Adverse effects, drug-drug interactions and bacterial resistance to the new quinolone antimicrobial agents are reviewed. Clinical adverse effects are reported to occur in 5-10% of patients, and include primarily gastrointestinal disturbances, central nervous system toxicity and rash. Laboratory abnormalities are reported to occur in 5-12% of patients, and include mild reversible elevations of transaminases. Quinolones are not recommended in persons whose bone growth is incomplete or in pregnant or nursing women because cartilage toxicity has been observed in juvenile beagles. Drug-drug interactions may occur between quinolones and theophylline, caffeine, and magnesium- or aluminium-containing compounds such as antacids and sucralfate. Bacterial resistance occurs by chromosomal mutations which alter the target enzyme DNA gyrase or decrease drug accumulation. Emergence of resistance during therapy is uncommon to date but can be problematic in infections with Pseudomonas aeruginosa. Staphylococcus aureus and other bacteria for which the therapeutic index may be low. In summary, quinolones thus far have been well tolerated, but more experience is needed to determine the exact nature and extent of adverse effects and emergence of bacterial resistance.
The antimicrobial agent novobiocin, an inhibitor of the bacterial enzyme topoisomerase II (DNA gyrase), is known to antagonize Trypanosoma cruzi amastigotes growing in cell-free medium. To determine sites of antagonism of novobiocin, the effects of drug on parasite ultrastructure and incorporation of radiolabeled precursors of DNA, RNA and protein into macromolecules were determined. The predominant ultrastructural abnormality seen after exposure to 0.40 mM novobiocin for 24 h was the presence of electron-dense clumps in the mitochondrion-kinetoplast organelle in 95 of 257 (37%) of cells, in comparison to no clumps seen in 110 drug-free cells. In addition, in the nucleus, the karyosome was less distinct than in control cells and appeared to merge with the chromatin. In the radiolabeling studies, incorporation of thymidine was inhibited in a dose-dependent fashion by novobiocin (0.16-0.80 mM) in a range of drug concentrations that also inhibited parasite growth. For 0.16 and 0.24 mM novobiocin, incorporation of thymidine was inhibited up to 65% relative to drug-free control cells while uptake of uridine and leucine was unaltered. We interpret these ultrastructure and precursor-incorporation studies as suggesting that (i) the mitochondrion-kinetoplast and possibly the nucleus are sites of novobiocin antagonism of T. cruzi amastigotes and (ii) that novobiocin appears to antagonize DNA synthesis within these organisms. Whether the drug target is topoisomerase II, however, is as yet unknown.
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