Escherichia coli & ESBL Infection Models

Escherichia coli (E. coli) is the most common cause of urinary tract infection and a leading cause of Gram-negative bloodstream infection. It ranges from a harmless gut commensal to a virulent, multidrug-resistant pathogen depending on the strain. This diversity means that candidate efficacy has to be established against a defined strain in a defined disease model, not against E. coli in the abstract. TransPharm Preclinical Solutions’s validated in vivo models cover its principal infection types and produce the quantitative efficacy data a development program needs.

E. coli is a Gram-negative bacterium of the Enterobacterales order, found in the human gut, the environment, and contaminated food and water. Most strains are harmless commensals, but pathogenic strains can cause urinary tract infection, bloodstream and intra-abdominal infection, and diarrheal disease, and can progress to sepsis. Its clinical relevance is compounded by resistance: E. coli is the leading producer of extended-spectrum beta-lactamases (ESBLs) and a significant carrier of other transmissible resistance genes.

Because E. coli is so diverse, strain selection is the first design decision in an efficacy study; a uropathogenic isolate, a bloodstream isolate, and a resistant clinical isolate behave differently, and the model has to match the target indication. TransPharm Preclinical Solutions’s three validated models cover the infection types most relevant to E. coli drug development: urinary tract infection, peritonitis, and soft tissue infection.

TransPharm Preclinical Solutions has validated E. coli using uropathogenic isolates in the urinary tract infection model and additional isolates across the peritonitis and soft tissue models, including a carbapenem-resistant clinical strain. TransPharm Preclinical Solutions also maintains an on-site library of hundreds of validated pathogens, including many multidrug-resistant strains. Additional isolates, including sponsor-supplied or characterized resistant strains, can be sourced and validated to a program’s specifications upon request. Studies are available in mice, with rats available for some models.

Every study parameter – challenge strain, route of administration, comparator agents, and dosing schedule – is configurable to the scientific question. The core readouts are quantitative bacterial burden (CFU/g or CFU/mL) in target tissues, organs, and blood, with survival and mortality tracking where applicable.

The following are available as add-ons to any study:

• Pharmacokinetic profiling and PK/PD analysis
• Blood chemistry
• Additional tissue harvests
• Histopathology

An ascending urinary tract infection is established by intraurethral challenge, the model most relevant to uropathogenic E. coli. Test article can be delivered by oral gavage (PO) or by intraurethral, subcutaneous (SC), intraperitoneal (IP), or intravenous (IV) routes. The endpoint is CFU burden in harvested organs, including the kidney and bladder, and blood. Validated with uropathogenic E. coli CFT073 (ATCC 700928). Validated in mice.

Animals are challenged by intraperitoneal injection, with gastric mucin used to help establish infection where needed. Endpoints include survival (mortality tracking) and CFU burden in harvested organs and blood, supporting both lethality- and burden-based efficacy readouts. Validated in mice and rats. Validated isolates include the carbapenem-resistant (NDM-1) strain ATCC BAA-2469, along with additional isolates noted in the questions below.

Animals are challenged by intramuscular injection into one or both quadriceps — a configuration well suited to pharmacokinetic/pharmacodynamic characterization. Endpoints include bacterial burden in muscle and other harvested tissues, with survival tracking available. Validated in mice. Validated isolates include E. coli ATCC 25922, along with an additional isolate noted in the questions below.

In vitro susceptibility testing complements the in vivo models. TransPharm Preclinical Solutions runs MIC by agar and broth dilution per CLSI, along with MBC, time-kill kinetics, and checkerboard analysis. Checkerboard analysis is particularly relevant for resistant isolates, where combination regimens are frequently required.

E. coli is the leading producer of extended-spectrum beta-lactamases (ESBLs): plasmid-borne enzymes that hydrolyze most penicillins, the extended-spectrum (third-generation) cephalosporins, and monobactams, and that are now dominated worldwide by the CTX-M family. ESBL-producing E. coli spreads through both community and healthcare settings and is a frequent cause of empiric-therapy failure, since it defeats several of the beta-lactams that would otherwise be first-line treatments.

TransPharm Preclinical Solutions evaluates candidates against resistant E. coli in the same validated infection models described above. ESBL-producing isolates can be sourced and validated to your program’s specifications, and client-supplied resistant strains are welcome. TransPharm Preclinical Solutions’s validated E. coli library also includes a carbapenem-resistant (NDM-1) strain, ATCC BAA-2469; carbapenem resistance across the Enterobacterales is covered on the Klebsiella pneumoniae page.