Persistent Bacteremia in Rabbit Fetuses despite Maternal Antibiotic Therapy in a Novel Intrauterine-Infection Model

Abstract

ABSTRACT The effect of optimized maternal therapy by bactericidal agents was evaluated in a reproducible rabbit model of Escherichia coli maternofetal infection simulating human pharmacokinetics. Intravenous antibiotic therapy was begun in the pregnant rabbit 12 h after bacterial intrauterine inoculation, using a computer-controlled pump to simulate human pharmacokinetics of ceftriaxone (1 g/day) associated or not with gentamicin (3 mg/kg of body weight/day). Data were compared for fetal survival, quantitative blood cultures, fetal histology in treated versus untreated groups, and maternal and fetal antibiotic concentrations in plasma in treated animals. Antibiotic therapy led to dramatic improvement in maternal outcome (100% survival versus 100% death in the untreated group in association with maternal septicemia). Fetal survival also improved, with the two-drug combination providing a more potent effect. After 3 days of treatment, 32% of fetuses survived with one-drug therapy and 62% with two-drug therapy (Yates corrected χ 2 , P < 0.05). In untreated animals, bacterial counts in blood cultures increased rapidly during the first 24 h up to 8.1 ± 0.5 log CFU/ml, but remained relatively constant at all times with antibiotic treatment: 4.5 ± 0.7 log CFU/ml at the start of treatment and 6.2 ± 0.4 and 5.2 ± 0.9 log CFU/ml after 72 h for one- and two-drug therapy, respectively (data are means ± standard deviations). The failure of animals to be cured after 3 days of treatment was not due to an inadequate concentration of ceftriaxone, as the residual level in fetal serum at sacrifice was more than 1,000 times the MIC of the microbe. Unexpectedly, inflammation in fetal lung decreased in the treated group after as little as 24 h of antibiotic therapy, despite persistent bacteremia. Although maternal outcome improved and drug concentrations were above the MIC, the treatment did not achieve sterilization of fetuses in utero for this rabbit E. coli maternofetal infection. However, fetal survival showed some improvement, and the histologic features of lung inflammation were reduced.