Antimicrobial Drug Resistance

  • Marilyn MartinezEmail author
  • Peter Silley
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 199)


This chapter provides an overview of our current understanding of the mechanisms associated with the development of antimicrobial drug resistance, international differences in definitions of resistance, ongoing efforts to track shifts in drug susceptibility, and factors that can influence the selection of therapeutic intervention. The latter presents a matrix of complex variables that includes the mechanism of drug action, the pharmacokinetics (PK) of the antimicrobial agent in the targeted patient population, the pharmacodynamics (PD) of the bacterial response to the antimicrobial agent, the PK/PD relationship that will influence dose selection, and the integrity of the host immune system. Finally, the differences between bacterial tolerance and bacterial resistance are considered, and the potential for non-traditional anti-infective therapies is discussed.


Antimicrobial resistance PK/PD Dose selection Antimicrobial tolerance 


  1. Aarestrup F, Bager F, Jensen NE, Madsen M, Meyling A, Wegener HC (1998) Surveillance of antimicrobial resistance in bacteria isolates from food animals to antimicrobial growth promoters and related therapeutic agents in Denmark. Acta Pathol Microbiol Immunol Scand 106:606–622Google Scholar
  2. Asad S, Opal S (2008) Bench-to-bedside review: quorum sensing and the role of cell-to-cell communication during invasive bacterial infection. Crit Care (London) 12:236–247Google Scholar
  3. Bager F, Emborg H-D, Aarestrup FM, Wegener, HC (2002) DANMAP 2001: The Danish Experience Following the Ban of Antimicrobial Growth Promoters: Trends in Microbial Resistance and Antimicrobial Use. Proceedings of Alltech's 18th Annual Symposium: from niche markets to mainstream, Lexington, Kentucky, USA, 13–15 MayGoogle Scholar
  4. Ball KR, Rubin JE, Chirino-Trejo M, Dowling PM (2008) Antimicrobial resistance and prevalence of canine uropathogens at the Western College of Veterinary Medicine Veterinary Teaching Hospital, 2002–2007. Can Vet J 49:985–990PubMedGoogle Scholar
  5. Baquero F (1990) Resistance to quinolones in gram-negative microorganisms: mechanisms and prevention. Eur Urol 17(Suppl 1):3–12PubMedGoogle Scholar
  6. Baquero F, Negri MC (1997) Strategies to minimize the development of antibiotic resistance. J Chemother 9(Suppl 3):29–37PubMedGoogle Scholar
  7. Bedenic B, Vranes J, Suto S, Zagar Z (2005) Bactericidal activity of oral beta-lactam antibiotics in plasma and urine versus isogenic Escherichia coli strains producing broad- and extended-spectrum beta-lactamases. Int J Antimicrob Agents 25:479–487PubMedGoogle Scholar
  8. Benitez de Cruz L (2008) Extreme bacteria, Scienceray at:
  9. Blondeau JM, Hansen G, Metzler K, Hedlin P (2004) The role of PK/PD parameters to avoid selection and increase of resistance: Mutant prevention concentrations. J Chemother 16(Suppl 3):1–19PubMedGoogle Scholar
  10. Boak LM, Li J, Rayner CR, Nation RL (2007) Pharmacokinetic/pharmacodynamic factors influencing emergence of resistance to linezolid in an in vitro model. Antimicrob Agents Chemother 51:1287–1292PubMedGoogle Scholar
  11. Boy D, Well M, Kinzig-Schippers M, Sőrgel F, Ankel-Fuchs D, Naber KG (2004) Urinary bactericidal activity, urinary excretion and plasma concentrations of gatifloxacin (400 mg) versus ciprofloxacin (500 mg) in healthy volunteers after a single oral dose. Int J Antimicrob Agents 23(Suppl 1):S6–S16PubMedGoogle Scholar
  12. Boyen F, Eeckhaut V, Van Immerseel F, Pasmans F, Ducatelle R, Haesebrouck F (2009) Quorum sensing in veterinary pathogens: mechanisms, clinical importance and future perspectives. Vet Microbiol 135:187–195PubMedGoogle Scholar
  13. Bronzwaer S (2008) Harmonised monitoring of antimicrobial resistance in Salmonella and Campylobacter isolates from food animals in the European Union. Clin Microbiol Infect 14:522–533Google Scholar
  14. Bywater R, Simjee S, Silley P (2006) Antimicrobial breakpoints - definitions and conflicting requirements. Vet Microbiol 118:158–159PubMedGoogle Scholar
  15. Casewell M, Friis C, Marco E, McMullinP PI (2003) The European ban on growth-promoting antibiotics and emerging consequences for human and animal health. J Antimicrob Chemother 52:159–161PubMedGoogle Scholar
  16. Cegelski L, Marshall GR, Eldridge GR, Hultgren SJ (2008) The biology and future prospects of antivirulence therapies. Nat Rev Microbiol 6:17–27PubMedGoogle Scholar
  17. Chambers HF (2006) General Principles of Antimicrobial Therapy. In: Brunton LL, Lazo J, Parker K (eds) Goodman Gilman’s the pharmacological basis of therapeutics. McGraw-Hill, USA, pp 1095–1111Google Scholar
  18. Chiller TM, Barrett T, Angulo FJ (2004) CDC studies incorrectly summarized in ‘critical review’. J Antimicrob Chemother 54:275–276PubMedGoogle Scholar
  19. Clatworthy AE, Pierson E, Hung DT (2007) Targeting virulence: A new paradigm for antimicrobial therapy. Nat Chem Biol 3:541–548PubMedGoogle Scholar
  20. Clinical Laboratories Standards Institute (2007) Development of in vitro susceptibility testing criteria and quality control parameters for veterinary antimicrobial agents; approved guideline, 3rd edn. CLSI, PA, USAGoogle Scholar
  21. Collignon P (2004) Antibiotic growth promoters. J Antimicrob Chemother 54:272PubMedGoogle Scholar
  22. Conway TB, Beck FM, Walters JD (2000) Gingival fluid ciprofloxacin levels at healthy and inflamed human periodontal sites. J Periodontol 71:1448–1452PubMedGoogle Scholar
  23. Craig WA, Dalhoff A (1998) Pharmacodynamics of fluoroquinolones in experimental animals. In: Born GVR, Cuatrecas P, Ganten D, Herken H, Melmon KL, Starke K (eds) Handbook of experimental pharmacology. Springer, Berlin, pp 208–232Google Scholar
  24. Croisier D, Etienne M, Piroth L, Bergoin E, Lequeu C, Portier H, Chavanet P (2004) In vivo pharmacodynamic efficacy of gatifloxacin against Streptococcus pneumoniae in an experimental model of pneumonia: Impact of the low levels of fluoroquinolone resistance on the enrichment of resistant mutants. J Antimicrob Chemother 54:640–647PubMedGoogle Scholar
  25. Dalhoff A, Shalit I (2003) Immunomodulatory effects of quinolones. Lancet Infect Dis 3:359–371PubMedGoogle Scholar
  26. Davies J (1994) Inactivation of antibiotics and the dissemination of resistance genes. Science 264:375–382PubMedGoogle Scholar
  27. Davison HC, Low JC, Woolhouse MEJ (2000) What is antibiotic resistance and how can we measure it? Trends Microbiol 8:554–559PubMedGoogle Scholar
  28. De Leenheer P, Cogan NG (2008) Failure of antibiotic treatment in microbial populations. J Math Biol Dec 16 59:563–579Google Scholar
  29. del Pozo JL, Patel R (2007) The challenge of treating biofilm-associated bacterial infections. Clin Pharmacol Ther 82:204–209PubMedGoogle Scholar
  30. del Pozo JL, Rouse MS, Mandrekar JN, Steckelberg JM, Patel R (2009) The electricidal effect: reduction of Staphylococcus and pseudomonas biofilms by prolonged exposure to low-intensity electrical current. Antimicrob Agents Chemother 53:41–45PubMedGoogle Scholar
  31. Dong Y, Zhao X, Domagala J, Drlica K (1999) Effect of fluoroquinolone concentration on selection of resistant mutants of Mycobacterium bovis BCG and Staphylococcus aureus. Antimicrob Agents Chemother 43:1756–1758PubMedGoogle Scholar
  32. Dong Y, Zhao X, Kreiswirth CN, Drlica K (2000) Mutation prevention concentration as a measure of antibiotic potency: studies with clinical isolates of Mycobacteriusm tuberculosis. Antimicrob Agents Chemother 44:2581–2584PubMedGoogle Scholar
  33. Donlan RM, Costerton JW (2002) Biofilms: Survival mechanisms of clinically relevant microorganisms. Clin Microbiol Rev 15:167–193PubMedGoogle Scholar
  34. Drlica K, Zhao X (2007) Mutation selection window hypothesis updated. Clin Infect Dis 44:681–688PubMedGoogle Scholar
  35. Drlica K, Zhao X, Blondeau JM, Hesje C (2006) Low correlation between MIC and mutant prevention concentration. Antimicrob Agents Chemother 50:403–404PubMedGoogle Scholar
  36. Drusano GL (2007) Pharmacokinetics and pharmacodynamics of antimicrobials. Clin Infect Dis 45(Suppl 1):S89–S95PubMedGoogle Scholar
  37. Drusano GL, Johnson DE, Rosen M, Standiford HC (1993) Pharmacodynamics of a fluoroquinolone antimicrobial agent in a neutropenic rat model of Pseudomonas sepsis. Antimicrob Agents Chemother 37:483–490PubMedGoogle Scholar
  38. Drusano GL, Liu W, Brown DL, Rice LB, Louie A (2009) Impact of short-course quinolone therapy on susceptible and resistant populations of Staphylococcus aureus. J Infect Dis 199:219–226PubMedGoogle Scholar
  39. Duckworth DH, Gulig PA (2002) Bacteriophages: potential treatment for bacterial infections. BioDrugs 16:57–62PubMedGoogle Scholar
  40. Duquette RA, Nuttall TJ (2004) Methicillin-resistant Staphylococcus aureus in dogs and cats: an emerging problem? J Small Anim Pract 45:591–597PubMedGoogle Scholar
  41. EMEA (1999) Antibiotic resistance in the European union associated with therapeutic use of veterinary medicines, report and qualitative risk assessment by the Committee for Veterinary Medicinal Products. The European Agency for the Evaluation of Medicinal Products, EuropeGoogle Scholar
  42. Eng RHK, Padberg FT, Smith SM, Tan EN, Cherubin CE (1991) Bactericidal effects of antibiotics on slowly growing and nongrowing bacteria. Antimicrob Agents Chemother 35:1824–1828PubMedGoogle Scholar
  43. Epstein BJ, Gums JG, Drlica K (2004) The changing face of antibiotic prescribing: The mutant selection window. Ann Pharmacother 38:1675–1682PubMedGoogle Scholar
  44. Escaich S (2008) Antivirulence as a new antibacterial approach for chemotherapy. Curr Opin Chem Biol 12:400–408PubMedGoogle Scholar
  45. FDA/CVM Guidance for Industry (#152): Evaluating the safety of antimicrobial new animal drugs with regard to their microbiological effects on bacteria of human health concern, dated 10/23/2003.
  46. Forrest A, Nix DE, Ballow CH, Goss TF, Birmingham MC, Schentag JJ (1993) Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients. Antimicrob Agents Chemother 37:1073–1081PubMedGoogle Scholar
  47. Franklin A, Acar J, Anthony F, Gupta R, Nicholls T, Tamura Y, Thompson S, Threlfall EJ, Vose D, Van Vuuren M, White DG, Wegener HC, Costarrica ML (2001) Antimicrobial resistance: Harmonisation of national antimicrobial resistance monitoring and surveillance programmes in animals and in animal-derived food. Rev Sci Tech (Off Int Epizoot) 20:859–870Google Scholar
  48. Gilberta P, Brown MRW (1998) Biofilms and -lactam activity. J Antimicrob Chemother 41:571–572Google Scholar
  49. Gunderson BW, Ross GH, Ibrahim KH, Rotschafer JS (2001) What do we really know about antibiotic pharmacodynamics. Pharmacotherapy 21(10 pt2):302S–318SPubMedGoogle Scholar
  50. Hanlon GW (2007) Bacteriophages: An appraisal of their role in the treatment of bacterial infections. Int J Antimicrob Agents 30:118–128PubMedGoogle Scholar
  51. Harrison PF, Lederberg J (1998) Antimicrobial resistance: issues and options workshop report. National Academy Press, Washington DC, pp 1–11Google Scholar
  52. Harrison JJ, Turner RJ, Ceri H (2005) Persister cells, the biofilm matrix and tolerance to metal cations in biofilm and planktonic Pseudomonas aeruginosa. Environ Microbiol 7:981–994PubMedGoogle Scholar
  53. Hendriksen RS, Mevius DJ, Schroeter A, Teale C, Jouy E, Butaye P, Franco A, Utinane A, Amado A, Moreno M, Greko C, Stärk KDC, Berghold C, Myllyniemi AL, Hoszowski A, Sunde M, Aarestrup FM (2008a) Occurrence of antimicrobial resistance among bacterial pathogens and indicator bacteria in pigs in different European countries from year 2002–2004: the ARBAO_II study. Acta Vet Scand 50:19PubMedGoogle Scholar
  54. Hendriksen RS, Mevius DJ, Schroeter A, Teale C, Meunier D, Butaye P, Franco A, Utinane A, Amado A, Moreno M, Greko C, Stärk K, Berghold C, Myllyniemi AL, Wasyl D, Sunde M, Aarestrup FM (2008b) Prevalence of antimicrobial resistance among bacterial pathogens isolated from cattle in different European countries: 2002–2004. Acta Vet Scand 50:28PubMedGoogle Scholar
  55. Horswill AR, Nauseef WM (2008) Host interception of bacterial communication signals. Cell Host Microbe Prev 4:507–509Google Scholar
  56. Ibrahim KH, Hovde LB, Ross G, Gunderson B, Wright DH, Rotschafer JC (2002) Microbiologic effectiveness of time- or concentration-based dosing strategies in Streptococcus pneumoniae. Diagn Microbiol Infect Dis 44:265–271PubMedGoogle Scholar
  57. Illambas JM, Potter T, Rycroft AN, Lees P (2009) Pharmacodynamics of tulathromycin in vitro and in vivo against calf pathogens. J Vet Pharmacol Ther 32(Suppl 1):62–63Google Scholar
  58. Jayaraman R (2008) Bacterial persistence: Some new insights into an old phenomenon. J Biosci 33:795–805PubMedGoogle Scholar
  59. Jefferson KK (2004) What drives bacteria to produce a biofilm? FEMS Microbiol Lett 236:163–173PubMedGoogle Scholar
  60. Jensen VF, Neimann J, Hammerum AM, Molbak K, Wegener HC (2004) Does the use of antibiotics in food animals pose a risk to human health? An unbiased review? J Antimicrob Chemother 54:274–275PubMedGoogle Scholar
  61. Kaspar H (2006) Results of the antimicrobial agent susceptibility study raised in a representative, cross-sectional monitoring study on a national basis. Int J Med Microbiol 296(Suppl 41):69–79PubMedGoogle Scholar
  62. Kaufmann GF, Park J, Janda KM (2008) Bacterial quorum sensing: A new target for anti-infective immunotherapy. Exp Opin Biol Ther 8:719–724Google Scholar
  63. Keren I, Shah D, Spoering A, Kaldalu N, Lewis K (2004) Specialized persister cells and the mechanism of multidrug tolerance in Escherichia coli. J Bacteriol 186:8172–8180PubMedGoogle Scholar
  64. Kong KF, Vuong C, Otto M (2006) Staphylococcus quorum sensing in biofilm formation and infection. Int J Med Microbiol 296:133–139PubMedGoogle Scholar
  65. Körber B, Luhmer E, Wetzstein HG, Heisig P (2002) Abstracts 42nd ICAAC. San Diego, USA, Abstract F-567, p188Google Scholar
  66. Labro MT (1998) Anti-inflammatory activity of macrolides: a new therapeutic potential? J Antimicrob Chemother 41(Suppl B):37–46PubMedGoogle Scholar
  67. Lavda M, Clausnitzer CE, Walters JD (2004) Distribution of systemic ciprofloxacin and doxycycline to gingiva and gingival crevicular fluid. J Periodontol 75:1663–1667PubMedGoogle Scholar
  68. Lees P, Aliabadi FS, Toutain PL (2006) Minimising antimicrobial resistance through rational design of dosing schedules: A role for pre-clinical PK-PD modeling. J Vet Pharmacol Ther 29(Suppl 1):24–26Google Scholar
  69. Leslie G (2008) Surveying therapets for MRSA. Vet Rec 162:388PubMedGoogle Scholar
  70. Lewis K (2007) Persister cells, dormancy and infectious disease. Nat Rev Microbiol 5:48–56PubMedGoogle Scholar
  71. Lewis K (2008) Multidrug tolerance of biofilms and persister cells. Curr Top Microbiol Immunol 322:107–131PubMedGoogle Scholar
  72. Liautard JP, Jubier-Maurin V, Boigegrain RA, Köhler S (2006) Antimicrobials: Targeting virulence genes necessary for intracellular multiplication. Trends Microbiol 14:109–113PubMedGoogle Scholar
  73. Liu P, Müller M, Grant M, Webb AI, Obermann B, Derendorf H (2002) Interstitial tissue concentrations of cefpodoxime. J Antimicrob Chemother 50(Suppl 1):19–22PubMedGoogle Scholar
  74. Long KS, Poehlsgaard J, Kehrenberg C, Schwarz S, Vester B (2006) The Cfr rRNA methyltransferase confers resistance to phenicols lincosamides oxazolidinones pleuromutilins and streptogramin A antibiotics. Antimicrob Agents Chemother 7:2500–2505Google Scholar
  75. Lynch SV, Wiener-Kronish JP (2008) Novel strategies to combat bacterial virulence. Curr Opin Crit Care 14:593–599PubMedGoogle Scholar
  76. MacGowan A, Bowker K (2002) Development in PK/PD: Optimizing efficacy and prevention of resistance. A critical review of PK/PD in in vitro models. Int J Antimicrob Agents 19:291–298PubMedGoogle Scholar
  77. Maldonado EN, Romero JR, Ochoa B, Aveldaño MI (2001) Lipid and fatty acid composition of canine lipoproteins. Comp Biochem Physiol B Biochem Mol Biol 128:719–729PubMedGoogle Scholar
  78. Maldonado EN, Casanave EB, Aveldaño MI (2002) Major plasma lipids and fatty acids in four HDL mammals. Comp Biochem Physiol A Mol Integr Physiol 132:297–303PubMedGoogle Scholar
  79. Malik M, Hussain S, Drlica K (2007) Effect of anaerobic growth on quinolone lethality with Escherichia coli. Antimicrob Agents Chemother 51:28–34PubMedGoogle Scholar
  80. Marriott HM, Mitchell TJ, Dockrell DH (2008) Pneumolysin: A double-edged sword during the host-pathogen interaction. Curr Mol Med 8:497–509PubMedGoogle Scholar
  81. Martinez M, Modric S (2010) J Vet Pharmacol Ther (Submitted)Google Scholar
  82. Martinez M, Toutain PL, Walker RD (2006) The pharmacokinetic-pharmacodynamic (PK/PD) relationship of antimicrobial agents. In: Giguère S, Prescott JF, Baggot JS, Walker RD, Dowling PM (eds) Antimicrobial therapy in veterinary medicine, 4th edn. Blackwell, Oxford, pp 81–106Google Scholar
  83. Masterton R (2008) The importance and future of antimicrobial surveillance studies. Clin Infect Dis 47(Suppl 1):S21–S31PubMedGoogle Scholar
  84. McEwen SA, Fedorka-Cray PJ (2002) Antimicrobial use and resistance in animals. Clin Infect Dis 34(Suppl 3):S93–S106PubMedGoogle Scholar
  85. Melchior MB, van Osch MH, Graat RM, van Duijkeren E, Mevius DJ, Nielen M, Gaastra W, Fink-Gremmels J (2009) Biofilm formation and genotyping of Staphylococcus aureus bovine mastitis isolates: Evidence for lack of penicillin-resistance in Agr-type II strains. Vet Microbiol 137:83–89PubMedGoogle Scholar
  86. Merrikin DJ, Briant J, Rolinson GN (1983) Effect of protein binding on antibiotic activity in vivo. J Antimicrob Chemother 11:233–238PubMedGoogle Scholar
  87. Moroni P, Pisoni G, Antonini M, Villa R, Boettcher P, Carli S (2006) Short communication: Antimicrobial drug susceptibility of Staphylococcus aureus from subclinical bovine mastitis in Italy. J Dairy Sci 89:2973–2976PubMedGoogle Scholar
  88. Mouton JW, Dudley MN, Cars O, Derendorf H, Drusano GL (2005) Standardization of pharmacokinetic/pharmacodynamic (PK/PD) terminology for anti-infective drugs: an update. J Antimicrob Chemother 55:601–607PubMedGoogle Scholar
  89. Naber KG (2001) Which fluoroquinolones are suitable for the treatment of urinary tract infections? Int J Antimicrob Agents 17:331–341PubMedGoogle Scholar
  90. Nadell CD, Xavier JB, Foster KR (2009) The sociobiology of biofilms. FEMS Microbiol Rev 33:206–224PubMedGoogle Scholar
  91. Nicolau DP (2001) Predicting antibacterial response from pharmacodynamic and pharmacokinetic profiles. Infection 29(Suppl 2):11–5PubMedGoogle Scholar
  92. Noel AR, Bowker KE, MacGowan AP (2007) Variability in the size of the fluoroquinolone AUC/MIC for antibacterial effect in S. aureus: Impact for clinical breakpoints. Abstract 47th ICAAC, Chicago, USA, abstract A-23 pp5-6Google Scholar
  93. O'Brien TF (2002) Emergence, spread, and environmental effect of antimicrobial resistance: How use of an antimicrobial anywhere can increase resistance to any antimicrobial anywhere else. Clin Infect Dis 34(Suppl 3):S78–S84PubMedGoogle Scholar
  94. Opal SM (2007) Communal living by bacteria and the pathogenesis of urinary tract infections. PLoS Med 4:e349PubMedGoogle Scholar
  95. Owens RC, Ambrose PG (2007) Antimicrobial stewardship and the role of pharmacokinetics-pharmacodynamics in the modern antibiotic era. Diagn Microbiol Infect Dis 57(3 Suppl):77S–83SPubMedGoogle Scholar
  96. Periti P, Mazzei T (1998) Antibiotic-induced release of bacterial cell wall components in the pathogenesis of sepsis and septic shock: A review. J Chemother 10:427–448PubMedGoogle Scholar
  97. Peterson MM, Mack JL, Hall PR, Alsup AA, Alexander SM, Sully EK, Sawires YS, Cheung AL, Otto M, Gresham HD (2008) Apolipoprotein B is an innate barrier against invasive Staphylococcus aureus infection. Cell Host Microbe 4:555–566PubMedGoogle Scholar
  98. Pfaller MA (2006) Flavophospholipol use in animals: Positive implications for antimicrobial resistance based on its microbiologic properties. Diagn Microbiol Infect Dis 56:115–121PubMedGoogle Scholar
  99. Phillips I (2007) Withdrawal of growth-promoting antibiotics in Europe and its effects in relation to human health. Int J Antimicrob Agents 30:101–107PubMedGoogle Scholar
  100. Phillips I, Casewell M, Cox T, De Groot B, Friis C, Jones R, Nightingale C, Preston R, Waddell J (2004a) Does the use of antibiotics in food animals pose a risk to human health? A critical review of published data. J Antimicrob Chemother 53:28–52PubMedGoogle Scholar
  101. Phillips I, Casewell M, Cox T, De Groot B, Friis C, Jones R, Nightingale C, Preston R, Waddell J (2004b) Does the use of antibiotics in food animals pose a risk to human health? A reply to critics. J Antimicrob Chemother 54:276–278Google Scholar
  102. Potter T, Illambas J, Rycroft AN, Brentnall C, McKellar QA, Lees P (2009a) Integration and modeling of pharmacokinetic and pharmacodynamic data for oxytetracycline in calves. J Vet Pharmacol Ther 32(Suppl 1):66–67Google Scholar
  103. Potter T, Illambas J, Rycroft AN, Lees P (2009b) Integration and modeling of pharmacokinetic and pharmacodynamic data for marbofloxacin in calves. J Vet Pharmacol Ther 32(Suppl 1):142–143Google Scholar
  104. Prescott JF, Baggot JD (1993) Aminoglycosides and aminocyclitols. In: Prescott JF, Baggot JD (eds) Antimicrobial therapy in veterinary medicine, 2nd edn. Iowa State University Press, Ames, IA, pp 144–178Google Scholar
  105. Preston SL, Drusano GL, Berman AL, Fowler CL, Chow AT, Dornseif B, Reichl V, Natarajan J, Corrado M (1998) Pharmacodynamics of levofloxacin: a new paradigm for early clinical trials. J Am Med Assoc 279:125–129Google Scholar
  106. Projan SJ, Novick RP (1997) The molecular basis of pathogenicity. In: Crossley KB, Archer GL (eds) The Staphylococci in human diseases. Churchill Livingstone, New York, NY, pp 55–82Google Scholar
  107. Reato G, Cuffini AM, Tullio V, Mandras N, Roana J, Banche G, Foa R, Carlone NA (2004) Immunomodulating effect of antimicrobial agents on cytokine production by human polymorphonuclear neutrophils. Int J Antimicrob Agents 23:150–154PubMedGoogle Scholar
  108. Rice KC, Bayles KW (2008) Molecular control of bacterial death and lysis. Microbiol Mol Biol Rev 72:85–109PubMedGoogle Scholar
  109. Rybak MJ (2006) Pharmacodynamics: Relation to antimicrobial resistance. Am J Infect Control 34(Suppl 1):S38–S45PubMedGoogle Scholar
  110. Safdar N, Andes D, Craig WA (2004) In vivo pharmacodynamic activity of daptomycin. Antimicrob Agents Chemother 48:63–68PubMedGoogle Scholar
  111. Schrag SJ, Peña C, Fernández J, Sánchez J, Gómez V, Pérez E, Feris JM, Besser RE (2001) Effect of short-course, high-dose amoxicillin therapy on resistant pneumococcal carriage: A randomized trial. J Am Med Assoc 286:49–56Google Scholar
  112. Schwegmann A, Brombacher F (2008) Host-directed drug targeting of factors hijacked by pathogens. Sci Signal 1(29):re8PubMedGoogle Scholar
  113. Shah PM, Zwischenbrugger H, Stille W (1976) Bactericidal dose–activity relationships with E. coli, K. pneumoniae and S. aureus (author’s translation). Dtsch Med Wochenschr 101:325–328PubMedGoogle Scholar
  114. Shryock TR, Mortensen JE, Baumholtz M (1998) The effects of macrolides on the expression of bacterial virulence mechanisms. J Antimicrob Chemother 41:505–512PubMedGoogle Scholar
  115. Siegel RE (2008) Emerging gram-negative antibiotic resistance: daunting challenges, declining sensitivities, and dire consequences. Respir Care 53:471–479PubMedGoogle Scholar
  116. Silverman JA, Mortin LI, Vanpraagh AD, Li T, Alder J (2005) Inhibition of daptomycin by pulmonary surfactant: In vitro modeling and clinical impact. J Infect Dis 191:2149–2152PubMedGoogle Scholar
  117. Simjee S, Silley P, Werling HO, Bywater R (2008) Potential confusion regarding the term ‘resistance’ in epidemiological surveys. J Antimicrob Chemother 61:228–229PubMedGoogle Scholar
  118. Slocombe RF, Malark J, Ingersoll R, Derksen JF, Robinson NE (1985) Importance of neutrophils in the pathogenesis of acute pneumonia pasteurellosis in calves. Am J Vet Res 46:2253–2258PubMedGoogle Scholar
  119. Smith K, Perez A, Ramage G, Gemmell CG, Lang S (2009) Comparison of biofilm-associated cell survival following in vitro exposure of meticillin-resistant Staphylococcus aureus biofilms to the antibiotics clindamycin, daptomycin, linezolid, tigecycline and vancomycin. Int J Antimicrob Agents 33:374–378PubMedGoogle Scholar
  120. Soto SM, Smithson A, Horcajada JP, Martinez JA, Mensa JP, Vila J (2006) Implication of biofilm formation in the persistence of urinary tract infection caused by uropathogenic Escherichia coli. Clin Microbiol Infect 12:1034–1036PubMedGoogle Scholar
  121. Steenbergen JN, Alder J, Thorne GM, Tally FP (2005) Daptomycin: A lipopeptide antibiotic for the treatment of serious Gram-positive infections. J Antimicrob Chemother 55:283–288PubMedGoogle Scholar
  122. Stein RA (2008) When less is more: High-dose, short duration regimens and antibiotic resistance. Int J Clin Pract 62:1304–1305PubMedGoogle Scholar
  123. Sung JM, Chantler PD, Lloyd DH (2006) Accessory gene regulator locus of Staphylococcus intermedius. Infect Immun 74:2947–2956PubMedGoogle Scholar
  124. Tam VA, Louie A, Fritsche TR, Deziel M, Liu W, Brown DL, Deshpande L, Leary R, Jones RN, Drusano GL (2007) Impact of drug-exposure intensity and duration of therapy on the emergence of Staphylococcus aureus resistance to a quinolone antimicrobial. J Infect Dis 195:1818–1827PubMedGoogle Scholar
  125. Tanaka G, Shigeta M, Komatsuzawa H, Sugai M, Suginaka H, Usui T (1999) Effect of the growth rate of Pseudomonas aeruginosa biofilms on the susceptibility to antimicrobial agents: Beta-lactams and fluoroquinolones. Chemotherapy 45:28–36PubMedGoogle Scholar
  126. Tateda K, Standiford TJ, Pechere JC, Yamaguchi K (2004) Regulatory effects of macrolides on bacterial virulence: Potential role as quorum-sensing inhibitors. Curr Pharm Des 10:3055–3065PubMedGoogle Scholar
  127. Threlfall EJ, Day M, de Pinna E, Charlett A, Goodyear KL (2006) Assessment of factors contributing to changes in the incidence of antimicrobial drug resistance in Salmonella enterica serotypes Enteritidis and Typhimurium from humans in England and Wales in 2000, 2002 and 2004. Int J Antimicrob Agents 28:389–395PubMedGoogle Scholar
  128. Tollefson L (2004) Factual errors in review article. J Antimicrob Chemother 54:271PubMedGoogle Scholar
  129. Toutain PL (2002) Pharmacokinetic/Pharmacodynamic integration in drug development and dosage-regimen optimization for veterinary medicine. AAPS Pharm Sci 4(4):160–188Google Scholar
  130. Turnidge J (2004) Antibiotic use in animals—prejudices, perceptions, and realities. J Antimicrob Chemother 53:26–27PubMedGoogle Scholar
  131. Turnidge J, Paterson DL (2007) Setting and revising antibacterial susceptibility breakpoints. Clin Microbiol Rev 20:391–408PubMedGoogle Scholar
  132. van den Broek PJ (1989) Antimicrobial drugs, microorganisms, and phagocytes. Rev Infect Dis 11:213–245PubMedGoogle Scholar
  133. Wallmann J, Schröter K, Wieler LH, Kroker R (2003) National antibiotic resistance monitoring in veterinary pathogens from sick food-producing animals: The German programme and results from the 2001 pilot study. Int J Antimicrob Agents 22:420–428PubMedGoogle Scholar
  134. Wassenaar TM (2005) Use of antimicrobial agents in veterinary medicine and implications for human health. Crit Rev Microbiol 31:155–169PubMedGoogle Scholar
  135. Wassenaar TM, Silley P (2008) Antimicrobial resistance in zoonotic bacteria: Lessons learned from host-specific pathogens. Anim Health Res Rev 9:177–186PubMedGoogle Scholar
  136. Wassenaar TM, Kist M, de Jong A (2007) Re-analysis of the risks attributed to ciprofloxacin-resistant Campylobacter jejuni infections. Int J Antimicrob Agents 30:195–201PubMedGoogle Scholar
  137. Well M, Naber KG, Kinzig-Schippers M, Sőrgel F (1998) Urinary bactericidal activity and pharmacokinetics of enoxacin versus norfloxacin and ciprofloxacin in healthy volunteers after a single oral dose. Int J Antimicrob Agents 10:31–38PubMedGoogle Scholar
  138. WHO (2001) Surveillance standards for antimicrobial resistance, WHO, Who/CDS/CDSR/DRS/2001.5, see
  139. Winstanley C, Fothergill JL (2009) The role of quorum sensing in chronic cystic fibrosis Pseudomonas aeruginosa infections. FEMS Microbiol Lett 290:1–9PubMedGoogle Scholar
  140. Wright DH, Brown GH, Peterson ML, Rotschafer JC (2000) Application of fluoroquinolone pharmacodynamics. J Antimicrob Chemother 46:669–683PubMedGoogle Scholar
  141. Yang Q, Nakkula RJ, Walters JD (2002) Accumulation of ciprofloxacin and minocycline by cultured human gingival fibroblasts. J Dent Res 81:836–840PubMedGoogle Scholar
  142. Zelenitsky S, Ariano R, Harding G, Forrest A (2005) Evaluating ciprofloxacin dosing for Pseudomonas aeruginosa infection by using clinical outcome-based Monte Carlo simulations. Antimicrob Agents Chemother 49:4009–4014PubMedGoogle Scholar
  143. Zhanel GG, Karlowsky JA, Davidson RJ, Hoban DJ (1991) Influence of human urine on the in vitro activity and postantibiotic effect of ciprofloxacin against Escherichia coli. Chemotherapy 37:218–223PubMedGoogle Scholar
  144. Zhao X, Drlica K (2001) Restricting the selection of antibiotic-resistant mutants: a general strategy derived from fluoroquinolone studies. Clin Infect Dis 33(Suppl 3):S147–S156PubMedGoogle Scholar
  145. Zhao X, Drlica K (2008) A unified anti-mutant dosing strategy. J Antimicrob Chemother 62:434–436PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.Office of New Animal Drug Evaluation (HFV-130)Center for Veterinary Medicine Food and Drug AdministrationRockvilleUSA
  2. 2.MB Consult Limited, Enterprise HouseSouthamptonUK

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