Abstract
We developed a new animal model to study antibiotic synergy in neutropenia. Infant rats were rendered neutropenic by 3 intraperitoneal (IP) 50 mg/kg doses of cytarabine over 36 hrs. Mean absolute neutrophil counts were <300/mm3 on post-treatment days 3-8 and normalized on days 9-10, with <1% mortality. Pseudomonas aeruginosa (PA) with MIC/MBC of Amikacin (A) = 8/16 μg/ml and N-formimidoyl thienamycin (T) = 4/8 μg/ml was studied; no synergy between A and T was demonstrated by the killing curve method. Neutropenic rats, inoculated IP with 2-6×106 CFU of PA (∼200 LD5 0), were treated IP 4 hrs later with: saline (S); A 10 mg/kg; T 6.25 mg/kg; A + T (same doses); or A/2 + T/2, each every 6 hrs for 48 hrs. Peak serum levels of eahc antibiotic were less than the MIC/MBC for PA. Six hrs after the last dose, survival (# alive/#treated) was as shown:
In vivo, both half-dose and full-dose combination therapy produced significantly greater survival than either agent alone. A + T was superior to T (p<0.005) and to A (p< 0.001), and A/2 + T/2 was superior to T (p<0.01) and to A (p<0.001) by X2 analysis. This new, reproducible infant rat model of neutropenia enabled us to demonstrate "synergism" between A + T in Pseudomonas aeruginosa sepsis when in vitro synergy for this organism was not evident.
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Chadwick, E., Yogev, R. & Shulman, S. PSEUDOMONAS AERUGINOSA SEPSIS IN THE NEUTROPENIC HOST: IN VIVO SURGERY BETWEEN N-FORMIMIDOYL THIENAMYCIN AND AMIKACIN. Pediatr Res 18 (Suppl 4), 237 (1984). https://doi.org/10.1203/00006450-198404001-00867
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DOI: https://doi.org/10.1203/00006450-198404001-00867