In vivo therapeutic efficacy of cefdinir (FK482), a new oral cephalosporin, against Staphylococcus aureus and Haemophilus influenzae in mouse infection models.

Cefdinir (FK482), a new oral cephalosporin, displayed potent oral activity versus induced infections in mice. In studies using beta-lactamase-nonproducing (beta LAC-) and -producing (beta LAC+) Staphylococcus aureus strains, respective PD50s (in mg/kg) were 11 and 24 for preventing subcutaneous abscess and 2.7 and 2.3 for preventing lethal systemic infection. In studies using beta LAC- and beta LAC+ Haemophilus influenzae, respective PD50s were 5.8 and 3.1 for preventing lethal systemic infection. Time-kill studies versus H. influenzae showed that 6- to 12-mg/kg dosing was effective in reducing viable counts of these strains in blood by > or = 100-fold by 24 h after challenge. This in vivo performance was comparable to or exceeded values generated by cefaclor, cefpodoxime proxetil, and ampicillin.

Enoxacin: in-vitro and animal evaluation as a parenteral and oral agent against hospital bacterial isolates.

Enoxacin was evaluated in in-vitro tests and in studies of effectiveness and blood concentrations in the mouse. Enoxacin was active against both susceptible and multiresistant hospital isolates of Enterobacteriaceae, Pseudomonas aeruginosa, Haemophilus influenzae, Neisseria gonorrhoeae and staphylococci. Less susceptible were streptococci and anaerobes. Of nine quinolones tested, only norfloxacin was equivalent in vitro. The MBCs of enoxacin were one- to twofold greater than the MICs, and enoxacin was rapidly bactericidal. No single-step resistant mutants could be detected at 10 mg/l against large inocula and six to 11 steps were required for selection of resistant clones. In systemic mouse infections, enoxacin was effective in a single oral or subcutaneous dose against one strain each of Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Providencia rettgeri and Ps. aeruginosa, and two Staphylococcus aureus strains. Single oral and subcutaneous enoxacin doses (50 mg/kg) gave peak mouse blood levels of 4.9 and 9.5 mg/l and an elimination half-life of 1.8 h.

Induction of bacterial mutations by aminopyrazoles, compounds which cause mammary cancer in rats.

An aminopyrazole PD 71627 (5-amino-1,3-dimethyl-1H-pyrazol-4-yl) (2-fluorophenyl)methanone, and two amide derivatives, PD 108298, N-[4-(2-fluorobenzoyl)-1,3-dimethyl-1H-pyrazol-5-yl]-2- ([3-(2-methyl-1- piperidinyl)-propyl]amino) acetamide-(Z)-2-butanedioate (1:2), and PD 109394, 2-(diethylamino)-N-[4-(2- fluorobenzoyl)-1,3-dimethyl-1H-pyrazol-5-yl]acetamide hydrochloride, proposed neuroleptic drugs, were found to elicit mammary adenocarcinomas in male rats after 13 weeks of treatment. These compounds were assessed for their ability to induce His+ revertants (rev) in five strains of Salmonella typhimurium (TA98, TA100, TA1535, TA1537 and TA1538) in the presence and absence of S9 activation. All were found to be potent mutagens in TA98 and TA100 after a 20 min pre-incubation with Aroclor 1254-induced rat liver S9. However, the activity of the amino-pyrazole PD 71627 was much greater than the amide derivatives, PD 108298 or PD 109394, with activity of 11,800 rev/mumol, 670 rev/mumol, and 230 rev/mumol respectively in TA100, the strain showing the greatest response. A comparison of liver S9 fractions from rats untreated or pretreated with phenobarbital (PB) or Aroclor 1254 showed that S9 from animals pretreated with PB provided the greatest activation capability for the aminopyrazole PD 71627 (59,300 rev/mumol in TA100). Three structural analogs of the aminopyrazole PD 71627, two without the amine and one with a methyl substituent on the amine, were compared with PD 71627 for induction of revertants in TA100 and TA98. The compounds without the amine had no mutagenic activity while the methyl derivative induced 3100 rev/mumol in TA100 after preincubation with Aroclor 1254-induced S9. This confirmed that the amine on the pyrazole ring was required for mutagenic activity. The results of these studies support the hypothesis that these compounds cause cancer in animals as a result of DNA damage.