazole is only reduced in this way in anaerobic bacteria, it is a specific antibiotic for anaerobic infections.

Coverage

Used against anaerobic bacteria including C. difficile, oral infections and intra-abdominal or pelvic infections.

However, it is also active against protozoal infections e.g. giardiasis, dysentery and trichomonas vaginalis.

Common Side Effects

  • GI upset
  • Hypersensitivity reactions
  • Peripheral and optic neuropathy (high dose/long term use only)
  • Seizures and encephalopathy (high dose/long term use only)

Interactions

  • Inhibits CYP450 so increases the effect of drugs metabolised by these enzymes, and in turn these drugs will decrease the efficacy of metronidazole
  • Lithium – metronidazole increases the risk of lithium toxicity

Cautions/Contraindications

  • Alcohol must not be drunk while on metronidazole and for ~48 hours after the end of the course. Metronidazole interferes with alcohol metabolism and gives severe side effects as a result.
  • Use with caution in severe liver disease

Nitrofurantoin

Mechanism

Damages bacterial DNA causing cell death. The detail behind this is beyond the scope of the article.

Coverage

Used to treat UTIs caused by both Gram-positive and Gram-negative bacteria.

Common Side Effects

  • GI upset
  • Hypersensitivity reactions

Cautions/Contraindications

  • Contraindicated in pregnant women towards term and babies in the first 3 months of life
  • Contraindicated in renal impairment
  • Caution if using as long-term prevention as higher risk of side effects

Monitoring

If using as long-term prophylaxis for UTIs, monitor the patient for side effects such as breathlessness and pins and needles.

Trimethoprim

Mechanism

Inhibits bacterial folate synthesis through inhibition of dihydrofolate reductase.

Coverage

  • Similar to Nitrofurantoin – used to treat UTIs caused by both Gram-positive and Gram-negative bacteria, although resistance is increasing and therefore it is less commonly used now as the first-line treatment for UTI.
  • Also used as treatment or prophyalxis for Pneumocystis pneumonia as Co-Trimoxazole (Trimethoprim combined with Sulfamethoxazole, a sulfonamide antibiotic)

Common Side Effects

  • Commonly causes a skin rash
  • GI upset
  • Hypersensitivity is common and can be severe
  • Hyperkalaemia

Interactions

  • Drugs which also cause hyperkalaemia e.g. ACE inhibitors, spironolactone, angiotensin II receptor blockers
  • Folate antagonists or drugs that increase folate metabolism e.g. methotrexate and phenytoin
  • Enhances effect of Warfarin due to gut flora death

Cautions and Contraindications

  • Contraindicated in 1st trimester of pregnancy
  • Caution in folate deficiency and renal impairment