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Drugs

, Volume 73, Issue 2, pp 159–177 | Cite as

Ceftazidime-Avibactam: a Novel Cephalosporin/β-lactamase Inhibitor Combination

  • George G. ZhanelEmail author
  • Christopher D. Lawson
  • Heather Adam
  • Frank Schweizer
  • Sheryl Zelenitsky
  • Philippe R. S. Lagacé-Wiens
  • Andrew Denisuik
  • Ethan Rubinstein
  • Alfred S. Gin
  • Daryl J. Hoban
  • Joseph P. Lynch3rd
  • James A. Karlowsky
Review Article

Abstract

Avibactam (formerly NXL104, AVE1330A) is a synthetic non-β-lactam, β-lactamase inhibitor that inhibits the activities of Ambler class A and C β-lactamases and some Ambler class D enzymes. This review summarizes the existing data published for ceftazidime-avibactam, including relevant chemistry, mechanisms of action and resistance, microbiology, pharmacokinetics, pharmacodynamics, and efficacy and safety data from animal and human trials. Although not a β-lactam, the chemical structure of avibactam closely resembles portions of the cephem bicyclic ring system, and avibactam has been shown to bond covalently to β-lactamases. Very little is known about the potential for avibactam to select for resistance. The addition of avibactam greatly (4-1024-fold minimum inhibitory concentration [MIC] reduction) improves the activity of ceftazidime versus most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzyme(s). Against Pseudomonas aeruginosa, the addition of avibactam also improves the activity of ceftazidime (~fourfold MIC reduction). Limited data suggest that the addition of avibactam does not improve the activity of ceftazidime versus Acinetobacter species or most anaerobic bacteria (exceptions: Bacteroides fragilis, Clostridium perfringens, Prevotella spp. and Porphyromonas spp.). The pharmacokinetics of avibactam follow a two-compartment model and do not appear to be altered by the co-administration of ceftazidime. The maximum plasma drug concentration (Cmax) and area under the plasma concentration-time curve (AUC) of avibactam increase linearly with doses ranging from 50 mg to 2,000 mg. The mean volume of distribution and half-life of 22 L (~0.3 L/kg) and ~2 hours, respectively, are similar to ceftazidime. Like ceftazidime, avibactam is primarily renally excreted, and clearance correlates with creatinine clearance. Pharmacodynamic data suggest that ceftazidime-avibactam is rapidly bactericidal versus β-lactamase-producing Gram-negative bacilli that are not inhibited by ceftazidime alone.

Clinical trials to date have reported that ceftazidime-avibactam is as effective as standard carbapenem therapy in complicated intra-abdominal infection and complicated urinary tract infection, including infection caused by cephalosporin-resistant Gram-negative isolates. The safety and tolerability of ceftazidime-avibactam has been reported in three phase I pharmacokinetic studies and two phase II clinical studies. Ceftazidime-avibactam appears to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date.

In conclusion, avibactam serves to broaden the spectrum of ceftazidime versus ß-lactamase-producing Gram-negative bacilli. The exact roles for ceftazidime-avibactam will be defined by efficacy and safety data from further clinical trials. Potential future roles for ceftazidime-avibactam include the treatment of suspected or documented infections caused by resistant Gram-negative-bacilli producing extended-spectrum ß-lactamase (ESBL), Klebsiella pneumoniae carbapenemases (KPCs) and/or AmpC ß-lactamases. In addition, ceftazidime-avibactam may be used in combination (with metronidazole) for suspected polymicrobial infections. Finally, the increased activity of ceftazidime-avibactam versus P. aeruginosa may be of clinical benefit in patients with suspected or documented P. aeruginosa infections.

Keywords

Ceftazidime Meropenem AmpC Ceftaroline Complicated Urinary Tract Infection 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

Dr George G. Zhanel has received research funding from AstraZeneca. No other conflicts are reported for the other authors. Chris Lawson was supported by a summer studentship paid in part by the University of Manitoba and AstraZeneca. The authors would like to thank AstraZeneca for their assistance in developing the ceftazidime-avibactam bibliography.

References

  1. 1.
    Andes D, Craig W. Cephalosporins. In: Mandell G, Bennett J, Dolin R, editors. Principles and practice of infectious diseases. 7th ed. Philadelphia: Churchill Livingstone Elsevier; 2010. p. 323–37.Google Scholar
  2. 2.
    Pitout JD. Infections with extended-spectrum beta-lactamase-producing enterobacteriaceae: changing epidemiology and drug treatment choices. Drugs. 2010;70(3):313–33.PubMedCrossRefGoogle Scholar
  3. 3.
    Bush K. Alarming beta-lactamase-mediated resistance in multidrug-resistant Enterobacteriaceae. Curr Opin Microbiol. 2010;13(5):558–64.PubMedCrossRefGoogle Scholar
  4. 4.
    Livermore DM, Woodford N. The beta-lactamase threat in Enterobacteriaceae, Pseudomonas and Acinetobacter. Trends Microbiol. 2006;14(9):413–20.PubMedCrossRefGoogle Scholar
  5. 5.
    Livermore DM. Has the era of untreatable infections arrived? J Antimicrob Chemother. 2009;64(Suppl 1):i29–36.PubMedCrossRefGoogle Scholar
  6. 6.
    Turner PJ. MYSTIC Europe 2007: activity of meropenem and other broad-spectrum agents against nosocomial isolates. Diagn Microbiol Infect Dis. 2009;63(2):217–22.PubMedCrossRefGoogle Scholar
  7. 7.
    Hawser SP, Badal RE, Bouchillon SK, et al. Trending eight years of in vitro activity of ertapenem and comparators against Escherichia coli from intra-abdominal infections in North America–SMART 2002–2009. J Chemother. 2011;23(5):266–72.PubMedGoogle Scholar
  8. 8.
    Hoban DJ, Nicolle LE, Hawser S, et al. Antimicrobial susceptibility of global inpatient urinary tract isolates of Escherichia coli: results from the Study for Monitoring Antimicrobial Resistance Trends (SMART) program: 2009–2010. Diagn Microbiol Infect Dis. 2011;70(4):507–11.PubMedCrossRefGoogle Scholar
  9. 9.
    Bhattacharya S, Bonnet A, Dedhiya M, et al. inventors; Novexel SA and Forest laboratories holdings, assignees. Polymorphic and pseudopolymorphic forms of a pharmaceutical compound. International patent WO 042560 A2. 2011 April 14.Google Scholar
  10. 10.
    Coleman K. Diazabicyclooctanes (DBOs): a potent new class of non-beta-lactam beta-lactamase inhibitors. Curr Opin Microbiol. 2011;14(5):550–5.PubMedCrossRefGoogle Scholar
  11. 11.
    Beale J. Antibacterial antibiotics. In: Beale J, Block J, editors. Wilson and Gisvold’s textbook of organic medicinal and pharmaceutical chemistry. 12th ed. Baltimore: Lippincott Williams & Wilkins; 2011. p. 258–329.Google Scholar
  12. 12.
    Caprile KA. The cephalosporin antimicrobial agents: a comprehensive review. J Vet Pharmacol Ther. 1988;11(1):1–32.PubMedCrossRefGoogle Scholar
  13. 13.
    Dunn GL. Ceftizoxime and other third-generation cephalosporins: structure-activity relationships. J Antimicrob Chemother. 1982;10(Suppl. C):1–10.PubMedCrossRefGoogle Scholar
  14. 14.
    Neu HC. Beta-lactam antibiotics: structural relationships affecting in vitro activity and pharmacologic properties. Rev Infect Dis. 1986;8(Suppl. 3):S237–59.PubMedCrossRefGoogle Scholar
  15. 15.
    Neu HC. Beta-lactamase stability of cefoxitin in comparison with other beta-lactam compounds. Diagn Microbiol Infect Dis. 1983;1(4):313–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Miossec C, Merdjan H, Hodgson J. Safety and toxicokinetics of NXL104, a broad spectrum β-lactamase inhibitor, in the rat [abstract no. F-1461 plus poster]. In: 45th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2005 Dec 16–19; Washington (DC).Google Scholar
  17. 17.
    Miossec C. NXL104 β-lactamase inhibitor [abstract no. plus oral presentation]. Challenge of antibacterial drug development; 2007 Mar 21–22; San Diego, CA.Google Scholar
  18. 18.
    Popham DL, Young KD. Role of penicillin-binding proteins in bacterial cell morphogenesis. Curr Opin Microbiol. 2003;6(6):594–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Vollmer W, Blanot D, de Pedro MA. Peptidoglycan structure and architecture. FEMS Microbiol Rev. 2008;32(2):149–67.PubMedCrossRefGoogle Scholar
  20. 20.
    Sauvage E, Kerff F, Terrak M, et al. The penicillin-binding proteins: structure and role in peptidoglycan biosynthesis. FEMS Microbiol Rev. 2008;32(2):234–58.PubMedCrossRefGoogle Scholar
  21. 21.
    Hayes MV, Orr DC. Mode of action of ceftazidime: affinity for the penicillin-binding proteins of Escherichia coli K12, Pseudomonas aeruginosa and Staphylococcus aureus. J Antimicrob Chemother. 1983;12(2):119–26.PubMedCrossRefGoogle Scholar
  22. 22.
    Poole K. Resistance to beta-lactam antibiotics. Cell Mol Life Sci. 2004;61(17):2200–23.PubMedCrossRefGoogle Scholar
  23. 23.
    Bush K, Fisher JF. Epidemiological expansion, structural studies, and clinical challenges of new beta-lactamases from gram-negative bacteria. Annu Rev Microbiol. 2011;65:455–78.PubMedCrossRefGoogle Scholar
  24. 24.
    Ambler RP. The structure of beta-lactamases. Philos Trans R Soc Lond B Biol Sci. 1980;289(1036):321–31.PubMedCrossRefGoogle Scholar
  25. 25.
    Ambler RP, Coulson AF, Frere JM, et al. A standard numbering scheme for the class A beta-lactamases. Biochem J. 1991;276(Pt 1):269–70.PubMedGoogle Scholar
  26. 26.
    Jaurin B, Grundstrom T. ampC cephalosporinase of Escherichia coli K-12 has a different evolutionary origin from that of beta-lactamases of the penicillinase type. Proc Natl Acad Sci USA. 1981;78(8):4897–901.PubMedCrossRefGoogle Scholar
  27. 27.
    Ouellette M, Bissonnette L, Roy PH. Precise insertion of antibiotic resistance determinants into Tn21-like transposons: nucleotide sequence of the OXA-1 beta-lactamase gene. Proc Natl Acad Sci USA. 1987;84(21):7378–82.PubMedCrossRefGoogle Scholar
  28. 28.
    Bush K, Jacoby GA. Updated functional classification of beta-lactamases. Antimicrob Agents Chemother. 2010;54(3):969–76.PubMedCrossRefGoogle Scholar
  29. 29.
    Bush K, Jacoby GA, Medeiros AA. A functional classification scheme for beta-lactamases and its correlation with molecular structure. Antimicrob Agents Chemother. 1995;39(6):1211–33.PubMedCrossRefGoogle Scholar
  30. 30.
    Majiduddin FK, Materon IC, Palzkill TG. Molecular analysis of beta-lactamase structure and function. Int J Med Microbiol. 2002;292(2):127–37.PubMedCrossRefGoogle Scholar
  31. 31.
    Ghuysen JM. Serine beta-lactamases and penicillin-binding proteins. Annu Rev Microbiol. 1991;45:37–67.PubMedCrossRefGoogle Scholar
  32. 32.
    Tamilselvi A, Mugesh G. Zinc and antibiotic resistance: metallo-beta-lactamases and their synthetic analogues. J Biol Inorg Chem. 2008;13(7):1039–53.PubMedCrossRefGoogle Scholar
  33. 33.
    Knox JR. Extended-spectrum and inhibitor-resistant TEM-type beta-lactamases: mutations, specificity, and three-dimensional structure. Antimicrob Agents Chemother. 1995;39(12):2593–601.PubMedCrossRefGoogle Scholar
  34. 34.
    Docquier J, Stachyra T, Benvenuti M, et al. High resolution crystal structure of CTX-M-15 in complex with the new β-lactamase inhibitor NXL104 [abstract no. C1-1098 plus oral presentation]. In: 49th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2009 Sep 12–15; San Francisco (CA).Google Scholar
  35. 35.
    Xu H, Hazra S, Blanchard JS. NXL104 irreversibly inhibits the beta-lactamase from Mycobacterium tuberculosis. Biochemistry. 2012;51(22):4551–7.PubMedCrossRefGoogle Scholar
  36. 36.
    Docquier J, Benvenuti M, De Luca F, et al. Structure of the TRU-1 class C and OXA-10 class D β-lactamases in complex with NXL104: structural basis for broad-spectrum inhibition [abstract no. C1-1427 plus poster]. In: 50th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2010 Sep 12–15; Boston (MA).Google Scholar
  37. 37.
    Docquier J, Benvenuti M, De Luca F, et al. X-ray crystal structure of the Klebsiella pneumoniae OXA-48 class D carbapenemase inhibited by NXL104 [abstract no. C1-640 plus poster]. In: 50th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2010 Sep 12–15; Boston (MA).Google Scholar
  38. 38.
    Docquier J, Benvenuti M, Bruneau J, et al. X-ray crystal structure of the Acinetobacter baumannii OXA-24/40 Class D carbapenemase inhibited by NXL104 [abstract no. P609]. Clin Microbiol Infect. 2011;17(Suppl. 4):S125. Plus poster presented at 21st European Congress of Clinical Microbiology and Infectious Diseases; 2011 May 7–10; Milan.Google Scholar
  39. 39.
    Ehmann DE, Jahic H, Ross PL, et al. Avibactam is a covalent, reversible, non-beta-lactam beta-lactamase inhibitor. Proc Natl Acad Sci USA. 2012;109(29):11663–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Stachyra T, Pechereau M, Bruneau J, et al. The nature of inhibition of TEM-1 β-Lactamase by the non-β-Lactam inhibitor NXL104 [abstract no. C1-1374 plus poster]. In: 49th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2009 Sep 12–15; San Francisco (CA).Google Scholar
  41. 41.
    Stachyra T, Pechereau MC, Bruneau JM, et al. Mechanistic studies of the inactivation of TEM-1 and P99 by NXL104, a novel non-beta-lactam beta-lactamase inhibitor. Antimicrob Agents Chemother. 2010;54(12):5132–8.PubMedCrossRefGoogle Scholar
  42. 42.
    Bonnefoy A, Dupuis-Hamelin C, Steier V, et al. In vitro activity of AVE1330A, an innovative broad-spectrum non-beta-lactam beta-lactamase inhibitor. J Antimicrob Chemother. 2004;54(2):410–7.PubMedCrossRefGoogle Scholar
  43. 43.
    Miossec C, Claudon M, Platel D, et al. The β-lactamase inhibitor NXL104 does not induce ampC β-lactamase expression in Enterobacter cloacae: evaluation of ampC expression by quantitative polymerase chain reaction (Q-PCR) [abstract no. F-128 plus poster]. In: 46th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2006 Sep 27–30; San Francisco (CA).Google Scholar
  44. 44.
    Livermore DM, Mushtaq S, Barker K, et al. Characterization of beta-lactamase and porin mutants of Enterobacteriaceae selected with ceftaroline + avibactam (NXL104). J Antimicrob Chemother. 2012;67(6):1354–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Li M, Conklin B, Bonomo R, et al. Effect of N152G substitution of CMY-2 β-lactamase activity and inhibition [abstract no. A-1012 plus poster]. In: 111th General Meeting of the American Society of Microbiology; 2011 May 21–24; New Orleans (LA).Google Scholar
  46. 46.
    Skalweit M, Li M, Conklin B, et al. Effect of N152G, S and T substitution on CMY-2 β-lactamase activity and inhibition [abstract no. C1-601 plus poster]. In: 51st Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2011 Sep 17–20; Chicago (IL).Google Scholar
  47. 47.
    Aktas Z, Kayacan C, Oncul O. In vitro activity of NXL104 in combination with β-lactams against Gram-negative bacteria, including OXA-48 beta-lactamase producing Klebsiella pneumoniae [abstract no. E-808 plus poster]. In: 50th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2010 Sep 12–15; Boston (MA).Google Scholar
  48. 48.
    Aktas Z, Kayacan C, Oncul O. In vitro activity of avibactam (NXL104) in combination with beta-lactams against Gram-negative bacteria, including OXA-48 beta-lactamase-producing Klebsiella pneumoniae. Int J Antimicrob Agents. 2012;39(1):86–9.PubMedCrossRefGoogle Scholar
  49. 49.
    Biedenbach D, Konrardy M, Sader H, et al. In vitro activity of ceftazidime/NXL104 against pathogens collected during a phase II complicated urinary tract infection (cUTI) clinical trial [abstract no. E-137 plus poster]. In: 51st Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2011 Sep 17–20; Chicago (IL).Google Scholar
  50. 50.
    Castanheira M, Rhomberg P, Jones R, et al. Potent activity of ceftazidime/NXL104 tested against Enterobacteriaceae isolates carrying multiple β-lactamase enzymes [abstract no. P 1265]. Clin Microbiol Infect. 2010;16(Suppl. 2):S355. Plus poster presented at 20th European Congress of Clinical Microbiology and Infectious Diseases; 2010 Apr 10–13; Vienna.Google Scholar
  51. 51.
    Crandon J, Banevicius M, Nicolau D. Comparative potency of ceftazidime (CAZ) and ceftazidime-NXL104 (CAZ104) against a resistant population of clinical Pseudomonas aeruginosa (PSA) isolates [abstract no. 585 plus poster]. In: 49th Annual Meeting of the Infectious Diseases Society of America; 2011 Sep 12–15; Boston (MA).Google Scholar
  52. 52.
    Endimiani A, Choudhary Y, Bonomo RA. In vitro activity of NXL104 in combination with beta-lactams against Klebsiella pneumoniae isolates producing KPC carbapenemases. Antimicrob Agents Chemother. 2009;53(8):3599–601.PubMedCrossRefGoogle Scholar
  53. 53.
    Gin A, Dilay L, Karlowsky JA, et al. Piperacillin-tazobactam: a beta-lactam/beta-lactamase inhibitor combination. Expert Rev Anti Infect Ther. 2007;5(3):365–83.PubMedCrossRefGoogle Scholar
  54. 54.
    Lagacé-Wiens P, Simner P, Tailor F, et al. Activity of ceftazidime (CAZ)/NXL104 (CAZ104) versus CAZ alone and other comparators against 4548 Gram-negative bacilli—results from CANWARD 2009-10 [abstract no. E-1816 plus poster]. In: 51st Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2011 Sep 17–20; Chicago (IL).Google Scholar
  55. 55.
    Lagace-Wiens PR, Tailor F, Simner P, et al. Activity of NXL104 in combination with beta-lactams against genetically characterized Escherichia coli and Klebsiella pneumoniae isolates producing class A extended-spectrum beta-lactamases and class C beta-lactamases. Antimicrob Agents Chemother. 2011;55(5):2434–7.PubMedCrossRefGoogle Scholar
  56. 56.
    Levasseur P, Girard AM, Claudon M, et al. In vitro antibacterial activity of the ceftazidime-avibactam (NXL104) combination against Pseudomonas aeruginosa clinical isolates. Antimicrob Agents Chemother. 2012;56(3):1606–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Levasseur P, Miossec C, Girard A, et al. In vitro antibacterial activity of ceftazidime (CAZ) in combination with the β-lactamase inhibitor, NXL104 [abstract no. E-186 plus poster]. In: 49th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2009 Sep 12–15; San Francisco (CA).Google Scholar
  58. 58.
    Livermore DM, Mushtaq S, Warner M, et al. Activities of NXL104 combinations with ceftazidime and aztreonam against carbapenemase-producing Enterobacteriaceae. Antimicrob Agents Chemother. 2011;55(1):390–4.PubMedCrossRefGoogle Scholar
  59. 59.
    Mushtaq S, Warner M, Livermore DM. In vitro activity of ceftazidime + NXL104 against Pseudomonas aeruginosa and other non-fermenters. J Antimicrob Chemother. 2010;65(11):2376–81.PubMedCrossRefGoogle Scholar
  60. 60.
    Sader H, Castanheira M, Farrell J, et al. Antimicrobial activity of ceftazidime/NXL104 tested against Gram-negative organisms, including multidrug-resistant subjects, causing infections in USA and European medical centers [abstract no. E-811 plus poster]. In: 50th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2010 Sep 12–15; Boston (MA).Google Scholar
  61. 61.
    Sader H, Farrell D, Bell J, et al. Antimicrobial activity of ceftazidime/NXL104 (CAZ104) tested against Gram-negative organisms causing infections in medical centers from Europe (EU), Latin America (LA) and the Asia-Pacific Region (APAC) [abstract no. C2-1251 plus poster]. In: 51st Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2011 Sep 17–20; Chicago (IL).Google Scholar
  62. 62.
    Sahm D, Pillar C, Brown N, et al. Activity of ceftazidime/NXL104 and select comparators against geographically diverse clinical isolates of Pseudomonas aeruginosa [abstract no. E-194 plus poster]. In: 49th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2009 Sep 12–15; San Francisco (CA).Google Scholar
  63. 63.
    Tailor F, Lagacé-Wiens P, Simner P, et al. Activity of avibactam (NXL-104) in combination with β-lactams against molecularly characterized AmpC- and ESBL-producing Escherichia coli and Klebsiella pneumoniae for CANWARD 2007–2010 [abstract no. F1-165 plus poster]. In: 51st Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2011 Sep 17–20; Chicago (IL).Google Scholar
  64. 64.
    Walkty A, DeCorby M, Lagace-Wiens PR, et al. In vitro activity of ceftazidime combined with NXL104 versus Pseudomonas aeruginosa isolates obtained from patients in Canadian hospitals (CANWARD 2009 study). Antimicrob Agents Chemother. 2011;55(6):2992–4.PubMedCrossRefGoogle Scholar
  65. 65.
    Zhanel GG, Adam HJ, Low DE, et al. Antimicrobial susceptibility of 15,644 pathogens from Canadian hospitals: results of the CANWARD 2007–2009 study. Diagn Microbiol Infect Dis. 2011;69(3):291–306.PubMedCrossRefGoogle Scholar
  66. 66.
    Zhanel GG, Sniezek G, Schweizer F, et al. Ceftaroline: a novel broad-spectrum cephalosporin with activity against meticillin-resistant Staphylococcus aureus. Drugs. 2009;69(7):809–31.PubMedCrossRefGoogle Scholar
  67. 67.
    Borgonovi M, Merdjan H, Girard A, et al. Importance of NXL104 pharmacokinetics (PK) in the pharmacodynamics (PD) of ceftazidime + NXL104 combinations in an in vitro hollow fiber infection model [abstract no. A-023 plus poster]. In: 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2008 Oct 25–28; Washington (DC).Google Scholar
  68. 68.
    Borgonovi M, Miossec C, Lowther J. The efficacy of ceftazidime combined with NXL104, a novel β-lactamase inhibitor, in a mouse model of kidney infections induced by β-lactamase producing Enterobacteriaceae [abstract no. P794]. Clin Microbiol Infect. 2007;13(Suppl. 2):S199–200. Plus poster presented at 17th European Congress of Clinical Microbiology and Infectious Diseases; 2007 Mar 31–Apr 3; Munich.Google Scholar
  69. 69.
    Cottagnoud P, Merdjan H, Acosta F, et al. Pharmacokinetics of the new β-lactamase inhibitor NXL104 in an experimental rabbit meningitis model; restoration of the bacteriological efficacy of ceftazidime (CAZ) against a class C producing K. pneumoniae [abstract no. F1-321 plus poster]. In: 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2007 Sep 17–20; Chicago (IL).Google Scholar
  70. 70.
    Levasseur P, Girard A, Delachaume C, et al. NXL104, a novel β-lactamase inhibitor, restores the bactericidal activity of ceftazidime against ESBL and AmpC producing strains of Enterobacteriaceae [abstract no. F-127 plus poster]. In: 46th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2006 Sep 27–30; San Francisco (CA).Google Scholar
  71. 71.
    Levasseur P, Girard A, Lavallade L, et al. Efficacy of ceftazidime (CAZ)/NXL104 combination in murine septicaemia caused by CTX-M-producing Enterobacteriaceae species [abstract no. A1-005 plus poster]. In: 49th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2009 Sep 12–15; San Francisco (CA).Google Scholar
  72. 72.
    Levasseur P, Miossec C, Girard A, et al. Use of NXL104, a β-lactamase inhibitor, to detect Klebsiella pneumoniae carbapenemase (KPC) in Enterobacteriaceae [abstract no. D-291b plus poster]. In: 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2008 Oct 25–28; Washington (DC).Google Scholar
  73. 73.
    Livermore DM, Mushtaq S, Warner M, et al. NXL104 combinations versus Enterobacteriaceae with CTX-M extended-spectrum beta-lactamases and carbapenemases. J Antimicrob Chemother. 2008;62(5):1053–6.PubMedCrossRefGoogle Scholar
  74. 74.
    Mendes R, Woosley L, Deshpande L, et al. Characterization of resistance mechanisms and epidemiology of Enterobacteriaceae collected during a phase II clinical trial for ceftazidime-avibactam [abstract no. P1676]. Clin Microbiol Infect. 2012;18(Suppl 3):464. Plus poster presented at 22nd European Congress of Clinical Microbiology and Infectious Diseases; 2012 Mar 31–Apr 3; London.Google Scholar
  75. 75.
    Merdjan H, Girard A, Miossec C, et al. Pharmacokinetics (PK) and efficacy of ceftazidime (CAZ)/NXL104 combination in a murine pneumonia model caused by an AmpC-producing Klebsiella pneumoniae [abstract no. A1-006 plus poster]. In: 49th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2009 Sep 12–15; San Francisco (CA).Google Scholar
  76. 76.
    Miossec C, Poirel L, Livermore D, et al. In vitro activity of the new β-lactamase inhibitor NXL104: restoration of ceftazidime (CAZ) efficacy against carbapenem-resistant Enterobacteriaceae strains [abstract no. F1-318 plus poster]. In: 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2007 Sep 17–20; Chicago (IL).Google Scholar
  77. 77.
    Mushtaq S, Warner M, Miossec C, et al. NXL104/cephalosporin combinations vs. Enterobacteriaceae with CTX-M ESBLs [abstract no. F1-319 plus poster]. In: 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2007 Sep 17–20; Chicago (IL).Google Scholar
  78. 78.
    Pechereau M, Claudon M, Black M, et al. Activité in vitro de NXL104 sur CTX-M-15 et KPC-2: un nouvel inhibiteur de β-lactamases à spectre étendu (BLSE) et de carbapénèmases de classe A [abstract no. 468 plus poster]. 28ème Réunion Interdisciplinaire de Chimiothérapie Anti-infectieuse; 2008 Dec 3–4; Paris.Google Scholar
  79. 79.
    Pechereau M, Claudon M, Black M, et al. Activité in vitro de NXL104 sur SHV-4: un nouvel inhibiteur des β-lactamases à spectre étendu [abstract no. 382 plus poster]. 26ème Réunion Interdisciplinaire de Chimiothérapie Anti-infectieuse; 2006 Dec 7–8; Paris.Google Scholar
  80. 80.
    Shackcloth J, Williams L, Northwood J, et al. In vitro activity of AVE1330A, a novel β-lactamase inhibitor, in combination with aztreonam or ceftazidime against ceftazidime-resistant isolates of species of the Enterobacteriaceae [abstract no. P1571]. Clin Microbiol Infect. 2005;11(Suppl. 2):S511. Plus poster presented at 15th European Congress of Clinical Microbiology and Infectious Diseases; 2005 Apr 2–5; Copenhagen.Google Scholar
  81. 81.
    Stachyra T, Levasseur P, Pechereau MC, et al. In vitro activity of the {beta}-lactamase inhibitor NXL104 against KPC-2 carbapenemase and Enterobacteriaceae expressing KPC carbapenemases. J Antimicrob Chemother. 2009;64(2):326–9.PubMedCrossRefGoogle Scholar
  82. 82.
    Stachyra T, Pechereau M, Petrella S, et al. Activity of the new β-lactamase inhibitor NXL104 against KPC β-lactamases [abstract no. F1-320 plus poster]. In: 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2007 Sep 17–20; Chicago (IL).Google Scholar
  83. 83.
    Weiss W, Pulse M, Endimiani A, et al. Efficacy of NXL104 in combination with ceftazidime in murine infection models [abstract no. B-1339 plus poster]. In: 49th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2009 Sep 12–15; San Francisco (CA).Google Scholar
  84. 84.
    Citron D, Goldstein E. In vitro activity of NXL104/ceftazidime against β-lactamase producing anaerobic bacteria [abstract no. E-192 plus poster]. In: 49th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2009 Sep 12–15; San Francisco (CA).Google Scholar
  85. 85.
    Citron DM, Tyrrell KL, Merriam V, et al. In vitro activity of ceftazidime-NXL104 against 396 strains of beta-lactamase-producing anaerobes. Antimicrob Agents Chemother. 2011;55(7):3616–20.PubMedCrossRefGoogle Scholar
  86. 86.
    Dubreuil LJ, Mahieux S, Neut C, et al. Anti-anaerobic activity of a new beta-lactamase inhibitor NXL104 in combination with beta-lactams and metronidazole. Int J Antimicrob Agents. 2012;39(6):500–4.PubMedCrossRefGoogle Scholar
  87. 87.
    Zhanel G, Brunham R. Third-generation cephalosporins. Can J Hosp Pharm. 1988;41(4):183–94.Google Scholar
  88. 88.
    Merdjan H, Tarral A, Girard A, et al. Safety, single dose pharmacokinetics, and pharmacodynamics of β-lactamase inhibitor NXL104 in healthy young male adults [abstract no. A-809 plus poster]. In: 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2007 Sep 17–20; Chicago (IL).Google Scholar
  89. 89.
    Felices M, Gualano V, Tarral A, et al. Combined population pharmacokinetic analysis of four phase 1 studies with NXL104 [abstract no. P 1599]. Clin Microbiol Infect. 2010;16(Suppl. 2):S466. Plus poster presented at 20th European Congress of Clinical Microbiology and Infectious Diseases; 2010 Apr 10–13; Vienna.Google Scholar
  90. 90.
    Li J, Knebel W, Riggs M, et al. Population pharmacokinetic modeling of ceftazidime (CAZ) and avibactam (AVI) in healthy volunteers and patients with complicated intra-abdominal Infection (cIAI) [abstract no. A-634 plus poster]. In: 52nd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2012 Sep 9–12; San Francisco (CA).Google Scholar
  91. 91.
    Merdjan H, Tarral A, Haazen W, et al. Pharmacokinetics and tolerability of NXL104 in normal subjects and patients with varying degrees of renal insufficiency. [abstract no. P 1598]. Clin Microbiol Infect. 2010;16(Suppl. 2):S465. Plus poster presented at 20th European Congress of Clinical Microbiology and Infectious Diseases; 2010 Apr 10–13; Vienna.Google Scholar
  92. 92.
    Bowker K, Noel A, MacGowan A. Pharmacodynamics of NXL104 plus either ceftaroline or ceftazidine against an AmpC producing Enterobacter spp [abstract no. A2-556 plus poster]. In: 51st Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2011 Sep 17–20; Chicago (IL).Google Scholar
  93. 93.
    Endimiani A, Hujer KM, Hujer AM, et al. Evaluation of ceftazidime and NXL104 in two murine models of infection due to KPC-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2010;55(1):82–5.PubMedCrossRefGoogle Scholar
  94. 94.
    Crandon JL, Schuck VJ, Banevicius MA, et al. Comparative in vitro and in vivo efficacy of human simulated exposures of ceftazidime and ceftazidime-avibactam against Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2012;56(12):6137–46.PubMedCrossRefGoogle Scholar
  95. 95.
    Lucasti C, Popescu I, Ramesh M, et al. Efficacy and safety of ceftazidime/NXL104 plus metronidazole vs. meropenem in the treatment of complicated intra-abdominal infections in hospitalised adults [abstract no. P1532]. Clin Microbiol Infect. 2011;17(Suppl. 4):S437. Plus poster presented at 21st European Congress of Clinical Microbiology and Infectious Diseases; 2011 May 7–10; Milan.Google Scholar
  96. 96.
    Vazquez J, González Patzán L, Stricklin D, et al. Efficacy and safety of ceftazidime avibactam versus imipenem cilastatin for complicated urinary tract infections including acute pyelonephritis, in hospitalized adults: results of a prospective investigator-blinded randomized study. Curr Med Res Opin. 2012;28(12):1921–31.PubMedCrossRefGoogle Scholar
  97. 97.
    Tarral A, Lipka J, Gyaw S, et al. Effect of age and gender on the pharmacokinetics (PK) and safety of NXL104 in healthy subjects (protocol NXL104/1004) [abstract no. A1-007 plus poster]. In: 49th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2009 Sep 12–15; San Francisco (CA).Google Scholar
  98. 98.
    Li J, Edeki T, Das S, et al. Effect of a supratherapeutic dose of ceftazidime-avibactam on the QTc interval in a thorough QT study [abstract no. P1417]. Clin Microbiol Infect. 2012;18(Suppl. 3):372. Plus poster presented at 22nd European Congress of Clinical Microbiology and Infectious Diseases; 2012 Mar 31–Apr 3; London.Google Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  • George G. Zhanel
    • 1
    • 4
    • 9
    Email author
  • Christopher D. Lawson
    • 2
  • Heather Adam
    • 1
    • 6
  • Frank Schweizer
    • 1
    • 3
  • Sheryl Zelenitsky
    • 2
  • Philippe R. S. Lagacé-Wiens
    • 1
    • 7
  • Andrew Denisuik
    • 1
  • Ethan Rubinstein
    • 1
    • 4
  • Alfred S. Gin
    • 1
    • 2
    • 5
  • Daryl J. Hoban
    • 1
    • 6
  • Joseph P. Lynch3rd
    • 8
  • James A. Karlowsky
    • 1
    • 6
  1. 1.Department of Medical Microbiology, Faculty of MedicineUniversity of ManitobaWinnipegCanada
  2. 2.Faculty of PharmacyUniversity of ManitobaWinnipegCanada
  3. 3.Department of Chemistry, Faculty of ScienceUniversity of ManitobaWinnipegCanada
  4. 4.Department of MedicineHealth Sciences CentreWinnipegCanada
  5. 5.Department of PharmacyHealth Sciences CentreWinnipegCanada
  6. 6.Department of Clinical MicrobiologyHealth Sciences CentreWinnipegCanada
  7. 7.Department of Clinical MicrobiologySaint-Boniface General HospitalWinnipegCanada
  8. 8.Division of Pulmonary, Critical Care, Allergy and Clinical ImmunologyThe David Geffen School of Medicine at UCLALos AngelesUSA
  9. 9.Clinical Microbiology, Health Sciences CentreWinnipegCanada

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