Developing In Vivo Infection Models with MDR Pathogens for Evaluating Compound Efficacy

  • Andrea MarraEmail author


A key challenge in drug discovery is predicting the outcome between in vitro activity and clinical efficacy, but in antibiotic discovery, animal models do a credible job of bridging that gap. The ability to utilize the same epidemic, resistant strains and model dosing regimens to those of humans as well as the ability to target specific tissue sites is a powerful tool for designing clinical trials.


Animal infection models Multidrug-resistant pathogens Antibiotic discovery 


  1. Akers, K., Mende, K., Cheatle, K. A., Zera, W. C., Yu, X., Beckius, M. L., Aggarwal, D., Li, P., Sanchez, C. J., Wenke, J. C., Weintrob, A. C., Tribble, D. R., Murray, C. K., & and the Infectious Disease Clinical Research Program Trauma Infectious Disease Outcomes Study Group. (2014). Biofilms and persistent wound infections in United States military trauma patients: a case-control analysis. BMC Infectious Diseases, 14, 190–200.Google Scholar
  2. Alder, J., Li, T., Yu, D., Morton, L., Silverman, J., Zhang, X.-X., Critchley, I., & Thorne, G. (2003). Analysis of daptomycin efficacy and breakpoint standards in a murine model of Enterococcus faecalis and Enterococcus faecium renal infection. Antimicrobial Agents and Chemotherapy, 47(11), 3562–3566.CrossRefGoogle Scholar
  3. Centers for Disease Control and Prevention. (2013).
  4. Comber, K. R. (1976). Pathogenesis of an experimental pyelonephritis model in the mouse and its use in the evaluation of antibiotics. In J. D. Williams & A. M. Geddes (Eds.), Laboratory aspects of infections (Chemotherapy (Proceedings of the 9th International Congress of Chemotherapy held in London, July, 1975)) (Vol. 2). Boston: Springer.Google Scholar
  5. Comber, K. R., Basker, M. J., Osborne, C. D., & Sutherland, R. (1977). Synergy between ticarcillin and tobramycin against Pseudomonas aeruginosa and Enterobacteriaceae in vitro and in vivo. Antimicrobial Agents and Chemotherapy, 11(6), 956–964.CrossRefGoogle Scholar
  6. Coque, T. M., Baquero, F., & Canton, R. (2008). Increasing prevalence of ESBL-producing Enterobacteriaceae in Europe. Euro Surveillance, 13(47), 1–11.Google Scholar
  7. Cryz, S. J., Furer, E., & Germanier, R. (1983). Simple model for the study of Pseudomonas aeruginosa infections in leukopenic mice. Infection and Immunity, 39(3), 1067–1071.PubMedPubMedCentralGoogle Scholar
  8. Druilhe, P., Hagan, P., & Rook, G. A. W. (2002). The importance of models of infection in the study of disease resistance. Trends in Microbiology, 10(10), S38–S46.CrossRefGoogle Scholar
  9. Endimiani, A., Hujer, K. M., Hujer, A. M., Pulse, M. E., Weiss, W. J., & Bonomo, R. A. (2011). Evaluation of ceftazidime and NXL104 in two murine models of infection due to KPC-producing Klebsiella pneumoniae. Antimicrobial Agents and Chemotherapy, 55(1), 82–85.CrossRefGoogle Scholar
  10. Ford, C. W., Hamel, J. C., Stapert, D., & Yancey, R. J. (1989). Establishment of an experimental model of a Staphylococcal aureus abscess in mice by use of dextran and gelatin microcarriers. Journal of Medical Microbiology, 28, 259–266.CrossRefGoogle Scholar
  11. Fothergill, L. D., Dingle, J. H., & Chandler, C. A. (1937). Studies on Haemophilus influenzae. I. Infection of mice with mucin suspensions of the organism. Journal of Experimental Medicine, 65, 721–735.CrossRefGoogle Scholar
  12. Freedman, L. R. (1966). Experimental pyelonephritis: XIII. On the ability of water diuresis to induce susceptibility to E. coli bacteriuria in the normal rat. Yale Journal of Biology and Medicine, 39(4), 255–266.Google Scholar
  13. Green, G. M., & Kass, E. H. (1963). The role of the alveolar macrophage in the clearance of bacteria from the lung. Journal of Experimental Medicine, 119(1), 167–179.CrossRefGoogle Scholar
  14. Hagberg, L., Engberg, I., Freter, R., Lam, J., Olling, S., & Svanborg Eden, C. (1983). Ascending, unobstructed urinary tract infection in mice caused by pyelonephritogenic Escherichia coli of human origin. Infection and Immunity, 40(1), 273–283.PubMedPubMedCentralGoogle Scholar
  15. Hagberg, L., Hull, R., Hull, S., McGhee, J. R., Michalek, S. M., & Svanborg Eden, C. (1984). Difference in susceptibility to Gram-negative urinary tract infection between C3H/HeJ and C3H/HeN mice. Infection and Immunity, 46(3), 839–844.PubMedPubMedCentralGoogle Scholar
  16. Hagihara, M., Crandon, J. L., Urban, C., & Nicolau, D. P. (2013). Efficacy of doripenem and ertapenem against KC-2-producing and non-KPC-producing Klebsiella pneumoniae with similar MICs. Journal of Antimicrobial Chemotherapy, 68, 1616–1618.CrossRefGoogle Scholar
  17. Hormaeche, C. E. (1979). Natural resistance to Salmonella typhimurium in different inbred mouse strains. Immunology, 37, 311–318.PubMedPubMedCentralGoogle Scholar
  18. Jacobs, A. C., Thompson, M. G., Black, C. C., et al. (2014). AB5075, a highly virulent isolate of Acinetobacter baumannii, as a model strain for the evaluation of pathogenesis and antimicrobial treatments. mBio, 5(3), e1075–e1014.CrossRefGoogle Scholar
  19. Keane, W. F., & Freedman, L. R. (1967). Experimental pyelonephritis. XIV. Pyelonephritis in normal mice produced by inoculation of Escherichia coli into the bladder lumen during water diuresis. Yale Journal of Biology and Medicine, 40(3), 231–237.PubMedGoogle Scholar
  20. Marra, A., Asundi, J., Bartilson, M., Lawson, S., Fang, F., Christine, J., Wiesner, C., Brigham, D., Schneider, W. P., & Hromockyj, A. E. (2002). Differential fluorescence induction analysis of Streptococcus pneumoniae identifies genes involved in pathogenesis. Infection and Immunity, 70(3), 1422–1433.CrossRefGoogle Scholar
  21. Marshall, S., Hujer, A. M., Rojas, L. J., et al. (2017). Can ceftazidime-avibactam and aztreonam overcome β-lactam resistance conferred by metallo-β-lactamases in Enterobacteriaceae? Antimicrobial Agents and Chemotherapy, 61(4), e02243–e02216.CrossRefGoogle Scholar
  22. Nakano, Y., Kasahara, T., Mukaida, N., Ko, Y.-C., Nakano, M., & Matsushima, K. (1994). Protection against lethal bacterial infection in mice by monocyte-chemotactic and -activating factor. Infection and Immunity, 62(2), 377–383.PubMedPubMedCentralGoogle Scholar
  23. Nordmann, P., Poirel, L., & Toleman, M. A. (2011). Does broad-spectrum β-lactam resistance due to NDM-1 herald the end of the antibiotic era for treatment of infections caused by Gram-negative bacteria? Journal of Antimicrobial Chemotherapy, 66, 689–692.CrossRefGoogle Scholar
  24. Olotzki, K. (1948). Mucin as a resistance-lowering substance. Bacteriological Review, 12, 149–172.Google Scholar
  25. Percival, S. L., McCarty, S. M., & Lipsky, B. (2015). Biofilms and wounds: An overview of the evidence. Advances in Wound Care, 4(7), 373–381.CrossRefGoogle Scholar
  26. Potter, R. F., D’Souza, A. W., & Dantas, G. (2016). The rapid spread of carbapenem-resistant Enterobacteriaceae. Drug Resistance Updates, 29, 30–46.CrossRefGoogle Scholar
  27. Sawai, T., Tomono, K., et al. (1997). Role of coagulase in a murine model of hematogenous pulmonary infection induced by intravenous injection of Staphylococcus aureus enmeshed in agar beads. Infection and Immunity, 65(2), 466–471.PubMedPubMedCentralGoogle Scholar
  28. Singh, R., Kim, A., Tanudra, M. A., Harris, J. J., McLaughlin, R. E., Patey, S., O’Donnell, J. P., Bradford, P. A., & Eakin, A. E. (2015). Pharmacokinetics/pharmacodynamics of a β-lactam and β-lactamase inhibitor combination: A novel approach for aztreonam/avibactam. Journal of Antimicrobial Chemotherapy, 70, 2618–2626.CrossRefGoogle Scholar
  29. Soubirou, J. F., Rossi, B., Couffignal, C., Ruppe, E., Chau, F., Massius, L., Lepeule, R., Mentre, F., & Fantin, B. (2015). Activity of temocillin in a murine model of urinary tract infection due to Escherichia coli producing or not producing the ESBL CTX-M-15. Journal of Antimicrobial Chemotherapy, 70, 1466–1472.CrossRefGoogle Scholar
  30. Sykes, R. B., Griffiths, A., & Ryan, D. M. (1977). Comparative activity of ampicillin and cefuroxime against three types of Haemophilus influenzae. Antimicrobial Agents and Chemotherapy, 11(4), 599–604.Google Scholar
  31. Tang, H.-J., Chuang, Y.-C., Ko, W.-C., Chen, C.-C., Shieh, J.-M., Chen, C.-H., Lee, N.-Y., & Chiang, S.-R. (2012). Comparative evaluation of intratracheal colistimethate sodium, imipenem, and meropenem in BALB/c mice with carbapenem-resistant Acinetobacter baumannii pneumonia. International Journal of Infectious Diseases, 16, e34–e40.CrossRefGoogle Scholar
  32. Thaden, J. T., Pogue, J. M., & Kaye, K. S. (2017). Role of newer and re-emerging older agents in the treatment of infections caused by carbapenem-resistant Enterobacteriaceae. Virulence, 8(4), 403–416.CrossRefGoogle Scholar
  33. Thomas, W. E., Trintchina, E., Forero, M., Vogel, V., & Sokurenko, E. V. (2002). Bacterial adhesion to target cells enhanced by shear force. Cell, 109, 913–923.CrossRefGoogle Scholar
  34. Thompson, M. G., Black, C. C., Pavlicek, R. L., Honnold, C. L., Wise, M. C., Alamneh, Y. A., Moon, J. K., Kessler, J. L., Si, Y., Williams, R., Yildirim, S., Kirkup, B. C., Jr., Green, R. K., Hall, E. R., Palys, T. J., & Zurawski, D. V. (2013). Validation of a novel murine wound model of Acinetobacter baumannii infection. Antimicrobial Agents and Chemotherapy, 58(3), 1332–1342.CrossRefGoogle Scholar
  35. van Heeckeren, A. M., & Schluchter, M. D. (2002). Murine models of chronic Pseudomonas aeruginosa lung infection. Laboratory Animals, 36, 291–312.CrossRefGoogle Scholar
  36. Williams, B. J., Dehnbostel, J., & Blackwell, T. S. (2010). Pseudomonas aeruginosa: Host defense in lung diseases. Respirology, 15, 1037–1056.CrossRefGoogle Scholar
  37. Woodford, N., Carattoli, A., Karisik, E., Underwood, A., Ellington, M. J., & Livermore, D. M. (2009). Complete nucleotide sequences of plasmids pEK204, pEK499 and pEK516, encoding CTX-M enzymes in three major Escherichia coli lineages from the United Kingdom, all belonging to the international 025:H4-ST131 clone. Antimicrobial Agents and Chemotherapy, 53(10), 4472–4482.CrossRefGoogle Scholar
  38. Zak, O., & Sande, M. A. (1999). In O. Zak & M. A. Sande (Eds.), Handbook of animal models of infection. Experimental models in antimicrobial chemotherapy. London: Academic Press.Google Scholar
  39. Zhao, G., Usui, M. L., Lippman, S. I., James, G. A., Stewart, P. S., Fleckman, P., & Olerud, J. E. (2013). Biofilms and inflammation in chronic wounds. Advances in Wound Care, 2(7), 389–399.CrossRefGoogle Scholar
  40. Zhi, J., Nightingale, C. H., & Quintiliani, R. (1988). Microbial pharmacodynamics of pipericillin in neutropenic mice of systemic infection due to Pseudomonas aeruginosa. Journal of Pharmacokinetics and Biopharmaceutics, 16(4), 355–375.CrossRefGoogle Scholar

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© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Micromyx, IncKalamazooUSA

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