Antibacterial agent - iclaprim

The discovery of penicillin was surely one of the greatest advances in medicine, and many antibiotics were developed in its wake.

However, mutation of bacteria into resistant strains has meant that once curable bacterial infections are reemerging - notably MRSA (methicillin resistant Staphylococcus aureus). Now bacteria resistant to vancomycin - the last line of antibiotic defence - are being observed with alarming frequency.

As a result, new antibacterial agents, particularly those with novel mechanisms of action, are desperately needed. A potential target is the enzyme dihydrofolate reductase (DHFR), which is essential for a bacterium's survival. It is part of the process involved in the production and recycling of tetrahydrofolate. Both bacteria and mammals need this enzyme, but its active site in the two is very different, making it a good target for pharmaceutical attack.

Trimethoprim, launched more than 40 years ago, inhibits DHFR. However, it is only weakly bacteriocidal, as are its newer analogues such as brodimoprim. Resistance has also developed, and the mutations responsible for this have been pinpointed. As a result, Roche developed a more effective derivative, iclaprim, which has since been licensed by Swiss company Arpida.¹ It is active against Gram positive bacteria, including MRSA and several other resistant strains. It can be administered both orally and intravenously.

In a randomised double blind phase II trial, which was comparator-controlled with standard vancomycin therapy, a total of 92 patients with complicated soft tissue and skin infections were given 1 or 2mg/kg iclaprim intravenously twice a day for 10 days, or vancomycin. Few adverse events were observed, and 26 out of 28 patients given the lower dose, and 29 of the 31 given the higher dose responded, compared with 26 of 28 receiving vancomycin. Phase II trials continue.

If successful, iclaprim could become a much needed addition to the antibiotic arsenal.