Antituberculars

crop_square Summary

While antibiotic classes like penicillins or cephalosporins share certain molecular and biological characteristics, antitubercular antibiotics are grouped together because they are used as first-line drugs in tuberculosis and other mycobacterial infections. As you will see below, these antibiotics differ in many aspects from one another. Standard therapy for tuberculosis is two months of Isoniazid (INH), Rifampicin (RIF), Ethambutol (EMB) and Pyrazinamide (PZA) followed by four months of INH and RIF.

crop_square Isoniazid (INH)

INH was first synthesised over a hundred years ago. It consists of a pyridine ring with an attached hydrazine group. This antibiotic is a pro-drug, meaning it needs to be metabolised into its pharmacologically active form. Once inside the mycobacterial cell, INH is activated by an enzyme called KatG, which results in the formation of isonicotinic acyl radicals and other free radicals. These radicals interact with cellular enzymes inhibiting cell wall synthesis eventually causing cell death. INH is bactericidal in replicating mycobacteria but bacteriostatic in dormant cells. It is very active against mycobacteria but not against most other microorganisms. Resistance against INH occurs regularly in mycobacteria. It is therefore given in combination with other antibiotics to prevent the emergence of resistant strains. Oral bioavailability and tissue penetration are excellent. INH is metabolised by the liver and excreted in the urine. It is a liver enzyme inducer which may alter the metabolization of other drugs such as paracetamol and carbamazepine. Common side effects include peripheral neuropathy and deranged liver enzymes.

crop_square Ethambutol (EMB)

EMB is a synthetic antibiotic dating back to the 1960es. It is an ethylenediamine derivate with varying degrees of antimycobacterial activity between the different stereoisomers. EMB disrupts the mycobacterial cell wall by inhibiting the synthesis of an important cell wall molecule, arabinogalactan. It is a bacteriostatic antibiotic and resistances develop quickly. It should only be given in combination with other antibiotics in mycobacterial infections. EMB is recommended in Mycobacterium avium complex (MAC) infections caused by and . It is rapidly absorbed from the gastrointestinal tract but does not cross the blood-brain barrier well. Elimination is partly via the urine and partly via faeces. The best-known EMB adverse effect is visual disturbance due to optic neuritis, however, this is rarely seen in patients treated with recommended drug doses.

crop_square Rifampicin (RIF)

RIF, which is known as Rifampin or Rifampicin, is a semisynthetic drug derived from Rifamycin, a antibiotic isolated from Streptomyces mediterranei bacteria. It has a characteristic orange colour and a heterocyclic structure belonging to the ansamycins. RIF inhibits RNA synthesis by binding to an enzyme called DNA-dependent RNA polymerase, ultimately leading to cell death. It may be bactericidal or bacteriostatic depending on the targeted organism. In the treatment of active mycobacterial disease, RIF is usually given as a combination therapy. RIF is active against a very broad spectrum of organisms, notably (including ) Oral bioavailability and tissue penetration are good. RIF is hepatically metabolised and mostly eliminated by faeces. The arguably best best-known, though benign, side effect is an orange colouration of bodily fluids. RIF may be hepatotoxic. Flu-like symptoms may occur.

crop_square Pyrazinamide (PZA)

PZA is a prodrug structurally related to vitamin B3 (nicotinamide). Inside the mycobacterial cell, PZA is hydrolysed to pyrazinoic acid, which is hypothesised to interfere with crucial cellular pathways. The exact mechanism of action remains unclear. PZA is exclusively used against infection in combination with other antitubercular antibiotics. Oral bioavailability and tissue penetration are excellent. PZA is metabolised by the liver and eliminated via the urine. Hepatotoxicity is a concerning adverse drug effect.