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Review article: Biomedical intelligence

Vol. 145 No. 3132 (2015)

Development of new antibiotics: taking off finally?

  • Esther Bettiol
  • Stephan Harbarth
DOI
https://doi.org/10.4414/smw.2015.14167
Cite this as:
Swiss Med Wkly. 2015;145:w14167
Published
26.07.2015

Summary

Since 2010, awareness of the global threat caused by antimicrobial resistance (AMR) has risen considerably and multiple policy and research initiatives have been implemented. Research and development (R&D) of much-needed new antibiotics active against multiresistant pathogens is a key component of all programmes aiming at fighting AMR, but it has been lagging behind owing to scientific, regulatory and economic challenges.

Although a few new antibiotics might be available in Switzerland in the next 5 years, these new agents are not based on new mechanisms of action and are not necessarily active against resistant pathogens for which there is the highest unmet medical need, i.e. multiresistant Gram-negative bacteria. Of the three new antibiotics with pending authorisation in Switzerland for systemic treatment of severe infections, oritavancin and tedizolid target Gram-positive pathogens, while only ceftolozane+tazobactam partially covers multiresistant Gram-negative pathogens. Among six antibiotics currently in phase III of clinical development, delafloxacin and solithromycin will also be useful mostly for Gram-positive infections. Importantly, the four other compounds are active against multiresistant Gram-negative pathogens: ceftazidime+avibactam, meropenem+RPX7009, eravacycline and plazomicin. The three last compounds are also active against carbapenem-resistant Enterobacteriaceae (CRE). A few compounds active against such pathogens are currently in earlier clinical development, but their number may decrease, considering the risk of failure over the course of clinical development.

At last, through public and political awareness of pathogens with high public health impact and unmet medical need, development of innovative economic incentives and updated regulatory guidance, R&D of new antibiotics is slowly taking off again.

References

  1. Carlet J, Collignon P, Goldmann D, Goossens H, Gyssens IC, Harbarth S, et al. Society’s failure to protect a precious resource: antibiotics. Lancet. 2011;378(9788):369–71. Epub 2011/04/12.
  2. CDC. Antibiotic resistance threats in the United States. Report, 2013.
  3. The Lancet. Antimicrobial resistance: in terms politicians understand. Lancet. 2014;384(9961):2173.
  4. UK Review on Antimicrobial Resistance. Antimicrobial Resistance: Tackling a Crisis for the Health and Wealth of Nations. 2014.
  5. Graves N, Harbarth S, Beyersmann J, Barnett A, Halton K, Cooper B. Estimating the cost of health care-associated infections: mind your p’s and q’s. Clin Infect Dis. 2010;50(7):1017–21. Epub 2010/02/25.
  6. World Health Organization. Antimicrobial resistance: Global report on surveillance. 2014.
  7. Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect. 2012;18(3):268–81. Epub 2011/07/29.
  8. Laxminarayan R, Duse A, Wattal C, Zaidi AK, Wertheim HF, Sumpradit N, et al. Antibiotic resistance-the need for global solutions. Lancet Infect Dis. 2013;13(12):1057–98.
  9. Seiffert SN, Hilty M, Kronenberg A, Droz S, Perreten V, Endimiani A. Extended-spectrum cephalosporin-resistant Escherichia coli in community, specialized outpatient clinic and hospital settings in Switzerland. J Antimicrob Chemother. 2013;68(10):2249–54.
  10. ANRESIS. Swiss Centre for Antibiotic resistance [08.03.2015]. Available from: http://www.anresis.ch/.
  11. Kronenberg A, Hilty M, Endimiani A, Muhlemann K. Temporal trends of extended-spectrum cephalosporin-resistant Escherichia coli and Klebsiella pneumoniae isolates in in- and outpatients in Switzerland, 2004 to 2011. Euro Surveill. 2013;18(21).
  12. Silver LL. Challenges of antibacterial discovery. Clinical microbiology reviews. 2011;24(1):71–109.
  13. Bax R, Green S. Antibiotics: the changing regulatory and pharmaceutical industry paradigm. J Antimicrob Chemother. 2015;70(5):1281-4.
  14. Rex JH, Goldberger M, Eisenstein BI, Harney C. The evolution of the regulatory framework for antibacterial agents. Ann N Y Acad Sci. 2014;1323:11–21.
  15. Nambiar S, Laessig K, Toerner J, Farley J, Cox E. Antibacterial drug development: challenges, recent developments, and future considerations. Clin Pharmacol Ther. 2014;96(2):147–9.
  16. Spellberg B, Bartlett J, Wunderink R, Gilbert DN. Novel Approaches Are Needed to Develop Tomorrow’s Antibacterial Therapies. Am J Respir Crit Care Med. 2015;191(2):135–40.
  17. So AD, Gupta N, Brahmachari SK, Chopra I, Munos B, Nathan C, et al. Towards new business models for R&D for novel antibiotics. Drug Resist Updat. 2011;14(2):88–94.
  18. Kinch MS, Patridge E, Plummer M, Hoyer D. An analysis of FDA-approved drugs for infectious disease: antibacterial agents. Drug Discov Today. 2014;19(9):1283–7.
  19. Rice LB. Federal funding for the study of antimicrobial resistance in nosocomial pathogens: no ESKAPE. J Infect Dis. 2008;197(8):1079–81.
  20. US eCFR Title 21, Chapter I, Subchapter D, §317.2 List of qualifying pathogens that have the potential to pose a serious threat to public health. 2014 [12.01.2015]. Available from: http://www.ecfr.gov/cgi-bin/retrieveECFR.
  21. Spellberg B, Shlaes D. Prioritized current unmet needs for antibacterial therapies. Clin Pharmacol Ther. 2014;96(2):151–3.
  22. BARDA. Biomedical Advanced Research and Development Authority 2014 [03.03.2015]. Available from: http://www.phe.gov/about/barda/Pages/default.aspx.
  23. ReAct. [05.01.2015]. Available from: http://www.reactgroup.org/#.
  24. WAAAR. The WAAAR declaration against antibiotic resistance [05.01.2015]. Available from: http://www.ac2bmr.fr/index.php/en/waaar-declaration.
  25. Antibiotic Action. [05.01.2015]. Available from: http://antibiotic-action.com/.
  26. CHMP. Addendum to the guideline on the evaluation of medicinal products indicated for treatment of bacterial infections. EMA/CHMP/351889/2013. London, UK, 2013.
  27. CDER. Draft guidance for industry: antibacterial therapies for patients with unmet medical need for the treatment of serious bacterial diseases. UCM359184. Silver Spring, MD, USA: US Department of Health and Humans Services, Food and Drug Administration, 2013 UCM359184.
  28. Hall AK, Carlson MR. The current status of orphan drug development in Europe and the US. Intractable Rare Dis Res. 2014;3(1):1–7.
  29. Milne CP. Prospects for rapid advances in the development of new medicines for special medical needs. Clin Pharmacol Ther. 2014;95(1):98–109.
  30. IDSA. White paper: recommendations on the conduct of superiority and organism-specific clinical trials of antibacterial agents for the treatment of infections caused by drug-resistant bacterial pathogens. Clin Infect Dis. 2012;55(8):1031–46.
  31. Rex JH, Eisenstein BI, Alder J, Goldberger M, Meyer R, Dane A, et al. A comprehensive regulatory framework to address the unmet need for new antibacterial treatments. Lancet Infect Dis. 2013;13(3):269–75.
  32. Talbot GH, Powers JH, Fleming TR, Siuciak JA, Bradley J, Boucher H, et al. Progress on developing endpoints for registrational clinical trials of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections: update from the Biomarkers Consortium of the Foundation for the National Institutes of Health. Clin Infect Dis. 2012;55(8):1114–21.
  33. COMBACTE. Combating bacterial resistance in Europe [03.03.2015]. Available from: https://www.combacte.com/.
  34. ND4BB. New Drugs for Bad Bugs [03.03.2015]. Available from: http://www.imi.europa.eu/content/nd4bb.
  35. DRIVE-AB [10.03.2015]. Available from: http://drive-ab.eu/.
  36. Infectious disease leads in first phase of Europe’s IMI effort. Nat Med. 2014;20(1):5.
  37. Longitude Prize. UK 2014 [03.03.2015]. Available from: http://www.longitudeprize.org/.
  38. Joint Programming Initiative on Antimicrobial Resistance (JPI-AMR). [05.01.2015]. Available from: http://www.jpiamr.eu/.
  39. UK review on antimicrobial resistance. [05.01.2015]. Available from: http://amr-review.org/.
  40. WHO. Draft global action plan on antimicrobial resistance. December 2014 Contract No.: EB136/20.
  41. Zhanel GG, Chung P, Adam H, Zelenitsky S, Denisuik A, Schweizer F, et al. Ceftolozane/tazobactam: a novel cephalosporin/beta-lactamase inhibitor combination with activity against multidrug-resistant gram-negative bacilli. Drugs. 2014;74(1):31–51.
  42. Zhanel GG, Calic D, Schweizer F, Zelenitsky S, Adam H, Lagace-Wiens PR, et al. New lipoglycopeptides: a comparative review of dalbavancin, oritavancin and telavancin. Drugs. 2010;70(7):859–86.
  43. Kisgen JJ, Mansour H, Unger NR, Childs LM. Tedizolid: a new oxazolidinone antimicrobial. Am J Health Syst Pharm. 2014;71(8):621–33.
  44. Zhanel GG, Lawson CD, Adam H, Schweizer F, Zelenitsky S, Lagace-Wiens PR, et al. Ceftazidime-avibactam: a novel cephalosporin/beta-lactamase inhibitor combination. Drugs. 2013;73(2):159–77.
  45. Dauner DG, Nelson RE, Taketa DC. Ceftobiprole: A novel, broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus. Am J Health Syst Pharm. 2010;67(12):983–93.
  46. Chahine EB. Ceftobiprole: Farewell or just a delay? Am J Health Syst Pharm. 2010;67(12):981.
  47. de Kraker ME, Jarlier V, Monen JC, Heuer OE, van de Sande N, Grundmann H. The changing epidemiology of bacteraemias in Europe: trends from the European Antimicrobial Resistance Surveillance System. Clin Microbiol Infect. 2013;19(9):860–8.
  48. Lee AS, Cooper BS, Malhotra-Kumar S, Chalfine A, Daikos GL, Fankhauser C, et al. Comparison of strategies to reduce meticillin-resistant Staphylococcus aureus rates in surgical patients: a controlled multicentre intervention trial. BMJ Open. 2013;3(9):e003126.
  49. FDA approves new antibacterial drug Avycaz [Internet]. February 25, 2015 [cited 20.03.2015]. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm435629.htm
  50. Actavis Receives U.S. FDA Approval for AVYCAZ™ (CEFTAZIDIME-AVIBACTAM) [Internet]. [cited 10.03.2015]. Available from: http://www.actavis.com/NEWS/News/Thomson-Reuters/Actavis-Receives-U-S-FDA-Approval-for-AVYCAZ-CEFT
  51. Bassetti M, Della Siega P, Pecori D, Scarparo C, Righi E. Delafloxacin for the treatment of respiratory and skin infections. Expert Opin Investig Drugs. 2015;24(3):433–42.
  52. Oldach D, Clark K, Schranz J, Das A, Craft JC, Scott D, et al. Randomized, double-blind, multicenter phase 2 study comparing the efficacy and safety of oral solithromycin (CEM-101) to those of oral levofloxacin in the treatment of patients with community-acquired bacterial pneumonia. Antimicrob Agents Chemother. 2013;57(6):2526–34.
  53. Liapikou A, Cilloniz C, Mensa J, Torres A. New antimicrobial approaches to gram positive respiratory infections. Pulm Pharmacol Ther. 2015;32:137-43.
  54. Drawz SM, Papp-Wallace KM, Bonomo RA. New beta-lactamase inhibitors: a therapeutic renaissance in an MDR world. Antimicrob Agents Chemother. 2014;58(4):1835–46.
  55. Shlaes DM. New beta-lactam-beta-lactamase inhibitor combinations in clinical development. Ann N Y Acad Sci. 2013;1277:105–14.
  56. Solomkin JS, Ramesh MK, Cesnauskas G, Novikovs N, Stefanova P, Sutcliffe JA, et al. Phase 2, randomized, double-blind study of the efficacy and safety of two dose regimens of eravacycline versus ertapenem for adult community-acquired complicated intra-abdominal infections. Antimicrob Agents Chemother. 2014;58(4):1847–54.
  57. Walkty A, Adam H, Baxter M, Denisuik A, Lagace-Wiens P, Karlowsky JA, et al. In vitro activity of plazomicin against 5,015 gram-negative and gram-positive clinical isolates obtained from patients in canadian hospitals as part of the CANWARD study, 2011–2012. Antimicrob Agents Chemother. 2014;58(5):2554–63.
  58. Lemmenmeier E, Kohler P, Bruderer T, Goldenberger D, Kleger GR, Schlegel M. First documented outbreak of KPC-2-producing Klebsiella pneumoniae in Switzerland: infection control measures and clinical management. Infection. 2014;42(3):529–34.
  59. Seiffert SN, Perreten V, Johannes S, Droz S, Bodmer T, Endimiani A. OXA-48 carbapenemase-producing Salmonella enterica serovar Kentucky isolate of sequence type 198 in a patient transferred from Libya to Switzerland. Antimicrob Agents Chemother. 2014;58(4):2446–9.
  60. Seiffert SN, Marschall J, Perreten V, Carattoli A, Furrer H, Endimiani A. Emergence of Klebsiella pneumoniae co-producing NDM-1, OXA-48, CTX-M-15, CMY-16, QnrA and ArmA in Switzerland. Int J Antimicrob Agents. 2014;44(3):260–2.
  61. Poirel L, Schrenzel J, Cherkaoui A, Bernabeu S, Renzi G, Nordmann P. Molecular analysis of NDM-1-producing enterobacterial isolates from Geneva, Switzerland. J Antimicrob Chemother. 2011;66(8):1730–3.
  62. Poirel L, Bonnin RA, Boulanger A, Schrenzel J, Kaase M, Nordmann P. Tn125-related acquisition of blaNDM-like genes in Acinetobacter baumannii. Antimicrob Agents Chemother. 2012;56(2):1087–9.
  63. Abbas M, Cherkaoui A, Fankhauser C, Schrenzel J, Harbarth S. [Epidemiology and clinical implications of carbapenemase-producing bacteria in Switzerland]. Revue medicale suisse. 2012;8(338):882–4, 6–9. French.
  64. Wernli D, Haustein T, Conly J, Carmeli Y, Kickbusch I, Harbarth S. A call for action: the application of The International Health Regulations to the global threat of antimicrobial resistance. PLoS Med. 2011;8(4):e1001022.
  65. Lee CS, Doi Y. Therapy of Infections due to Carbapenem-Resistant Gram-Negative Pathogens. Infection & chemotherapy. 2014;46(3):149–64.
  66. Geser N, Stephan R, Korczak BM, Beutin L, Hachler H. Molecular identification of extended-spectrum-beta-lactamase genes from Enterobacteriaceae isolated from healthy human carriers in Switzerland. Antimicrob Agents Chemother. 2012;56(3):1609–12.
  67. Pasricha J, Koessler T, Harbarth S, Schrenzel J, Camus V, Cohen G, et al. Carriage of extended-spectrum beta-lactamase-producing enterobacteriacae among internal medicine patients in Switzerland. Antimicrob Resist Infect Control. 2013;2:20.
  68. Bonkat G, Muller G, Braissant O, Frei R, Tschudin-Suter S, Rieken M, et al. Increasing prevalence of ciprofloxacin resistance in extended-spectrum-beta-lactamase-producing Escherichia coli urinary isolates. World J Urol. 2013;31(6):1427–32.
  69. Meier S, Weber R, Zbinden R, Ruef C, Hasse B. Extended-spectrum beta-lactamase-producing Gram-negative pathogens in community-acquired urinary tract infections: an increasing challenge for antimicrobial therapy. Infection. 2011;39(4):333–40.
  70. The Pew Charitable Trusts Antibiotics and Innovation project [13.02.2015]. Available from: http://www.pewtrusts.org/en/projects/antibiotics-and-innovation.
  71. Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J. Clinical development success rates for investigational drugs. Nature biotechnology. 2014;32(1):40–51.
  72. Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH, Lindborg SR, et al. How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nat Rev Drug Discov. 2010;9(3):203–14.
  73. Roche and Polyphor join efforts to combat multi-drug-resistant bacterial infections [Internet]. 2013. Available from: http://www.roche.com/media/media_releases/med-cor-2013-11-04.htm
  74. Roche, Meiji and Fedora join forces to tackle increasing bacterial resistance to antibiotics [Internet]. January 2015. Available from: http://www.roche.com/med-cor-2015-01-13-e.pdf
  75. Novartis. Responding to the Superbug Alarm 2014 [08.03.2015]. Available from: http://www.novartis.com/newsroom/feature-stories/2014/09/responding-to-the-superbug-alarm.shtml.
  76. Novartis Institute for Biomedical Research (NIBR) - Infectious Diseases. [19.12.2014]. Available from: http://nibr.com/research/disease/infectious.shtml.
  77. Butler MS, Blaskovich MA, Cooper MA. Antibiotics in the clinical pipeline in 2013. J Antibiot. 2013;66(10):571–91.
  78. Ling LL, Schneider T, Peoples AJ, Spoering AL, Engels I, Conlon BP, et al. A new antibiotic kills pathogens without detectable resistance. Nature. 2015;517(7535):455–9.

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