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Antibiotic Resistance pp 167–183Cite as

Antibiotics in Phase II and III Clinical Trials

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Part of the book series: Handbook of Experimental Pharmacology ((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.

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References

  • 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):19–27

    Article  PubMed  CAS  Google Scholar 

  • Becker D, Selbach M, Rollenhagen C, Ballmaier M, Meyer TF, Mann M, Bumann D (2006) Robust salmonella metabolism limits possibilities for new antimicrobials. Nature 16:303–307

    Article  Google Scholar 

  • 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):276–278

    Article  PubMed  CAS  Google Scholar 

  • Belley A (2010) Oritavancin disrupts membrane integrity of Staphylococcus aureus and vancomycin-resistant enterococci to effect rapid bacterial killing. Antimicrob Agents Chemother 54:5369–5371

    Article  PubMed  CAS  Google Scholar 

  • 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):1–12

    Article  PubMed  Google Scholar 

  • 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):775–85

    Article  PubMed  Google Scholar 

  • 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 2:7–13

    CAS  Google Scholar 

  • Butler MS, Buss AD (2006) Natural products–the future scaffolds for novel antibiotics? Biochem Pharmacol 71(7):919–29

    Article  PubMed  CAS  Google Scholar 

  • Butler MS, Cooper MA (2011) Antibiotics in the clinical pipeline in 2011. J Antibiot (Tokyo) 64(6):413–25

    Article  CAS  Google Scholar 

  • Cantón R, Morosini MI (2011) Emergence and spread of antibiotic resistance following exposure to antibiotics. FEMS Microbiol Rev 35(5):977–91

    Article  PubMed  Google Scholar 

  • 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):5874–80

    Article  PubMed  CAS  Google Scholar 

  • 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):1256–62

    Article  PubMed  CAS  Google Scholar 

  • 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

  • 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):176

    Article  Google Scholar 

  • CMR International Institute for Regulatory Science in April 2003 in Nutfield, Surrey, UK

    Google Scholar 

  • Coates AR, Hu Y (2007) Novel approaches to developing new antibiotics for bacterial infections. Br J Pharmacol 152(8):1147–54

    Article  PubMed  CAS  Google Scholar 

  • Coates ARM, Halls G, Hu Y (2011) Novel classes of antibiotics or more of the same? Brit J Pharmacol 163:184–194

    Article  CAS  Google Scholar 

  • 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):5790–7

    Article  PubMed  CAS  Google Scholar 

  • Crofton J (1958) Sputum conversion and the metabolism of isoniazid. Am Rev Tuberc 77:869–871

    PubMed  CAS  Google Scholar 

  • 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):4036

    Article  Google Scholar 

  • 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):457–61

    Article  PubMed  Google Scholar 

  • 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):1814–8

    Article  PubMed  CAS  Google Scholar 

  • 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 35:537–543

    Article  CAS  Google Scholar 

  • 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):3631–4

    Article  PubMed  CAS  Google Scholar 

  • 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 23:347–366

    PubMed  CAS  Google Scholar 

  • 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–S279

    PubMed  CAS  Google Scholar 

  • 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):118–24

    Article  PubMed  Google Scholar 

  • 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 23

    Article  PubMed  CAS  Google Scholar 

  • 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):3427–31

    Article  PubMed  CAS  Google Scholar 

  • 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 2576–2607

    Google Scholar 

  • 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):1483–512

    Article  PubMed  CAS  Google Scholar 

  • 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

  • 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 Ltd

    Article  CAS  Google Scholar 

  • 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):62–75

    Article  PubMed  CAS  Google Scholar 

  • Kohno S, Yamaguchi K, Tanigawara Y, Watanabe A, Aoki A, Niki Y, Fujita J (2007) Abstr. 47th Intersci. Conf. Antimicrob. Agents Chemother., abstr. L-485

    Google Scholar 

  • 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 10:597–602

    Article  PubMed  CAS  Google Scholar 

  • 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 28

    Article  PubMed  CAS  Google Scholar 

  • 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):1972–4

    Article  PubMed  CAS  Google Scholar 

  • 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):48–53

    Article  PubMed  CAS  Google Scholar 

  • 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):390–4

    Article  PubMed  CAS  Google Scholar 

  • 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):5337–43

    Article  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Medical Research Council (1948) Streptomycin treatment of pulmonary tuberculosis. Br Med J 2:769–782

    Article  Google Scholar 

  • Medical Research Council (1950) Treatment of pulmonary tuberculosis with streptomycin and para-amino-salicylic acid. Br Med J 2:1073–1085

    Article  Google Scholar 

  • Meyer AL (2005) Prospects and challenges of developing new agents for tough Gram-negatives. Curr Opin Pharmacol 5(5):490–4

    Article  PubMed  CAS  Google Scholar 

  • Mitchison DA (1954) Problems of drug resistance. Br Med Bull 69:640–641

    CAS  Google Scholar 

  • Mitchison DA (1998) How drug resistance emerges as a result of poor compliance during short course chemotherapy for tuberculosis. Int J Tuberc Lung Dis 2:10–15

    PubMed  CAS  Google Scholar 

  • Morgan A, Cofer C, Stevens DL (2009) Iclaprim: a novel dihydrofolate reductase inhibitor for skin and soft tissue infections. Future Microbiol 4(2):131–44

    Article  PubMed  CAS  Google Scholar 

  • 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):1428–32

    Article  PubMed  CAS  Google Scholar 

  • No authors. (2009) Deal watch: Novartis acquires marketing rights for novel broad-spectrum antibiotic. Nat Rev Drug Discov 2009 (12):922

    Google Scholar 

  • 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):29–40

    Article  PubMed  CAS  Google Scholar 

  • 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):316–21

    Article  PubMed  CAS  Google Scholar 

  • 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):210–25

    PubMed  CAS  Google Scholar 

  • Piel J (2011) Approaches to capturing and designing biologically active small molecules produced by uncultured microbes. Annu Rev Microbiol 65:431–53

    Article  PubMed  CAS  Google Scholar 

  • 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):111–6

    Article  PubMed  CAS  Google Scholar 

  • 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):256–262

    Article  PubMed  CAS  Google Scholar 

  • 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

  • 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 10

    Article  PubMed  CAS  Google Scholar 

  • 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):699–704

    Article  PubMed  Google Scholar 

  • 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):97–103

    PubMed  Google Scholar 

  • 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):561–8

    Article  PubMed  CAS  Google Scholar 

  • 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):326–9

    Article  PubMed  CAS  Google Scholar 

  • 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, DC

    Google Scholar 

  • Sutcliffe JA (2011) Antibiotics in development targeting protein synthesis. Ann N Y Acad Sci 1241(1):122–52

    Article  PubMed  CAS  Google Scholar 

  • Targanta Revives Oritavancin: Next Weapon Against cSSSI? BioWorld Today, November 26, 2007

    Google Scholar 

  • Traugott KA, Echevarria K, Maxwell P, Green K, Lewis JS 2nd (2011) Monotherapy or combination therapy? The Pseudomonas aeruginosa conundrum. Pharmacotherapy 31(6):598–608

    Article  PubMed  CAS  Google Scholar 

  • 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):97–107

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Medical Microbiology, Division of Clinical Sciences, Centre for Infection, St George’s University of London, Cranmer Terrace, London, SW17 ORE, UK

    Anthony R. M. Coates

  2. Medical Marketing Services, Beaconsfield, Buckinghamshire, UK

    Gerry Halls

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  1. Anthony R. M. Coates
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  2. Gerry Halls
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Correspondence to Anthony R. M. Coates .

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  1. , Div of Cellular and Molecular Medicine, St. George's, University of London, Cranmer Terrace, London, SW17 0RE, United Kingdom

    Anthony R.M. Coates

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Coates, A.R.M., Halls, G. (2012). Antibiotics in Phase II and III Clinical Trials. In: Coates, A. (eds) Antibiotic Resistance. Handbook of Experimental Pharmacology, vol 211. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-28951-4_11

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