The Epidemiology of Invasive, Multipleantibiotic–resistantKlebsiella pneumoniaeInfection in a Breeding Colony of Immunocompromised NSG Mice

Abstract

Klebsiella pneumoniae (Kp) is a gram-negative opportunistic pathogen that causes severe pneumonia, pyelonephritis, and sepsis in immunocompromised hosts. During a 4-mo interval, several NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) breeders and pups in our facilities were diagnosed with Kp infections. An initial 6 adult and 1 juvenile NSG mice were submitted for necropsy and histologic examination because of acute onset of diarrhea and death. The evaluation revealed typhlocolitis in 2 of the mice and tritrichomoniasis in all 7. Escherichia coli positive for polyketide synthase (pks+) and Kp were isolated from the intestines. Given a history of sepsis due to pks+ E. coli in NSG mice in our facilities and determination of its antimicrobial susceptibility, trimethoprim–sulfamethoxazole (TMP–SMX) was administered to the colony in the drinking water for 4 wk. After this intervention, an additional 21 mice became ill or died; 11 of these mice had suppurative pneumonia, meningoencephalitis, hepatitis, metritis, pyelonephritis, or sepsis. Kp was cultured from pulmonary abscesses or blood of 10 of the mice. Whole-genome sequencing (WGS) indicated that the Kp isolates contained genes associated with phenotypes found in pore-forming Kp isolates cultured from humans with ulcerative colitis and primary sclerosing cholangitis. None of the Kp isolates exhibited a hyperviscous phenotype, but 13 of 14 were resistant to TMP–SMX. Antimicrobial susceptibility testing indicated sensitivity of the Kp to enrofloxacin, which was administered in the drinking water. Antibiotic sensitivity profiles were confirmed by WGS of the Kp strains; key virulence and resistance genes to quaternary ammonia compounds were also identified. Enrofloxacin treatment resulted in a marked reduction in mortality, and the study using the NSG mice was completed successfully. Our findings implicate intestinal translocation of Kp as the cause of pneumonia and systemic infections in NSG mice and highlight the importance of identification of enteric microbial pathogens and targeted antibiotic selection when treating bacterial infections in immunocompromised mice.

Next-Generation Sequencing-Based Identification of Enterobacter hormaechei as Causative Agent of High Mortality Disease in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) Mice

“…37 More recently, Klebsiella pneumoniae was implicated as causing typhlocolitis, septicemia, and systemic disease including pneumonia and meningoencephalitis in a breeding colony of NSG mice. 44 A critical component of laboratory animal medicine is the protection of animal health and integrity of research by ensuring animals are free of infectious diseases. 32 Laboratory animal facilities have relied on diagnostic and surveillance methods including serology and polymerase chain reaction (PCR) to exclude harmful pathogens.…”

“…37 More recently, Klebsiella pneumoniae was implicated as causing typhlocolitis, septicemia, and systemic disease including pneumonia and meningoencephalitis in a breeding colony of NSG mice. 44…”

Chlamydia muridarum infection causes bronchointerstitial pneumonia in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice

“…13,16,21 These defects in adaptive and innate immunity result in severe immunosuppression leaving the mice susceptible to opportunistic bacterial agents including Enterococcus spp., Klebsiella pneumoniae, Klebsiella oxytoca, pks + Escherichia coli , and others. 5,22…”

“…13,16,21 These defects in adaptive and innate immunity result in severe immunosuppression leaving the mice susceptible to opportunistic bacterial agents including Enterococcus spp., Klebsiella pneumoniae, Klebsiella oxytoca, pks + Escherichia coli, and others. 5,22 Chlamydia spp. represent a diverse group of gram-negative obligate intracellular bacteria known for causing disease in numerous animal species and humans.…”

Epizootic of enterocolitis and clostridial overgrowth in NSG and NSG-related mouse strains

“…Another report described an epidemic of antibiotic resistant Klebsiella pneumoniae with gastrointestinal disease leading to systemic infections and sudden death in an NSG breeding colony. 27 NSG and NSG-related mouse colonies have more recently been the target of diarrheal outbreaks in multiple facilities. 18,21 In one report, rapid spread of low-mortality diarrheal disease throughout a barrier facility led to its depopulation before fecal microbiome profiling suggested intestinal dysbiosis may have been causal.…”