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Current and Future Challenges in the Development of Antimicrobial Agents

Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 211)

Abstract

Micro-organisms exist to survive. Even in the absence of antimicrobial agents, many have determinants of resistance that may be expressed phenotypically, should the need arise. With the advent of the antibiotic age, as more and more drugs were developed to treat serious infections, micro-organisms (particularly bacteria) rapidly developed resistance determinants to prevent their own demise.

The most important determinants of resistance have been in the Gram-positive and Gram-negative bacteria. Among Gram-positive bacteria, methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and penicillin-resistant Streptococcus pneumoniae (PRSP) have taxed researchers and pharmaceutical companies to develop new agents that are effective against these resistant strains. Among the Gram-negative bacteria, extended-spectrum beta-lactamase (ESBL) enzymes, carbapenemases (CREs) and the so-called amp-C enzymes that may be readily transferred between species of enterobacteriaceae and other facultative species have created multi-drug resistant organisms that are difficult to treat. Other resistance determinants have been seen in other clinically important bacterial species such as Neisseria gonorrhoeae, Clostridium difficile, Haemophilus influenzae and Mycobacterium tuberculosis. These issues have now spread to fungal agents of infection.

A variety of modalities have been used to stem the tide of resistance. These include the development of niche compounds that target specific resistance determinants. Other approaches have been to find new targets for antimicrobial activity, use of combination agents that are effective against more than one target in the cell, or new delivery mechanism to maximize the concentration of antimicrobial agents at the site of infection without causing toxicity to the host. It is important that such new modalities have been proved effective for clinical therapy. Animal models and non-mammalian systems have been developed to determine if new agents will reach sufficient concentrations at infection sites to predict clinical efficacy without toxicity. It will also be key to consider antimicrobial stewardship as an important component of the continuing battle to prevent the development of antimicrobial resistance.

Keywords

Antimicrobial resistance Drug development Animal models Stewardship 

References

  1. Ananda-Rajah MR, Slavin MA, Thursky KT (2012) The case for antifungal stewardship. Curr Opin Infect Dis 25:107–115PubMedCrossRefGoogle Scholar
  2. Andes D, Craig WA (2002) Animal model pharmacokinetics and pharmacodynamics: a critical review. Int J Antimicrob Agents 19:261–268PubMedCrossRefGoogle Scholar
  3. Andes D, van Ogtrop ML, Peng J, Craig WA (2002) In vivo pharmacodynamics of a new oxazolidinone (linezolid). Antimicrob Agents Chemother 46:3484–3489PubMedCrossRefGoogle Scholar
  4. Aperis G, Alivanis P (2011) Posaconazole: a new antifungal weapon. Rev Recent Clin Trials 6:204–219PubMedCrossRefGoogle Scholar
  5. Bast D, Yue M, Chen X, Bell D, Dresser L, Saskin R, Mandell LA, Low DE, de Azavedo JCS (2004) Novel murine model of pneumococcal pneumonia: use of temperature as a measure of disease severity to compare the efficacies of moxifloxacin and levofloxacin. Antimicrob Agents Chemother 48:3343–3348PubMedCrossRefGoogle Scholar
  6. Bolan GA, Sparling PF, Wasserheit JN (2012) The emerging threat of untreatable gonococcal infection. N Engl J Med 366:485–487PubMedCrossRefGoogle Scholar
  7. Bowyer P, Moore CB, Rautemaa R, Denning DW, Richardson MD (2011) Azole antifungal resistance today: focus on Aspergillus. Curr Infect Dis Rep 13:485–491PubMedCrossRefGoogle Scholar
  8. Boyd N, Nailor MD (2011) Combination antibiotic therapy for empiric and definitive treatment of gram-negative infections: insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy 31:1073–1084PubMedCrossRefGoogle Scholar
  9. Bryskier A (2005) Epidemiology of resistance to antimicrobial agents. In: Bryskier A (ed) Antimicrobial agents: antibacterials and antifungals. ASM, Washington, DC, pp 39–92Google Scholar
  10. Bush K, Jacoby GA, Medeiros AA (1995) A functional classification scheme for beta- A functional classification scheme for beta-lactamases and its correlation with molecular structure. Antimicrob Agents Chemother 39:1211–1233PubMedCrossRefGoogle Scholar
  11. Bush K (2008) Extended-spectrum beta-lactamases in North America, 1987–2006. Clin Microbiol Infect 14(Suppl 1):134–143PubMedCrossRefGoogle Scholar
  12. Bush K, Jacoby GA (2010) Updated functional classification of beta-lactamases. Antimicrob Agents Chemother 2010(54):969–976CrossRefGoogle Scholar
  13. Chambers HF (2001) The changing epidemiology of Staphylococcus aureus. Emerg Infect Dis 7:178–182PubMedCrossRefGoogle Scholar
  14. Craig WA (1998) Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 26:1–10PubMedCrossRefGoogle Scholar
  15. Craig WA (2001) Does the dose matter? Clin Infect Dis 15(Suppl 3):S233–S237CrossRefGoogle Scholar
  16. Davies J (2006) Where have all the antibiotics gone? Can J Infect Dis Med Microbiol 17:287–290PubMedGoogle Scholar
  17. D’Costa VM, King CE, Kalan L, Morar M, Sung WW, Schwarz C, Froese D, Zazula G, Calmels F, Debruyne R, Golding GB, Poinar HN, Wright GD (2011) Antibiotic resistance is ancient. Nature 477:457–461PubMedCrossRefGoogle Scholar
  18. den Braber I, Mugwagwa T, Vrisekoop N, Westera L, Mögling R, Bregje de Boer A, Willems N, Schrijver EH, Spierenburg G, Gaiser K, Mul E, Otto SA, Ruiter AF, Ackermans MT, Miedema F, Borghans JA, de Boer RJ, Tesselaar K (2012) Maintenance of peripheral naive T cells is sustained by thymus output in mice but not humans. Immunity 36:288–297CrossRefGoogle Scholar
  19. Deurenberg RH, Vink C, Kalenic S, Friedricjh AW, Bruggeman CA, Stobbeeringh EE (2007) The molecular evolution of methicillin-resistant Staphylococus aureus. Clin Microbiol Infect 13:222–235PubMedCrossRefGoogle Scholar
  20. Diazgranados CA (2011) Prospective audit for antimicrobial stewardship in intensive care: Impact on resistance and clinical outcomes. Am J Infect Control. 2011 Sep 20. Epub ahead of print. In pressGoogle Scholar
  21. Fabrino DL, Leon LL, Genestra M, Parreira GG, Melo RC (2011) Rat models to investigate host macrophage defense against Trypanosoma cruzi. J Innate Immun 3:71–82PubMedCrossRefGoogle Scholar
  22. Farrell DJ, Jenkins SG, Brown SD, Patel M, Lavin BS, Klugman KP (2005) Emergence and spread of Streptococcus pneumoniae with erm(B) and mef(A) resistance. Emerg Infect Dis 11:851–858PubMedCrossRefGoogle Scholar
  23. Farrell DJ, Morrissey I, Bakker S, Morris L, Buckridge S, Felmingham D (2004) Molecular epidemiology of multiresistant Streptococcus pneumoniae with both erm(B)- and mef(A)-mediated macrolide resistance. J Clin Microbiol 42:764–768PubMedCrossRefGoogle Scholar
  24. Gardner P, Smith DH, Beer H, Moellering RC (1969) Recovery of resistance (R) factors from a drug-free community. Lancet 294:774–776CrossRefGoogle Scholar
  25. Ison CA, Alexander S (2011) Antimicrobial resistance in Neisseria gonorrhoeae in the UK: surveillance and management. Expert Rev Anti Infect Ther 9:867–876PubMedCrossRefGoogle Scholar
  26. Jenkins SG, Farrell DJ (2009) Increase in pneumococcus macrolide resistance, United States. Emerg Infect Dis 15:1260–1264PubMedCrossRefGoogle Scholar
  27. Jiang Z, Vasil AI, Hale JD, Hancock RE, Vasil ML, Hodges RS (2008) Effects of net charge and the number of positively charged residues on the biological activity of amphipathic alpha-helical cationic antimicrobial peptides. Biopolymers 90:369–383PubMedCrossRefGoogle Scholar
  28. Jiang Z, Vasil AI, Gera L, Vasil ML, Hodges RS (2011) Rational design of α-helical antimicrobial peptides to target Gram-negative pathogens, Acinetobacter baumannii and Pseudomonas aeruginosa: utilization of charge, ‘specificity determinants’, total hydrophobicity, hydrophobe type and location as design parameters to improve the therapeutic ratio. Chem Biol Drug Des 77:225–240PubMedCrossRefGoogle Scholar
  29. Jones RN, Fritsche TR, Sader HS, Ross JE (2006) Activity of retapamulin (SB-275833), a novel peuromutilin, against selected resistant gram-positive cocci. Antimicrob Agents Chemother 50:2583–22586PubMedCrossRefGoogle Scholar
  30. Karlowsky J, Zhanel G, Hammond G, Rubinstein E, Wylie J, Du T, Mulvey M, Alfa M (2012) Multidrug-resistant, NAP2 Clostridium difficile was the predominant toxigenic, hospital-acquired strain in the Province of Manitoba, Canada in 2006–2007. J Med Microbiol 61(3):693–700PubMedCrossRefGoogle Scholar
  31. Katz AR, Komeya AY, Soge OO, Kiaha MI, Lee MV, Wasserman GM, Maningas EV, Whelen AC, Kirkcaldy RD, Shapiro SJ, Bolan GA, Holmes KK (2012) Neisseria gonorrhoeae with high-level resistance to azithromycin: case report of the first isolate identified in the United States. Clin Infect Dis 54:841–843PubMedCrossRefGoogle Scholar
  32. Laudano JB (2011) Ceftaroline fosamil: a new broad-spectrum cephalosporin. J Antimicrob Chemother 66(Suppl 3):11–18Google Scholar
  33. López-Rojas R, Sánchez-Céspedes J, Docobo-Pérez F, Domínguez-Herrera J, Vila J, Pachón J (2011) Pre-clinical studies of a new quinolone (UB-8902) against Acinetobacter baumannii resistant to ciprofloxacin. Int J Antimicrob Agents 38:355–359PubMedCrossRefGoogle Scholar
  34. Maurya IK, Pathak S, Sharma M, Sanwal H, Chaudhary P, Tupe S, Deshpande M, Chauhan VS, Prasad R (2011) Antifungal activity of novel synthetic peptides by accumulation of reactive oxygen species (ROS) and disruption of cell wall against Candida albicans. Peptides 32(8):1732–1740PubMedCrossRefGoogle Scholar
  35. Mulcahy H, Sibley CD, Surette MG, Lewenza S (2011) Drosophila melanogaster as an animal model for the study of Pseudomonas aeruginosa biofilm infections in vivo. PLoS Pathog 7:e1002299PubMedCrossRefGoogle Scholar
  36. Parr TR Jr, Bayer AS (1988) Mechanisms of aminoglycoside resistance in variants of Pseudomonas aeruginosa isolated during treatment of experimental endocarditis in rabbits. J Infect Dis 158:1003–1010PubMedCrossRefGoogle Scholar
  37. Patel G, Huprikar S, Factor SH, Jenkins SG, Calfee DP (2008) Outcomes of carbapenem-resistant Klebsiella pneumoniae infection and the impact of antimicrobial and adjunctive therapies. Infect Control Hosp Epidemiol 29:1099–2106PubMedCrossRefGoogle Scholar
  38. Pfaller MA (2012) Antifungal drug resistance: mechanisms, epidemiology, and consequences for treatment. Am J Med 125(Suppl):S3–13PubMedCrossRefGoogle Scholar
  39. Pitman SK, Drew RH, Perfect JR (2011) Addressing current medical needs in invasive fungal infection prevention and treatment with new antifungal agents, strategies and formulations. Expert Opin Emerg Drugs. Aug 17 Epub ahead of printGoogle Scholar
  40. Richmond MH (1976) The presence of a variant of type-IIIa beta-lactamase in a series of strains isolated in a burns unit. J Med Microbiol 9:363–364PubMedCrossRefGoogle Scholar
  41. Rodríguez-Baño J, Navarro MD, Romero L, Muniain MA, de Cueto M, Ríos MJ, Hernández JR, Pascual A (2006) Bacteremia due to extended-spectrum beta-lactamase-producing Escherichia coli in the CTX-M era: a new clinical challenge. Clin Infect Dis 431:407–414Google Scholar
  42. Rodríguez-Baño J, Miró E, Villar M, Coelho A, Gozalo M, Borrell N, Bou G, Conejo MC, Pomar V, Aracil B, Larrosa N, Agüero J, Oliver A, Fernández A, Oteo J, Pascual A, Navarro F (2012) Colonisation and infection due to Enterobacteriaceae producing plasmid-mediated AmpC β-lactamases. J Infect 64:176–183PubMedCrossRefGoogle Scholar
  43. Sader HS, Jones RN (2007) Cefdinir: an oral cephalosporin for the treatment of respiratory tract infections and skin and skin structure infections. Expert Rev Anti Infect Ther 5:29–43PubMedCrossRefGoogle Scholar
  44. Schwartz-Cornil I, Bonneau M, Dalod M, Bertho N (2011) Impact of large mammals models in immunology. Reprod Fertil Dev 24:287–288CrossRefGoogle Scholar
  45. Spanakis EK, Aperis G, Mylonakis E (2006) New agents for the treatment of fungal infections: clinical efficacy and gaps in coverage. Clin Infect Dis 43:1060–1068PubMedCrossRefGoogle Scholar
  46. Subramanian S, Roberts CL, Hart CA, Martin HM, Edwards SW, Rhodes JM, Campbell BJ (2008) Replication of colonic Crohn’s disease mucosal Escherichia coli isolates within macrophages and their susceptibility to antibiotics. Antimicrob Agents Chemother 52:427–434PubMedCrossRefGoogle Scholar
  47. Sutcliffe JA (2011) Antibiotics in development targeting protein synthesis. Ann N Y Acad Sci 1241:122–152PubMedCrossRefGoogle Scholar
  48. Talbot GH, Bradley J, Edwards JE Jr, Gilbert D, Scheld M, Bartlett JG (2006) Bad bugs need drugs: an update on the development pipeline from the antimicrobial availability task force of the Infectious Diseases Society of America. Clin Infect Dis 42:657–668PubMedCrossRefGoogle Scholar
  49. Talbot GH (2008) What is the pipeline for Gram-negative pathogens? Expert Rev Anti Infect Ther 6:39–49PubMedCrossRefGoogle Scholar
  50. Tsai TY, Chang SC, Hsueh PR, Feng NH, Wang JT (2007) In vitro activity of isepamicin and other aminoglycosides against clinical isolates of Gram-negative bacteria causing nosocomial bloodstream infections. J Microbiol Immunol Infect 40:481–486PubMedGoogle Scholar
  51. Unemo M, Shafer WM (2011) Antibiotic resistance in Neisseria gonorrhoeae: origin, evolution, and lessons learned for the future. Ann N Y Acad Sci 1230:E19–28PubMedCrossRefGoogle Scholar
  52. Unemo M, Golparian D, Nicholas R, Ohnishi M, Gallay A, Sednaoui P (2012) High-level cefixime- and ceftriaxone-resistant Neisseria gonorrhoeae in France: Novel penA mosaic allele in a successful international clone causes treatment failure. Antimicrob Agents Chemother 56:1273–1280PubMedCrossRefGoogle Scholar
  53. Venugopal AA, Johnson S (2012) Fidaxomicin: a novel marcocyclic antibiotic approved for treatment of Clostridium difficile infection. Clin Infect Dis 54:568–574PubMedCrossRefGoogle Scholar
  54. Wasan KM, Sivak O, Rosland M, Risovic V, Bartlett K (2007) Assessing the antifungal activity, pharmacokinetics, and tissue distribution of amphotericin B following the administration of Abelcet and Am Bisome in combination with caspofungin to rats infected with Aspergillus fumigatus. J Pharm Sci 96:1737–1747PubMedCrossRefGoogle Scholar
  55. Weiss K (2006) Vancomycin-resistant enterococci: the value of infection control and antibiotic control policy. Can J infect Dis Med Microbiol 17(Suppl):9B–12BGoogle Scholar
  56. Yong D, Toleman MA, Giske CG, Cho HS, Sundman K, Lee K, Walsh TR (2009) Characterization of a new metallo-beta-lactamase gene, bla(NDM-1), and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India. Antimicrob Agents Chemother 53:5046–5054PubMedCrossRefGoogle Scholar
  57. Zellweger JP (2011) Multidrug resistant tuberculosis—its extent, hazard and possible solutions. Rev Mal Respir 28:1025–1033PubMedCrossRefGoogle Scholar
  58. Zhanel GG, Lam A, Schweizer F, Thomson K, Wlakty A, Rubinstein E, Gin AS, Hoban DJ, Noreddin AM, Karlowsky JA (2008) Ceftribiprole: a review of a braod-spectrum and anti-MRSA cephalosporin. Am J Clin Dermatol 9:245–264PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Department of Laboratory Medicine and PathologyUniversity of AlbertaEdmontonCanada

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