Use of Carbapenems against Clinical, Nontyphoid Salmonella Isolates: Results from In Vitro and In Vivo Animal Studies

Abstract

fThe emergence of multidrug-resistant Salmonella isolates has created the need for new therapeutic agents. We evaluated the intracellular activity of four carbapenem compounds against clinical nontyphoid Salmonella (NTS) isolates in vitro and ex vivo. Subsequently, the efficacy of carbapenem treatment against selected Salmonella isolates in vivo was assessed using a murine peritonitis model. The MIC 50 and MIC 90 for 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 g/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 directly ex vivo from mice with Salmonella-induced peritonitis, cells from mice treated with ertapenem and ceftriaxone had intracellular and extracellular bacterial counts reduced 10 2 -to 10 4 -fold and exhibited killing effects similar to each other. The survival rates of mice inoculated with 1 ؋ 10 5 and 10 6 CFU of a ceftriaxone-susceptible Salmonella isolate that were subsequently treated with ertapenem or ceftriaxone were 100% and 90%, respectively. When mice were inoculated with 5 ؋ 10 4 and 10 5 CFU of a ceftriaxone-resistant and ciprofloxacin-resistant Salmonella isolate, 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 murine Salmonella infections and show that further clinical investigations on the potential use of ertapenem in treatment of human Salmonella infections are warranted.

Isolation, serotype diversity and antibiogram of Salmonella enterica isolated from different species of poultry in India

“…High sensitivity to chloramphenicol was similar to that of Elmadiena et al who also found majority of their Salmonella isolates sensitive to chloramphenicol [48] . Also, high susceptibility of isolates to meropenem was in agreement to results of Tang et al who found meropenem a good therapeutic option in testing various multidrug resistant Salmonella isolates [49] .…”

Organoid and Enteroid Modeling of Salmonella Infection

“…Many experimental models have been developed to study Salmonella infections including various in vitro, ex vivo , and in vivo models (Table 1 ). The most commonly used ones are the two-dimensional (2-D) immortalized cell line models including the Caucasian colon adenocarcinoma (Caco2) cells (Martinez-Argudo and Jepson, 2008 ), the immature human normal fetal intestinal epithelial cells (H4) (Newburg et al, 2016 ), the mature human metastatic colonic epithelial cells (T84) (Newburg et al, 2016 ), the human normal colon mucosal epithelial cells (NCM-460) (Newburg et al, 2016 ), the Microfold cells (or M cells) (Martinez-Argudo and Jepson, 2008 ), the RAW 264.7 murine macrophage cells (Tang et al, 2012 ), the cervical cancer (HeLa) cells (Fang et al, 2017 ), and the gut fermentation models (Le Blay et al, 2009 ). In addition, three-dimensional (3-D) organotypic models derived from the Int-407 cell line (later found to be a HeLa derivative) and the human colorectal adenocarcinoma cells (HT-29) (Nickerson et al, 2001 ; Höner Zu Bentrup et al, 2006 ).…”