In vitro activity of the novel diaminopyrimidine, iclaprim, in combination with folate inhibitors and other antimicrobials with different mechanisms of action

To assess the synergistic potential of the novel diaminopyrimidine iclaprim (formerly AR-100, Ro 48-2622), a specific and selective inhibitor of microbial dihydrofolate reductase (DHFR), in combination with other antimicrobial agents with distinctly different mechanisms of action. In chequerboard studies, iclaprim was tested in combination with 32 different antimicrobial agents against Gram-positive, Gram-negative and anaerobic bacteria including reference strains. Iclaprim was highly synergistic against the strains tested with the two sulphonamides selected, namely, sulfamethoxazole and sulfadiazine. With the other 28 antimicrobial agents, neither synergy nor antagonism was observed with macrolides, lincosamides, aminoglycosides, quinolones, β-lactams, trimethoprim, tetracyclines and glycopeptides. Furthermore, iclaprim exhibited no synergy or antagonism when evaluated in combination with metronidazole or aztreonam against a panel of 19 bacterial strains, including Gram-positive, Gram-negative and selected anaerobic bacteria. In agreement with the mechanism of action of microbial DHFR inhibitors, iclaprim exhibited synergism with sulphonamides and exhibited neither antagonism nor synergy with all the other antibiotics tested. Notably, iclaprim exhibited indifference in combination with aztreonam and metronidazole against Gram-negatives and anaerobes, respectively.