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All-in-One Prophylaximagic!

I had my six-monthly checkup with my immunology insultant consultant last week (no infections to report, trough IgG of 7.5 g L^-1 which is double what it was a year ago). I have common variable immunodeficiency, a genetic condition which means I don’t produce antibodies, so untreated I can get frequent and repeat infections.

We were reviewing my treatment plan, and discussing that I’ve now been on prophylactic antibiotics for six months. The antibiotic of choice at my hospital is azithromycin, a member of a family of antibiotics called macrolides which also includes erithromycin and clarithromycin.

Molecular structure of azithromycin (C38H72N2O12)

Molecular structure of azithromycin. Note the large ring in the top left of the image. Thanks to Wikimedia

Molecularly, macrolides are characterised by having a ring of 14 or more (mainly carbon) atoms, making them quite large. As a comparison, benzylpenicillin has 16 carbon atoms in total and a molecular mass of 334.4, whilst azithromycin has 38 carbon atoms and a molecular mass of 749.0, more than twice the mass.

Pharmacologically, macrolides block protein synthesis in bacteria. All cells (and bacteria are just cells with a thick wall) depend on constant replacement of their proteins, so blocking their manufacture kills bacteria rapidly.

Macrolides also have a cunning trick of getting to the bacteria. Neutrophils, a type of white blood cell which is attracted to infections sites, transport as much of the macrolide molecules as possible in the cell. Once neutrophils find the infection, they release bomblets of anti-bacterial chemicals along with the antibiotic. The net effect is they get to the bacteria very quickly and if the chemical warfare from the neutrophils doesn’t kill them off, the macrolides soon do.

However, macrolides are not a one trick pony. In addition to being efficient killers, they also have other beneficial effects, in particular being potent anti-inflammatories. Unlike common anti-inflammatories like ibuprofen, which have a single mode of action, macrolides are multi-modal and suppress inflammation in multiple ways.

One trick they have is protecting the body from the damage caused by the neutrophil attack chemicals. Another trick, also associated with neutrophils, is that they may promote the migration of the chemical warfare specialists to the infection sites, meaning more of them get to the infection, and they get there faster.

They have also been implicated in suppressing expression of endothelin-1. ET1, as it’s known, is a powerful vasodilator which promotes blood flow in the area around an infection, and is what causes infected wounds to go characteristically red and inflamed. In addition, macrolides have been associated with reduction of other signalling chemicals, cytokines and interleukins, which promote inflammation.

These effects have been shown to be beneficial, particularly in a range of respiratory conditions. This includes asthma, particularly where the patient is sensitive to environmental irritants such as dust, and a condition called diffuse panbronchiolitis (DPB). DPB is characterised by extensive bacterial infection in the lungs, and constriction of the airways in response. Treatment with macrolides has increased survival rates from around 50% to better than 96%, with it’s effects exceeding that of an antibiotic alone.

Whilst macrolides become concentrated in normal cells, they aren’t transported into the space in the lungs where air exchange occurs, the bronchial tree. However, they have been shown to have benefit on the lung function tests of patients with bronchiectasis and cystic fibrosis, not by directly affecting the flora, but by decreasing inflammation and promoting the migration of neutrophils. In addition, macrolides may have benefits in atheroma (fatty arteries, which have a strong association with serious and fatal heart disease), arthritis and some forms of cancer.

For those of us who do have poor immune systems, just reducing the bacterial infections is great, but reducing the inflammatory response is a buy-one-get-one-free bonus. So, here’s to an amazing group of drugs that’s making my life more liveable.