Primary Rodent Infection Models for Testing Antibacterial Compound Efficacy In Vivo

Andrea Marra1, Dennis Girard1

1 Pfizer Global Research and Development, Groton, Connecticut
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 13A.4
DOI:  10.1002/0471141755.ph13a04s31
Online Posting Date:  January, 2006
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Abstract

This unit describes three primary screening models for evaluating antibacterial efficacy. Included are systemic bacterial infection (peritonitis), pulmonary infection, also known as respiratory tract infection or RTI, and thigh lesion. All of these infection models can be performed in inexpensive, outbred mice and, as such, offer the advantage of being compoundā€sparing while allowing the testing of sufficient numbers to obtain statistically significant results early in the drug development process.

Keywords: murine systemic infection; murine respiratory tract infection; murine thigh lesion infection

     
 
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Table of Contents

  • Basic Protocol 1: Mouse Peritonitis Primary Infection Model to Evaluate Antibacterial Efficacy
  • Basic Protocol 2: Mouse Respiratory Tract Infection Model to Evaluate Antibacterial Efficacy
  • Basic Protocol 3: Mouse Thigh Lesion Model to Evaluate Antibacterial Efficacy
  • Commentary
  • Literature Cited
  • Tables
     
 
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Materials

Basic Protocol 1: Mouse Peritonitis Primary Infection Model to Evaluate Antibacterial Efficacy

  Materials
  • Microorganism
  • Sterile Dulbecco's phosphate‐buffered saline (1× liquid, PBS) or brain‐heart infusion broth (Difco; Becton‐Dickenson)
  • Outbred male or female CF‐1, CD‐1, ICR, DBA mice (3 to 5 weeks old; 18 to 30 g; Charles River Laboratories)
  • Skin disinfectant (e.g., betadine or 70% ethanol)
  • Mouse food
  • Test agents in appropriate vehicle
  • 1‐ or 5‐ml syringes, 20‐ or 26‐G needles
  • Mouse cages
  • UV spectrometer
  • GraphPad Prism 4.0 software or equivalent

Basic Protocol 2: Mouse Respiratory Tract Infection Model to Evaluate Antibacterial Efficacy

  Materials
  • Microorganism
  • Sterile Dulbecco's phosphate‐buffered saline (1× liquid, PBS) or brain‐heart infusion broth
  • Outbred male or female CF‐1, CD‐1, ICR, DBA mice (3 to 5 weeks old; 18 to 30 g; Charles River Laboratories)
  • Anesthesia: either isoflurane (3% to 4% in O 2) by inhalation or ketamine/xylazine via i.m. injection
  • Mouse food
  • Test agents and control drugs in an appropriate vehicle
  • UV spectrometer
  • 1‐ or 5‐ml syringes, 20‐ or 26‐G needles for drug administration
  • GraphPad Prism 4.0 software or equivalent

Basic Protocol 3: Mouse Thigh Lesion Model to Evaluate Antibacterial Efficacy

  Materials
  • Microorganism
  • Broth culture
  • PBS
  • Sterile Dulbecco's phosphate‐buffered saline (PBS) or brain‐heart infusion broth
  • Outbred male or female CF‐1, CD‐1, ICR, DBA mice (3 to 5 weeks old; 18 to 30 g; Charles River Laboratories)
  • Skin disinfectant (e.g., betadine or 70% ethanol)
  • Mouse food
  • Test compound or antibiotic
  • Rodent restrainer (VWR; Plas‐Labs), optional
  • 1‐ml syringe, 26‐G needles
  • Calipers
  • Petri dishes
  • Scissors
  • Stomacher or Tissuemizer
  • GraphPad Prism 4.0 software or equivalent
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Figures

Videos

Literature Cited

Literature Cited
   Acred, P. 1986. The Selbie or thigh lesion test. In: Experimental Models in Antimicrobial Chemotherapy (O. Zak, M.A. Sande, and M. Sande, eds.) pp. 109‐121. Academic Press, Inc., London.
   Andes, D. and Craig, W.A. 2002. Animal model pharmacokinetics and pharmacodynamics: A critical review. Int. J. Antimicrob. Agents 19:261‐268.
   Bergeron, M.G. 1978. A review of models for the therapy of experimental infections. Scand. J. of Infect. Dis. 14:89‐206.
   Dagan, R. 2003. Achieving bacterial eradication using pharmacokinetic/pharmacodynamic principles. Int. J. Infect. Dis. 7:S21‐S26.
   Fallon, M. 2002. Working with the IACUC: Writing an animal protocol. American Association for Laboratory Animal Science, Memphis, TN.
   Freise, H., Bruckner, U.B., and Spiegel, H.U. 2001. Animal models of sepsis. J. Invest. Surg. 14:195‐212.
   Greaves, P., Williams, A., and Eve, M. 2004. First dose of potential new medicines to humans: How animals help. Nat. Rev. Drug Discov. 3:226‐236.
   Jacobs, M.R. 2003. How can we predict bacterial eradication? Int. J. Infect. Dis. 7:S13‐S20.
   Morton, D.B. 1999. Ethical aspects of the use of animal models of infection. In Handbook of Animal Models of Infection (O. Zak and M. Sande, eds.) pp. 29‐48. Academic Press, Orlando, FL.
   NRC. 1996. Guide for the Care and Use of Laboratory Animals. (N.R. Council, ed.). National Academy Press, Washington, D.C.
   Olfert, E.D. and Godson, D.L. 2000. Humane endpoints for infectious disease animals models. ILAR J. 41:99‐104.
   Zak, O. and O'Reilly, T. 1990. Animal models as predictors of the safety and efficacy of antibiotics. Eur. J. Clin. Microbiol. Infect. Dis. 9:472‐478.
   Zak, O. and O'Reilly, T. 1991. Animal models in the evaluation of antimicrobial agents. Antimicrob. Agents Chemother. 35:1527‐1531.
   Zak, O. and O'Reilly, T. 1993. Animal infection models and ethics—The perfect infection model. J. Antimicrob. Chemother. 31:193‐205.
   Zak, O. and Sande, M.A. 1999. Handbook of Animal Models of Infection. Experimental Models in Antimicrobial Chemotherapy. Academic Press, London.
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