Antibiotics in Phase II and III Clinical Trials

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

Abstract

There are 19 compounds in late-stage clinical trials, of which ten may be suitable for Gram-positive infections. However, there are only five compounds in development for Gram-negative infections, in addition to four broad-spectrum ones. There are two new classes in late-stage clinical development. This chapter discusses in some detail each of the antibiotics in Phase II and Phase III clinical trials. Only those that appear in the literature are covered. The shortage of compounds in development for Gram-negatives and the small number of new classes in the pipeline is of serious concern; this matter needs to be addressed by governments, the regulatory authorities, the pharmaceutical industry and academia urgently.

Keywords

Antibiotics Phase II Phase III clinical trials Gram-positives Gram-negatives classes combinations resistance regulation pipeline 

References

  1. Abandeh FI, Drew ME, Sopirala MM (2012) Carbapenem-hydrolyzing gram-negative bacteria: current options for treatment and review of drugs in development. Recent Pat Antiinfect Drug Discov 7(1):19–27PubMedCrossRefGoogle Scholar
  2. Becker D, Selbach M, Rollenhagen C, Ballmaier M, Meyer TF, Mann M, Bumann D (2006) Robust salmonella metabolism limits possibilities for new antimicrobials. Nature 16:303–307CrossRefGoogle Scholar
  3. Bell JM, Turnidge JD, Inoue M, Kohno S, Hirakata Y, Ono Y, Jones RN (2005) Activity of a peptide deformylase inhibitor LBM415 (NVP PDF-713) tested against recent clinical isolates from Japan. J Antimicrob Chemother 55(2):276–278PubMedCrossRefGoogle Scholar
  4. Belley A (2010) Oritavancin disrupts membrane integrity of Staphylococcus aureus and vancomycin-resistant enterococci to effect rapid bacterial killing. Antimicrob Agents Chemother 54:5369–5371PubMedCrossRefGoogle Scholar
  5. Boucher HW, Talbot GH et al (2009) Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis 48(1):1–12PubMedCrossRefGoogle Scholar
  6. Burrowes B, Harper DR, Anderson J, McConville M, Enright MC (2011) Bacteriophage therapy: potential uses in the control of antibiotic-resistant pathogens. Expert Rev Anti Infect Ther 9(9):775–85PubMedCrossRefGoogle Scholar
  7. Busse KH, Oltrogge KM, Oxencis CJ, Peppard WJ (2010) Dalbavancin: a review of its use in the treatment of gram-positive infections. Clin Med Insights Ther 2:7–13Google Scholar
  8. Butler MS, Buss AD (2006) Natural products–the future scaffolds for novel antibiotics? Biochem Pharmacol 71(7):919–29PubMedCrossRefGoogle Scholar
  9. Butler MS, Cooper MA (2011) Antibiotics in the clinical pipeline in 2011. J Antibiot (Tokyo) 64(6):413–25CrossRefGoogle Scholar
  10. Cantón R, Morosini MI (2011) Emergence and spread of antibiotic resistance following exposure to antibiotics. FEMS Microbiol Rev 35(5):977–91PubMedCrossRefGoogle Scholar
  11. Cass RT, Brooks CD, Havrilla NA, Tack KJ, Borin MT, Young D, Bruss JB (2011) Pharmacokinetics and safety of single and multiple doses of ACHN-490 injection administered intravenously in healthy subjects. Antimicrob Agents Chemother 55(12):5874–80PubMedCrossRefGoogle Scholar
  12. Chen DZ, Patel DV, Hackbarth CJ, Wang W, Dreyer G, Young DC, Margolis PS, Wu C, Ni ZJ, Trias J, White RJ, Yuan Z (2000) Actinonin, a naturally occurring antibacterial agent, is a potent deformylase inhibitor. Biochemistry 39(6):1256–62PubMedCrossRefGoogle Scholar
  13. Chan M (2011) Combat drug resistance: no action today means no cure tomorrow. Statement by WHO Director-General, Dr Margaret Chan. World Health Day, 6 April 2011. http://www.who.int/mediacentre/news/statements/2011/whd_20110407/en/index.html. Accessed 2nd February 2012
  14. Cirz RT, Chin JK, Andes DR, de Crécy-Lagard V, Craig WA, Romesberg FE (2005) Inhibition of mutation and combating the evolution of antibiotic resistance. PLoS Biol 3(6):176CrossRefGoogle Scholar
  15. CMR International Institute for Regulatory Science in April 2003 in Nutfield, Surrey, UKGoogle Scholar
  16. Coates AR, Hu Y (2007) Novel approaches to developing new antibiotics for bacterial infections. Br J Pharmacol 152(8):1147–54PubMedCrossRefGoogle Scholar
  17. Coates ARM, Halls G, Hu Y (2011) Novel classes of antibiotics or more of the same? Brit J Pharmacol 163:184–194CrossRefGoogle Scholar
  18. Covington P, Davenport JM, Andrae D, O'Riordan W, Liverman L, McIntyre G, Almenoff J (2011) Randomized, double-blind, phase II, multicenter study evaluating the safety/tolerability and efficacy of JNJ-Q2, a novel fluoroquinolone, compared with linezolid for treatment of acute bacterial skin and skin structure infection. Antimicrob Agents Chemother 55(12):5790–7PubMedCrossRefGoogle Scholar
  19. Crofton J (1958) Sputum conversion and the metabolism of isoniazid. Am Rev Tuberc 77:869–871PubMedGoogle Scholar
  20. D’Agata EM, Dupont-Rouzeyrol M, Magal P, Olivier D, Ruan S (2008) The impact of different antibiotic regimens on the emergence of antimicrobial-resistant bacteria. PLoS One 3(12):4036CrossRefGoogle Scholar
  21. 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(7365):457–61PubMedCrossRefGoogle Scholar
  22. Dalhoff A, Stubbings W, Schubert S (2011) Comparative in vitro activities of the novel antibacterial finafloxacin against selected Gram-positive and Gram-negative bacteria tested in Mueller-Hinton broth and synthetic urine. Antimicrob Agents Chemother 55(4):1814–8PubMedCrossRefGoogle Scholar
  23. Farrell DJ, Sader HS, Castanheira M, Biedenbach DJ, Rhomberg PR, Jones RN (2010) Antimicrobial characterization of CEM-101 activity against respiratory tract pathogens including multidrug-resistant pneumococcal serogroup 19A isolates. Int J Antimicrob Agent 35:537–543CrossRefGoogle Scholar
  24. Farrell DJ, Liverman LC, Biedenbach DJ, Jones RN (2011) JNJ-Q2, a new fluoroquinolone with potent in vitro activity against Staphylococcus aureus, including methicillin- and fluoroquinolone-resistant strains. Antimicrob Agents Chemother 55(7):3631–4PubMedCrossRefGoogle Scholar
  25. Fox W, Sutherland I, Daniels M (1954) A five-year assessment of patients in a controlled trial of streptomycin in pulmonary tuberculosis. Q J Med 23:347–366PubMedGoogle Scholar
  26. Fox W, Ellard GA, Mitchison DA (1999) Studies on the treatment of tuberculosis undertaken by the British Medical Research Council Tuberculosis Units, 1946–1986, with relevant subsequent publications. Int J Tuberc Lung Dis 3:S231–S279PubMedGoogle Scholar
  27. Freire-Moran L, Aronsson B, Manz C, Gyssens IC, So AD, Monnet DL, Cars O (2011) ECDC-EMA Working Group. Critical shortage of new antibiotics in development against multidrug-resistant bacteria-time to react is now. Drug Resist Updat 14(2):118–24PubMedCrossRefGoogle Scholar
  28. Furuie H, Saisho Y, Yoshikawa T, Shimada J (2010) Intrapulmonary pharmacokinetics of S-013420, a novel bicyclolide antibacterial, in healthy Japanese subjects. Antimicrob Agents Chemother 54(2):866–70, Epub 2009 Nov 23PubMedCrossRefGoogle Scholar
  29. Ge Y, Whitehouse MJ, Friedland I, Talbot GH (2010) Pharmacokinetics and safety of CXA-101, a new antipseudomonal cephalosporin, in healthy adult male and female subjects receiving single- and multiple-dose intravenous infusions. Antimicrob Agents Chemother 54(8):3427–31PubMedCrossRefGoogle Scholar
  30. Haas DW (2000) Mycobacterial diseases, Chapter 240. In: Mandell GL, Bennett JE, Dolin R (eds) Principles and practice of infectious diseases, vol 2, 5th edn. Churchill Livingstone, Philadelphia, London, pp 2576–2607Google Scholar
  31. Hair PI, Keam SJ (2007) Daptomycin: a review of its use in the management of complicated skin and soft-tissue infections and Staphylococcus aureus bacteraemia. Drugs 67(10):1483–512PubMedCrossRefGoogle Scholar
  32. http://www.farm.ucl.ac.be/Full-texts-FARM/Domenech-2009-1.pdf. “Interactions of oritavancin, a new lipoglycopeptide derived from vancomycin, with phospholipid bilayers: Effect on membrane permeability and nanoscale lipid membrane organization” 2009
  33. Johnson KW, Lofland D, Moser HE (2005) PDF inhibitors: an emerging class of antibacterial drugs. Curr Drug Target Infect Disord 5:39–52, 1568-0053/05 © 2005 Bentham Science Publishers LtdCrossRefGoogle Scholar
  34. Hurdle JG, O’Neill AJ, Chopra I, Lee RE (2011) Targeting bacterial membrane function: an underexploited mechanism for treating persistent infections. Nat Rev Microbiol 9(1):62–75PubMedCrossRefGoogle Scholar
  35. Kohno S, Yamaguchi K, Tanigawara Y, Watanabe A, Aoki A, Niki Y, Fujita J (2007) Abstr. 47th Intersci. Conf. Antimicrob. Agents Chemother., abstr. L-485Google Scholar
  36. Kumarasamy KK, Toleman MA, Walsh TR, Bagaria J, Butt F, Balakrishnan R, Chaudhary U, Doumith M, Giske CG, Irfan S, Krishnan P, Kumar AV, Maharjan S, Mushtag S, Noorie T, Paterson DL, Pearson A, Perry C, Pike R, Rao B, Ray U, Sarma JB, Sharma M, Sheridan E, Thirunarayan MA, Turton J, Upadhyay S, Warner M, Welfare W, Livermore DM, Woodford N (2010) Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological and epidemiological study. Lancet Infect Dis 10:597–602PubMedCrossRefGoogle Scholar
  37. Leuthner KD, Vidaillac C, Cheung CM, Rybak MJ (2010) In vitro activity of the new multivalent glycopeptide-cephalosporin antibiotic TD-1792 against vancomycin-nonsusceptible Staphylococcus isolates. Antimicrob Agents Chemother 54(9):3799–803, Epub 2010 Jun 28PubMedCrossRefGoogle Scholar
  38. Livermore DM, Mushtaq S, Ge Y (2010) Chequerboard titration of cephalosporin CXA-101 (FR264205) and tazobactam versus beta-lactamase-producing Enterobacteriaceae. J Antimicrob Chemother 65(9):1972–4PubMedCrossRefGoogle Scholar
  39. Livermore DM, Warner MSM, Zhang J-C, Maharjan S, Doumith M, Woodford N (2011a) Activity of aminoglycosides, including ACHN-490, against carbapenem-resistant Enterobacteriaceae isolates. J Antimicrob Chemother 66(1):48–53PubMedCrossRefGoogle Scholar
  40. Livermore DM, Mushtaq S, Warner M, Zhang J, Maharjan S, Doumith M, Woodford N (2011b) Activities of NXL104 combinations with ceftazidime and aztreonam against carbapenemase-producing Enterobacteriaceae. Antimicrob Agents Chemother 55(1):390–4PubMedCrossRefGoogle Scholar
  41. Locke JB, Finn J, Hilgers M, Morales G, Rahawi S, Picazo JJ, Im W, Shaw KJ, Stein JL (2010) Structure-activity relationships of diverse oxazolidinones for linezolid-resistant Staphylococcus aureus strains possessing the cfr methyltransferase gene or ribosomal mutations. Agents Chemother 54(12):5337–43CrossRefGoogle Scholar
  42. Mangion IK, Ruck RT, Rivera N, Huffman MA, Shevlin M (2011) A concise synthesis of a β-lactamase inhibitor. Org Lett 13(20):5480–3, http://antibiotics-theperfectstorm.blogspot.com/2010/09/superbug-ndm-1.html PubMedCrossRefGoogle Scholar
  43. Medical Research Council (1948) Streptomycin treatment of pulmonary tuberculosis. Br Med J 2:769–782CrossRefGoogle Scholar
  44. Medical Research Council (1950) Treatment of pulmonary tuberculosis with streptomycin and para-amino-salicylic acid. Br Med J 2:1073–1085CrossRefGoogle Scholar
  45. Meyer AL (2005) Prospects and challenges of developing new agents for tough Gram-negatives. Curr Opin Pharmacol 5(5):490–4PubMedCrossRefGoogle Scholar
  46. Mitchison DA (1954) Problems of drug resistance. Br Med Bull 69:640–641Google Scholar
  47. Mitchison DA (1998) How drug resistance emerges as a result of poor compliance during short course chemotherapy for tuberculosis. Int J Tuberc Lung Dis 2:10–15PubMedGoogle Scholar
  48. Morgan A, Cofer C, Stevens DL (2009) Iclaprim: a novel dihydrofolate reductase inhibitor for skin and soft tissue infections. Future Microbiol 4(2):131–44PubMedCrossRefGoogle Scholar
  49. Mushtaq S, Warner M, Williams G, Critchley I, Livermore DM (2010) Activity of chequerboard combinations of ceftaroline and NXL104 versus beta-lactamase-producing Enterobacteriaceae. J Antimicrob Chemother 65(7):1428–32PubMedCrossRefGoogle Scholar
  50. No authors. (2009) Deal watch: Novartis acquires marketing rights for novel broad-spectrum antibiotic. Nat Rev Drug Discov 2009 (12):922Google Scholar
  51. Payne DJ, Gwynn MN, Holmes DJ, Pompliano DL (2007) Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Discov 6(1):29–40PubMedCrossRefGoogle Scholar
  52. Peirano G, Pitout JD (2010) Molecular epidemiology of Escherichia coli producing CTX-M beta-lactamases: the worldwide emergence of clone ST131 O25:H4. Int J Antimicrob Agents 35(4):316–21PubMedCrossRefGoogle Scholar
  53. Peppard WJ, Schuenke CD (2008) Iclaprim, a diaminopyrimidine dihydrofolate reductase inhibitor for the potential treatment of antibiotic-resistant staphylococcal infections. Curr Opin Investig Drugs 9(2):210–25PubMedGoogle Scholar
  54. Piel J (2011) Approaches to capturing and designing biologically active small molecules produced by uncultured microbes. Annu Rev Microbiol 65:431–53PubMedCrossRefGoogle Scholar
  55. Potron A, Poirel L, Nordmann P (2011) Plasmid-mediated transfer of the bla(NDM-1) gene in Gram-negative rods. FEMS Microbiol Lett 324(2):111–6PubMedCrossRefGoogle Scholar
  56. Rolan P, Sun H, MacLeod C, Bracken K, Evans TG (2011) Pharmacokinetics and unexpected safety issues of LBM415, a novel oral peptide deformylase inhibitor. Clin Pharmacol Ther 90(2):256–262PubMedCrossRefGoogle Scholar
  57. Rubino C, Bhavnani S, Burak E, Ambrose P (2010) Pharmacokinetic-pharmacodynamic (PK-PD) target attainment (TA) analyses supporting delafloxacin (DFX) Phase 3 dose regimen decisions. ICAAC. http://www.drugs.com/clinical_trials/rib-x-pharmaceuticals-presents-data-supporting-delafloxacin-potential-best-class-fluoroquinolone-10109.html
  58. Sato T, Tateda K, Kimura S, Iwata M, Ishii Y, Yamaguchi K (2011) In vitro antibacterial activity of modithromycin, a novel 6,11-bridged bicyclolide, against respiratory pathogens, including macrolide-resistant Gram-positive cocci. Antimicrob Agents Chemother 55(4):1588–93, Epub 2011 Jan 10PubMedCrossRefGoogle Scholar
  59. Scheifele DW, Marty K, LaJeunesse C, Fan SY, Bjornson G, Langley JM, Halperin SA (2011) Strategies for successful rapid trials of influenza vaccine. Clin Trials 8(6):699–704PubMedCrossRefGoogle Scholar
  60. Scheinfeld N (2007) A comparison of available and investigational antibiotics for complicated skin infections and treatment-resistant Staphylococcus aureus and enterococcus. J Drugs Dermatol 6(4):97–103PubMedGoogle Scholar
  61. Shoemaker NB, Vlamakis H, Hayes K, Salyers AA (2001) Evidence for extensive resistance gene transfer among Bacteroides spp. and among Bacteroides and other genera in the human colon. Appl Environ Microbiol 67(2):561–8PubMedCrossRefGoogle Scholar
  62. Stachyra T, Levasseur P, Péchereau MC, Girard AM, Claudon M, Miossec C, Black MT (2009) In vitro activity of the {beta}-lactamase inhibitor NXL104 against KPC-2 carbapenemase and Enterobacteriaceae expressing KPC carbapenemases. J Antimicrob Chemother 64(2):326–9PubMedCrossRefGoogle Scholar
  63. Stryjewski ME, Barriere SL, Kitt MM, Corey GR (2007) TD-1792 vs vancomycin (VAN) for treatment of complicated gram-positive skin and skin structure infections (cSSSIs), poster L-1147a. Abstract 47th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington, DCGoogle Scholar
  64. Sutcliffe JA (2011) Antibiotics in development targeting protein synthesis. Ann N Y Acad Sci 1241(1):122–52PubMedCrossRefGoogle Scholar
  65. Targanta Revives Oritavancin: Next Weapon Against cSSSI? BioWorld Today, November 26, 2007Google Scholar
  66. Traugott KA, Echevarria K, Maxwell P, Green K, Lewis JS 2nd (2011) Monotherapy or combination therapy? The Pseudomonas aeruginosa conundrum. Pharmacotherapy 31(6):598–608PubMedCrossRefGoogle Scholar
  67. Wagenlehner FM, Wagenlehner CM, Blenk B, Blenk H, Schubert S, Dalhoff A, Naber KG (2011) Urinary pharmacokinetics and bactericidal activity of finafloxacin (200 and 800 mg) in healthy volunteers receiving a single oral dose. Chemotherapy 57(2):97–107PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Medical Microbiology, Division of Clinical Sciences, Centre for InfectionSt George’s University of LondonLondonUK
  2. 2.Medical Marketing ServicesBeaconsfieldUK

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