Imipenem therapy of Pseudomonas aeruginosa bacteraemia in neutropenic rats

Abstract

Rats were made neutropenic by intraperitoneal (ip) injection of cyclophosphamide. Those neutropenic (mean white blood cell count of 470/mm ³ ) rats were challenged intraperitoneally with Pseudomonas aeruginosa to assess the efficacy of single agent therapy with either imipenem, latamoxef (moxalactam) or amikacin, or combination therapy with imipenem-amikacin or latamoxef (moxalactam)—amikacin. Pharmacokinetic studies were performed in rats to assure that therapy was equivalent during therapeutic trials. Three levels of bacterial challenge (4 LD ₅₀ , 13 LD ₅₀ and 250 LD ₅₀ ) were examined. At all challenge levels, single agent therapy with latamoxef (moxalactam) failed to significantly protect rats from fatal bacteraemia. Single-agent therapy with amikacin did significantly protect rats from fatal bacteraemia at the lower challenge levels, but not at the 250 LD ₅₀ challenge. Single agent therapy with imipenem significantly protected rats at all challenge levels. In-vitro studies established a synergistic effect when combination antibiotics were used. This correlated with in-vivo findings that combination therapy resulted in improved rat survival and recovery of fewer Ps. aeruginosa isolates. The latamoxef (moxalactam)-amikacin combination was more effective than either agent alone, but was not more effective than imipenem alone. The imipenem-amikacin combination was the most effective therapeutic regimen tested. These results suggest that imipenem alone, and particularly when combined with an aminoglycoside, is effective in treating serious Ps. aeruginosa infections in neutropenic rats. Clinical studies in infected immunocompromised patients may be warranted.