Use of Carbapenems against Clinical, Nontyphoid Salmonella Isolates: Results fromIn VitroandIn VivoAnimal Studies

Abstract

ABSTRACTThe emergence of multidrug-resistantSalmonellaisolates has created the need for new therapeutic agents. We evaluated the intracellular activity of four carbapenem compounds against clinical nontyphoidSalmonella(NTS) isolatesin vitroandex vivo. Subsequently, the efficacy of carbapenem treatment against selectedSalmonellaisolatesin vivowas assessed using a murine peritonitis model. The MIC50and MIC90for doripenem, ertapenem, imipenem, and meropenem against 126 NTS isolates were found to be 0.062 and 0.062, 0.015 and 0.015, 0.5 and 1, and 0.031 and 0.031 μg/ml, respectively. The intracellular killing effect of ertapenem was sustained for 24 h and was superior to that of imipenem, meropenem, and doripenem; its effect was comparable to that of ceftriaxone. Ertapenem demonstrated an excellent pharmacokinetic profile with a percent time above the MIC of 75.5% and an area under the concentration-time curve/MIC ratio of 20,733. When peritoneal exudate cells were examined directlyex vivofrom mice withSalmonella-induced peritonitis, cells from mice treated with ertapenem and ceftriaxone had intracellular and extracellular bacterial counts reduced 102- to 104-fold and exhibited killing effects similar to each other. The survival rates of mice inoculated with 1 × 105and 106CFU of a ceftriaxone-susceptibleSalmonellaisolate that were subsequently treated with ertapenem or ceftriaxone were 100% and 90%, respectively. When mice were inoculated with 5 × 104and 105CFU of a ceftriaxone-resistant and ciprofloxacin-resistantSalmonellaisolate, mice treated with ertapenem had a higher survival rate than mice treated with ceftriaxone (70% versus 0% and 50% versus 0%, respectively;P< 0.001). Our results suggest that ertapenem is at least as effective as ceftriaxone in treating murineSalmonellainfections and show that further clinical investigations on the potential use of ertapenem in treatment of humanSalmonellainfections are warranted.