In vitro activities and targets of three cephem antibiotics against Haemophilus influenzae.

The antimicrobial activities of cefixime, cefpodoxime, and ceftibuten were determined with 18 ampicillin-susceptible (Amps), 13 ampicillin-resistant beta-lactamase-producing (AmprBLP), and 7 ampicillin-resistant non-beta-lactamase-producing (AmprNBLP) strains of Haemophilus influenzae. An effect of inoculum density on apparent MIC, the bactericidal activity of these agents, and the targets of the three cephems were determined. The MICs of cefixime, cefpodoxime, and ceftibuten for 90% of the Amps and AmprBLP isolates were 0.04, 0.08, and 0.08 microgram/ml, respectively. In contrast, the MICs for 90% of the AmprNBLP strains were 0.96, 1.92, and 7.68 micrograms/ml. No significant inoculum effect was observed for any group of strains comparing inocula of 10(3) and 10(5) CFU, whereas only the AmprNBLP isolates showed a marked effect at an inoculum of 10(6) CFU. Although bactericidal levels were achieved for the Amps and AmprBLP strains, tolerance to cefixime and ceftibuten was observed. The bactericidal activity for the AmprNBLP strains was limited, with cefixime showing the highest activity of the three cephems. Penicillin-binding proteins 2, 4, and 5 revealed high affinity, with 50% inhibitory concentration levels below the MIC for all three cephems, suggesting that these are important targets of these agents in H. influenzae. We conclude that the cephems are highly active in vitro against Amps and AmprBLP strains of H. influenzae, but less so against AmprNBLP isolates.

The effect of hyperthermia on the cytotoxicity of melphalan in Chinese hamster ovary cells.

The heat stability of melphalan during incubation at temperatures from 37 degrees C to 45 degrees C was determined by spectrophotometric and HPLC analyses and by direct measurement of melphalan cytotoxicity using a colonogenic assay Although OD 250 changed little during exposure to temperatures up to 45 degrees C for periods of up to 1 h, the melphalan HPLC peak decreased as function of incubation time and temperature. Loss of cytotoxicity following heating paralleled the decay of the melphalan HPLC peak. Despite the inactivation of melphalan by heat, the cytotoxic effects of melphalan were enhanced at elevated temperatures from 38 degrees C to 42 degrees C and synergism was observed at lethal temperatures above 42 degrees C.