[Mutagenicity tests of tazobactam/piperacillin, tazobactam and piperacillin].

As a part of safety tests of tazobactam/piperacillin (TAZ/PIPC), the reverse mutation tests using bacteria, the chromosomal aberration tests using cultured cells and the micronucleus tests using male mice were conducted in order to evaluate the in vitro and in vivo mutagenicity of TAZ, PIPC, TAZ/PIPC. 1. The reverse mutation tests were carried out on TAZ, PIPC and TAZ/PIPC at dose ranges, where few antibacterial effects could be detected, using Salmonella typhimurium strains TA100, TA1535, TA98 and TA1537, and Escherichia coli WP2uvrA. All of three test articles showed that no significant increases were observed in the number of colonies in all tester strains in both systems, with and without mammalian metabolic activation (S9 Mix), as compared with solvent controls. 2. The chromosomal aberration tests were carried out on these test articles using cultured Chinese hamster lung cells (CHL). The cells were treated with TAZ, PIPC or TAZ/PIPC at the doses of 2.5, 5.0 and 10 mM with and without S9 Mix. In the test of PIPC with S9 Mix, the dose of 1.25 mM was set in addition to the three doses. The incidences of structural- and numeral-aberration were 0-3% in the absence or presence of mammalian metabolic activation system, and no significant increases were observed in the incidence of chromosomal aberrations as compared with solvent controls. 3. The micronucleus tests were carried out at doses of 625-5000 mg/kg of TAZ or TAZ/PIPC, or at 625-2500 mg/kg of PIPC. The femoral marrow cells were 48 h after administering intravenously to CD-1 male mice. The frequencies of polychromatic erythrocyte with micronuclei were 0.02-0.17%, 0.02-0.10% and 0.03-0.07% in the groups treated with TAZ, PIPC and TAZ/PIPC, respectively, and no significant increases were observed with dose dependence. The results indicated that these test articles were negative in the assessment standard using the background data. 4. The present study indicates that TAZ, PIPC and TAZ/PIPC have no in vitro and in vivo mutagenic potential.