Klebsiella pneumoniae Infection Models

Klebsiella pneumoniae (K. pneumoniae) is a leading cause of drug-resistant healthcare-associated infection and the organism after which the most common carbapenemase – Klebsiella pneumoniae carbapenemase (KPC) – is named. It can cause infection at several body sites, most often the lungs, bloodstream, and urinary tract, and does so predominantly in hospitalized and immunocompromised patients. TransPharm Preclinical Solutions’s validated in vivo models cover the principal infection types of K. pneumoniae, including carbapenem-resistant strains, and produce the quantitative efficacy data that a development program needs.

K. pneumoniae is a Gram-negative bacterium of the Enterobacterales order and a normal resident of the human gut. In vulnerable patients, it becomes an opportunistic pathogen, causing pneumonia, bacteremia, urinary tract infection, and meningitis, and it spreads readily in healthcare settings. As one of the six ESKAPE pathogens, it also has strong capacity to acquire and disseminate antibiotic resistance, including resistance to carbapenems. This combination is what makes reproducible preclinical models essential to developing new therapies.

Because K. pneumoniae causes disease at several body sites, a meaningful efficacy study begins by matching the model to the target syndrome (respiratory, systemic or intra-abdominal, or urinary) and matching the challenge strain to the relevant resistance profile. TransPharm Preclinical Solutions’s validated models cover the three principal presentations, and its validated strains include both a virulence reference strain and a carbapenem-resistant clinical isolate, so a candidate can be tested in the disease context and against the resistance background that fit its intended use.

TransPharm Preclinical Solutions has validated K. pneumoniae using strain ATCC 43816 (pulmonary infection) and the carbapenem-resistant NDM-1 strain ATCC BAA-2146 (peritonitis and urinary tract infection). 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

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. This model is validated for K. pneumoniae with the carbapenem-resistant strain ATCC BAA-2146. Validated in mice and rats.

Infection is established by intranasal (IN) or intratracheal (IT) instillation, modeling K. pneumoniae respiratory disease. Endpoints include survival and CFU burden in the lungs and other harvested tissues. Validated for K. pneumoniae with the reference strain ATCC 43816. Validated in mice and rats.

An ascending urinary tract infection is established by intraurethral challenge. 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 kidney and bladder – and blood. Validated for K. pneumoniae with the carbapenem-resistant strain ATCC BAA-2146. Validated in mice.

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 carbapenem-resistant isolates, where combination regimens are frequently required.

Carbapenem-resistant Enterobacterales (CRE) are classified by the CDC as an urgent threat and by the WHO as a critical-priority group. K. pneumoniae is the most common CRE organism; the carbapenemase most associated with the group, KPC, is named for it. Resistance is most often conferred by carbapenemase enzymes, including KPC, NDM, OXA-48-type, VIM, and IMP, which hydrolyze carbapenems and most other beta-lactams; a second route combines outer-membrane porin loss with an ESBL or AmpC enzyme. These mechanisms leave few reliable treatment options and make CRE a priority target for new antimicrobial development.

TransPharm Preclinical Solutions maintains and has validated a carbapenem-resistant K. pneumoniae strain (ATCC BAA-2146, an NDM-1 producer) in vivo, and evaluates candidates against it in the peritonitis and urinary tract infection models. Characterized carbapenem-resistant isolates can also be sourced and validated to a program’s specifications, and client-supplied strains are welcome. Carbapenem resistance occurs across the Enterobacterales; for carbapenem-resistant E. coli and Enterobacter cloacae, see the E. coli and Enterobacter cloacae pages.