Advertisement

A Review of Animal Models Used for Antibiotic Evaluation

Chapter

Abstract

One of the foremost challenges of drug discovery in any therapeutic area is solidifying the correlation between in vitro activity and clinical efficacy. Intermediate between those two points is the validation that affecting a particular target in vivo will lead to a therapeutic benefit. In antibacterial drug discovery, there is an implicit advantage from the start, in that the targets are bacteria, and it is relatively straightforward to ascertain in vitro whether a compound has the desired effect (i.e., bacterial cell killing) and to understand the mechanism by which that occurs. The downstream criteria, whether a compound reaches the site of infection and attains levels necessary to affect bacterial viability, can be evaluated in animal models of infection. That is, once it is clear that a test compound is able to kill bacteria, and it is established that it can achieve appropriate concentrations in infection sites, it is possible to extrapolate that the desired clinical effect can be expected. In this way, animal models of infection can be a highly valuable and predictive bridge between in vitro drug discovery and early clinical evaluation.

Keywords

Bacterial Count Inoculum Size Infection Model Bacterial Inoculum Bacterial Reduction 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Nuermberger E (2005) Murine models of pneumococcal pneumonia and their applicability to the study of tissue-directed antimicrobials. Pharmacotherapy 25(12 Pt 2):134S–139SPubMedCrossRefGoogle Scholar
  2. 2.
    Jacobs MR (2007) Combating resistance: application of the emerging science of pharmacokinetics and pharmacodynamics. Int J Antimicrob Agents 30S:S122–S126CrossRefGoogle Scholar
  3. 3.
    Zak O, O’Reilly T (1993) Animal infection models and ethics – the perfect infection model. J Antimicrob Chemother 31(suppl D):193–205Google Scholar
  4. 4.
    Druilhe P, Hagan P, Rook GAW (2002) The importance of models of infection in the study of disease resistance. Trends Microbiol 10(10):S38–S46PubMedCrossRefGoogle Scholar
  5. 5.
    Lam-Yuk-Tseung S, Gros P (2003) Genetic control of susceptibility to bacterial infections in mouse models. Cell Microbiol 5(5):299–313PubMedCrossRefGoogle Scholar
  6. 6.
    Cooke GS, Hill AVS (2001) Genetics of susceptibility to human infectious diseases. Nat Rev Genet 2:967–977PubMedCrossRefGoogle Scholar
  7. 7.
    Hagberg L, Hull R, Hull S et al (1984) Difference in susceptibilty to Gram-negative urinary tract infection between C3H/HeJ and C3H/HeN mice. Infect Immun 46(3):839–844PubMedGoogle Scholar
  8. 8.
    Hormaeche CE (1979) Natural resistance to Salmonella typhimurium in different inbred mouse strains. Immunology 37:311–318PubMedGoogle Scholar
  9. 9.
    Tam M, Snipes GJ, Stevenson MM (1999) Characterization of chronic broncopulmonary Pseudomonas aeruginosa infection in resistant and susceptible inbred mouse strains. Am J Respir Cell Mol Biol 20:710–719PubMedGoogle Scholar
  10. 10.
    Gingles NA, Alexander JE, Kadioglu A et al (2001) Role of genetic resistance in invasive pneumococcal infection: identification and study of susceptibility and resistance in inbred mouse strains. Infect Immun 69(1):426–434PubMedCrossRefGoogle Scholar
  11. 11.
    Nakano Y, Kasahara T, Mukaida N et al (1994) Protection against lethal bacterial infection in mice by monocyte-chemotactic and -activating factor. Infect Immun 62(2):377–383PubMedGoogle Scholar
  12. 12.
    Zhi J, Nightingale CH, Quintiliani R (1988) Microbial pharmacodynamics of pipericillin in neutropenic mice of systemic infection due to Pseudomonas aeruginosa. J Pharmacokinet Biopharm 16(4):355–375PubMedCrossRefGoogle Scholar
  13. 13.
    Cryz SJ, Furer E, Germanier R (1983) Simple model for the study of Pseudomonas aeruginosa infections in leukopenic mice. Infect Immun 39(3):1067–1071PubMedGoogle Scholar
  14. 14.
    Goodner K, Horsfall FL (1935) The protective action of type I antipneumococcus serum in mice. J Exp Med 62:359–374PubMedCrossRefGoogle Scholar
  15. 15.
    Zak O, O’Reilly T (1990) Animal models as predictors of the safety and efficacy of antibiotics. Eur J Clin Microbiol Infect Dis 9(7):472–478PubMedCrossRefGoogle Scholar
  16. 16.
    Zak O, Sande MA (eds) (1999) Handbook of animal models of infection. Experimental models in antimicrobial chemotherapy. Academic, LondonGoogle Scholar
  17. 17.
    Marra A, Girard D (2006) Primary rodent infection models for testing of compound efficacy in vivo. In: Barrett J (ed) Current protocols in pharmacology. Wiley, RochesterGoogle Scholar
  18. 18.
    Dagan R (2003) Achieving bacterial eradication using pharmacokinetic/pharmacodynamic principles. Int J Infect Dis 7(suppl 1):S21–S26PubMedCrossRefGoogle Scholar
  19. 19.
    Fantin B, Leggett J, Ebert S et al (1991) Correlation between in vitro and in vivo activity of antimicrobial agents against Gram-negative bacilli in a murine infection model. Antimicrob Agents Chemother 35(7):1413–1422PubMedGoogle Scholar
  20. 20.
    Girard D, Finegan SM, Dunne MW (2005) Enhanced efficacy of single-dose versus multi-dose azithromycin regimens in preclinical infection models. J Antimicrob Chemother 56:365–371PubMedCrossRefGoogle Scholar
  21. 21.
    Soley C, Arguedas A (2005) Single-dose azithromycin for the treatment of children with acute otitis media. Expert Rev Anti Infect Ther 3(5):707–717PubMedCrossRefGoogle Scholar
  22. 22.
    Albus A, Arbeit RD, Lee JC (1991) Virulence of Staphylococcus aureus mutants altered in Type 5 capsule production. Infect Immun 59(3):1008–1014PubMedGoogle Scholar
  23. 23.
    Van den Bosch JF, de Graff J, MacLaren DM (1979) Virulence of Escherichia coli in experimental hematogenous pyelonephritis in mice. Infect Immun 25(1):68–74PubMedGoogle Scholar
  24. 24.
    Wilding EI, Kim D-Y, Bryant AP et al (2000) Essentiality, expression and characterization of the Class II 3-hydroxy-3-methylglutaryl coenzyme A reductase of Staphylococcus aureus. J Bacteriol 182(18):5147–5152PubMedCrossRefGoogle Scholar
  25. 25.
    Shankar N, Lockatell CV, Baghdayan AS et al (2001) Role of Enterococcus faecalis surface protein Esp in pathogenesis of ascending urinary tract infection. Infect Immun 69(7):4366–4372PubMedCrossRefGoogle Scholar
  26. 26.
    Iwahi T, Abe Y, Nakao M et al (1983) Role of type 1 fimbriae in the pathogenesis of ascending urinary tract infection induced by Escherichia coli in mice. Infect Immun 39(3):1307–1315PubMedGoogle Scholar
  27. 27.
    Iwahi T, Abe Y, Tsuchiya K (1982) Virulence of Escherichia coli in ascending urinary tract infection in mice. J Med Microbiol 15:303–316PubMedCrossRefGoogle Scholar
  28. 28.
    Keane WF, Freedman LR (1967) Experimental pyelonephritis XIV Pyelonephritis in normal mice produced by inoculation of E. coli into the bladder lumen during water diuresis. Yale J Biol Med 40:231–237PubMedGoogle Scholar
  29. 29.
    Andes D, van Ogtrop ML, Peng J et al (2002) In vivo pharmacokinetics of a new oxazolidinone (linezolid). Antimicrob Agents Chemother 46(11):3484–3489PubMedCrossRefGoogle Scholar
  30. 30.
    Girard AE, Cimochowski CR, Faiella JA (1996) Correlation of increased azithromycin concentrations with phagocyte inflitration into sites of localized infection. J Antimicrob Chemother 37(suppl C):9–19PubMedGoogle Scholar
  31. 31.
    Doring G, Dalhoff A, Vogel O et al (1984) In vivo activity of proteases of Pseudomonas aeruginosa in a rat model. J Infect Dis 149(4):532–537PubMedCrossRefGoogle Scholar
  32. 32.
    Arai S, Kobayashi S, Hayashi S et al (1988) Distribution of cefpirome (HR 810) to exudate in the croton oil-induces rat granuloma pouch and its therapeutic effects on experimental infections in the pouch. Antimicrob Agents Chemother 32(9):1396–1399PubMedGoogle Scholar
  33. 33.
    Jabes D, Candiani G, Romano G et al (2004) Efficacy of Dalbavancin against methicillin-resistant Staphylococcus aureus in the rat granuloma pouch infection model. Antimicrob Agents Chemother 48(4):1118–1123PubMedCrossRefGoogle Scholar
  34. 34.
    Worlitzsch D, Kaygin H, Steinhuber A et al (2001) Effects of amoxicillin, gentamicin, and moxifloxacin on the hemolytic activity of Staphylococcus aureus in vitro and in vivo. Antimicrob Agents Chemother 45(1):196–202PubMedCrossRefGoogle Scholar
  35. 35.
    Nishida M, Murakawa T (1977) Exudate levels and bactericidal activity of cefazolin in a new local infection system using rat granuloma pouches. Antimicrob Agents Chemother 11(6): 1042–1048PubMedGoogle Scholar
  36. 36.
    Dalhoff A, Frank G, Luckhaus G (1983) The granuloma pouch: an in vivo model for pharmacokinetic and chemotherapeutic investigations. II. Microbiological characterization. Infection 11(1):41–46PubMedCrossRefGoogle Scholar
  37. 37.
    Fuursted K, Schumacher H (2002) Significance of low-level resistance to ciprofloxacin in Klebsiella pneumoniae and the effect of increased dosage of ciprofloxacin in vivo using the rat granuloma pouch model. J Antimicrob Chemother 50:421–424PubMedCrossRefGoogle Scholar
  38. 38.
    Rahme LG, Stevens EJ, Wolfort SF et al (1995) Common virulence factors for bacterial pathogenicity in plants and animals. Science 268:1899–1902PubMedCrossRefGoogle Scholar
  39. 39.
    Rahme LG, Ausubel FM, Cao H et al (2000) Plants and animals share functionally common bacterial virulence factors. Proc Natl Acad Sci 97(16):8815–8821PubMedCrossRefGoogle Scholar
  40. 40.
    Mahajan-Miklos S, Tan M-W, Rahme LG et al (1999) Molecular mechanisms of bacterial virulence elucidated using a Pseudomonas aeruginosa-Caenorhabditis elegans pathogenesis model. Cell 96:47–56PubMedCrossRefGoogle Scholar
  41. 41.
    Tan M-W, Mahajan-Miklos S, Ausubel FM (1999) Killing of Caenorhabditis elegans by Pseudomonas aeruginosa used to model mammalian bacterial pathogenesis. Proc Natl Acad Sci 96:715–720PubMedCrossRefGoogle Scholar
  42. 42.
    Garsin DA, Sifri CD, Mylonakis E et al (2001) A simple model host for identifying Gram-positive virulence factors. Proc Natl Acad Sci 98(19):10892–10897PubMedCrossRefGoogle Scholar
  43. 43.
    Aballay A, Ausubel FM (2002) Caenorhabditis elegans as a host for the study of host-pathogen interactions. Curr Opin Microbiol 5:97–101PubMedCrossRefGoogle Scholar
  44. 44.
    Dionne MS, Ghori N, Schneider DS (2003) Drosophila melanogaster is a genetically tractable model host for Mycobacterium marinum. Infect Immun 71(6):3540–3550PubMedCrossRefGoogle Scholar
  45. 45.
    D’Argenio DA, Gallagher LA, Berg CA et al (2001) Drosophila as a model host for Pseudomonas aeruginosa infection. J Bacteriol 183(4):1466–1471PubMedCrossRefGoogle Scholar
  46. 46.
    Jander G, Rahme LG, Ausubel FM et al (2000) Positive correlation between virulence of Pseudomonas aeruginosa mutants in mice and insects. J Bacteriol 182(13):3843–3845PubMedCrossRefGoogle Scholar
  47. 47.
    Kaito C, Akimitsu N, Watanabe H et al (2002) Silkworm larvae as an animal model of bacterial infection pathogenic to humans. Microb Pathog 32(4):183–190PubMedCrossRefGoogle Scholar
  48. 48.
    Mahajan-Miklos S, Rahme LG, Ausubel FM et al (2000) Elucidating the molecular mechanisms of bacterial virulence using non-mammalian hosts. Mol Microbiol 37(5):981–988PubMedCrossRefGoogle Scholar
  49. 49.
    Van der Sar AM, Appelmelk BJ, Vandenbroucke-Grauls CMJE et al (2004) A star with stripes: zebrafish as an infection model. Trends Microbiol 12(10):451–457PubMedCrossRefGoogle Scholar
  50. 50.
    Kurz CL, Chauvet S, Andres E et al (2003) Virulence factors of the human opportunistic pathogen Serratia marcescens identified by in vivo screening. EMBO J 22(7):1451–1460PubMedCrossRefGoogle Scholar
  51. 51.
    Sifri CD, Begun J, Ausubel FM et al (2003) Caenorhabditis elegans as a model host for Staphylococcus aureus pathogenesis. Infect Immun 71(4):2208–2217PubMedCrossRefGoogle Scholar
  52. 52.
    Alegado RA, Campbell MC, Chen WC et al (2003) Characterization of mediators of microbial virulence and innate immunity using the Caenorhabditis elegans host-pathogen model. Cell Microbiol 5(7):435–444PubMedCrossRefGoogle Scholar
  53. 53.
    Buer J, Balling R (2003) Mice, microbes and models of infection. Nat Rev Genet 4:195–205PubMedCrossRefGoogle Scholar
  54. 54.
    Leulier F, Parquet C, Pili-Floury S et al (2003) The Drosophila immune system detects bacteria through specific peptidoglycan recognition. Nat Immunol 4(5):478–484PubMedCrossRefGoogle Scholar
  55. 55.
    Andersson DI, Levin BR (1999) The biological cost of antibiotic resistance. Curr Opin Microbiol 2(5):489–493PubMedCrossRefGoogle Scholar
  56. 56.
    Gould IM, MacKenzie FM (2002) Antibiotic exposure as a risk factor for emergence of resistance: the influence of concentration. J Appl Microbiol Symp Suppl 92:78S–84SGoogle Scholar
  57. 57.
    Hickey E (2007) Tools to define the relevance of PK/PD parameters to the efficacy, toxicity and emergence of resistance of antimicrobials. Curr Opin Drug Discov Devel 10(1):49–52PubMedGoogle Scholar
  58. 58.
    Moellering RC (1998) Antibiotic resistance: lessons for the future. Clin Infect Dis 27(suppl 1): S135–S140PubMedCrossRefGoogle Scholar
  59. 59.
    Nightingale CH (2005) Future in vitro and animal studies: development of pharmacokinetic and pharmacodynamic efficacy predictors for tissue-based antibiotics. Pharmacotherapy 25 (12 Part 2):146S–149SPubMedCrossRefGoogle Scholar
  60. 60.
    Contag CH, Contag PR, Mullins JI et al (1995) Photonic detection of bacterial pathogens in living hosts. Mol Microbiol 18:593–603PubMedCrossRefGoogle Scholar
  61. 61.
    Doyle TC, Burns SM, Contag C (2004) In vivo bioluminescence imaging for integrated studies of infection. Cell Microbiol 6(4):303–317PubMedCrossRefGoogle Scholar
  62. 62.
    Rocchetta HL, Boylan CJ, Foley JW et al (2001) Validation of a noninvasive, real-time imaging technology using bioluminescent Escherichia coli in the neutropenic mouse thigh model of infection. Antimicrob Agents Chemother 45(1):129–137PubMedCrossRefGoogle Scholar
  63. 63.
    Hutchens M, Luker GD (2007) Applications of bioluminescence imaging to the study of infectious diseases. Cell Microbiol 9(10):2315–2322PubMedCrossRefGoogle Scholar
  64. 64.
    Francis KP, Yu J, Bellinger-Kawahara C et al (2001) Visualizing pneumococcal infections in the lungs of live mice using bioluminescent Streptococcus pneumoniae transformed with a novel Gram-positive lux operon. Infect Immun 69(5):3350–3358PubMedCrossRefGoogle Scholar
  65. 65.
    Kadurugamuwa JL, Sin LV, Yu J et al (2003) Rapid direct method for monitoring antibiotics in a mouse model of bacterial biofilm infection. Antimicrob Agents Chemother 47(10): 3130–3137PubMedCrossRefGoogle Scholar
  66. 66.
    Payne DJ, Gwynn MN, Holmes DJ et al (2007) Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Discov 6:29–40PubMedCrossRefGoogle Scholar
  67. 67.
    Zak O, O’Reilly T (1991) Animal models in the evaluation of antimicrobial agents. Antimicrob Agents Chemother 35(8):1527–1531PubMedGoogle Scholar
  68. 68.
    Mestas J, Hughes CC (2004) Of mice and not men: differences between mouse and human immunology. J Immunol 172:2731–2738PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Rib-X PharmaceuticalsNew HavenUSA

Personalised recommendations