INFLUENCE OF ANTIMICROBIAL THERAPY ON KINETICS OF TUMOR-NECROSIS-FACTOR LEVELS IN EXPERIMENTAL ENDOCARDITIS CAUSED BY KLEBSIELLA-PNEUMONIAE

The kinetics of tumor necrosis factor (TNF) levels in serum during the rapy with cell wall-active agents (ceftriaxone, imipenem) and gentamic in were investigated in rabbits with experimental endocarditis caused by an isogenic pair of Klebsiella pneumoniae strains: a TEM-3 beta-lac tamase-producing strain (KpR) or its susceptible variant (KpS). In vit ro, KpR was resistant to ceftriaxone and was susceptible to gentamicin and imipenem, while KpS was susceptible to all three antibiotics. Ser um TNF levels were determined in control rabbits hourly after bacteria l inoculation and then daily; they were determined in treated animals hourly after the first antibiotic injection and then daily during a 4- day therapy with either imipenem (60 mg/kg of body weight four times d aily), ceftriaxone (75 mg/kg once daily), or gentamicin (4 mg/kg once daily) alone or in combination with ceftriaxone. After a transient pea k (10.2 +/- 3.1 ng/ml) at 90 min following bacterial challenge, serum TNF levels remained low and stable in control animals. The peak in the serum TNF levels occurred 4 h after the first antibiotic injection an d with ceftriaxone was significantly higher (P < 0.05) against KpS (1. 99 +/- 0.52 ng/ml) than against KpR (1.40 +/- 0.17 ng/ml). Against the KpR strain, the levels observed with ceftriaxone were significantly h igher (P < 0.05) than those obtained with the other therapeutic regime ns (0.70 to 0.80 ng/ml). On the day of sacrifice, effective regimens w ere associated with low TNF levels. We concluded that TNF production d epends on (i) the antibiotic's mechanism of action and the susceptibil ity of the strain at the early phase of therapy, without any effect of the rapidity of bacterial killing, and (ii) the final reduction of th e bacterial count at a later stage of therapy.