Skip to main content
SpringerLink
Log in

Clinical Pharmacokinetics and Pharmacodynamics of Ceftazidime–Avibactam Combination: A Model-Informed Strategy for its Clinical Development

  • Review Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Avibactam is a non-β-lactam, β-lactamase inhibitor of the diazabicyclooctane class that covalently acylates its β-lactamase targets, encompassing extended spectrum of activities that cover serine β-lactamases but not metallo-β-lactamases. Ceftazidime and avibactam have complementary pharmacokinetic (PK) profiles. Both drugs have a half-life of approximately 2 h, making them suitable to be combined in a fixed-dose combination ratio of 4:1 (ceftazidime:avibactam). Renal clearance is the primary elimination pathway of both ceftazidime and avibactam, and dose adjustment is required in patients with moderate and severe renal impairment. Population PK models of ceftazidime and avibactam were developed separately and incorporated body weight, disease state, ethnicity, and renal function (creatinine clearance) as covariates of clearance and volume of distribution. The clinical dosing regimen of ceftazidime/avibactam combination was determined from population PK model simulations in the patient population for dosing regimens that can achieve sufficient joint probability of target attainment for ceftazidime minimum inhibitory concentration (MIC) of 8 mg/L at a fixed 4 mg/L avibactam concentration (MIC ≤ 8/4 mg/L); 8 mg/L is the breakpoint of ceftazidime in Enterobacteriaceae and Pseudomonas aeruginosa for the target pharmacodynamic indices of ceftazidime and avibactam of 50% time at which the free ceftazidime concentration is above the MIC (fT > MIC) and 50% time at which the free avibactam is above a threshold concentration of 1 mg/L (fT > CT). Whereas the static index approach does not take into account the changing potency of ceftazidime in the presence of changing avibactam concentration, a mathematical model based on kill-curve kinetics was utilized to validate the dose selection in humans. The clinical dosing regimen of 2/0.5 g ceftazidime/avibactam administered every 8 h as a 2-h intravenous infusion in patients with normal renal function, with dose adjustment in renal impairment, demonstrated statistical non-inferiority to carbapenem in phase III studies on the treatment of complicated intra-abdominal infection, complicated urinary tract infection, and nosocomial pneumonia, including ceftazidime non-susceptible Gram-negative pathogens. The success of the phase III studies validated the dose selection and exposure target that were associated with efficacy based on a model-informed approach.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Solomkin JS, Mazuski JE, Baron EJ, Sawyer RG, Nathens AB, DiPiro JT, et al. Guidelines for the selection of anti-infective agents for complicated intra-abdominal infections. Clin Infect Dis. 2003;37(8):997–1005.

    Article  PubMed  Google Scholar 

  2. Singh KP, Li G, Mitrani-Gold FS, Kurtinecz M, Wetherington J, Tomayko JF, et al. Systematic review and meta-analysis of antimicrobial treatment effect estimation in complicated urinary tract infection. Antimicrob Agents Chemother. 2013;57(11):5284–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Wagenlehner FM, Naber KG. Current challenges in the treatment of complicated urinary tract infections and prostatitis. Clin Microbiol Infect. 2006;12(Suppl 3):67–80.

    Article  CAS  PubMed  Google Scholar 

  4. Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJ, Baron EJ, et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis. 2010;50(2):133–64.

    Article  CAS  PubMed  Google Scholar 

  5. Lucasti C, Popescu I, Ramesh MK, Lipka J, Sable C. Comparative study of the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infections in hospitalized adults: results of a randomized, double-blind, Phase II trial. J Antimicrob Chemother. 2013;68(5):1183–92.

    Article  CAS  PubMed  Google Scholar 

  6. Nicolle LE. AMMI Canadian, Guidelines Committee. Complicated urinary tract infection in adults. Can J Infect Dis Med Microbiol. 2005;16(6):349–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Vazquez JA, Gonzalez Patzan LD, Stricklin D, Duttaroy DD, Kreidly Z, Lipka J, et al. Efficacy and safety of ceftazidime–avibactam versus imipenem–cilastatin in the treatment of 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.

    Article  CAS  PubMed  Google Scholar 

  8. Wagenlehner FM, Sobel JD, Newell P, Armstrong J, Huang X, Stone GG, et al. Ceftazidime–avibactam versus doripenem for the treatment of complicated urinary tract infections, including acute pyelonephritis: RECAPTURE, a phase 3 randomized trial program. Clin Infect Dis. 2016;63(6):754–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Koenig SM, Truwit JD. Ventilator-associated pneumonia: diagnosis, treatment, and prevention. Clin Microbiol Rev. 2006;19(4):637–57.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Magill SS, Edwards JR, Bamberg W, Beldavs ZG, Dumyati G, Kainer MA, et al. Multistate point-prevalence survey of health care-associated infections. N Engl J Med. 2014;370(13):1198–208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Falco V, Burgos J, Papiol E, Ferrer R, Almirante B. Investigational drugs in phase I and phase II clincial trials for the treatment of hospital-acquired pneumonia. Expert Opin Investig Drugs. 2016;25(6):653–65.

    Article  CAS  PubMed  Google Scholar 

  12. Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, et al. Executive summary: management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63(5):575–82.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Jones RN. Microbial etiologies of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. Clin Infect Dis. 2010;51(Suppl 1):S81–7.

    Article  PubMed  Google Scholar 

  14. MacVane SH. Antimicrobial resistance in the intensive care unit: a focus on Gram-negative bacterial infections. J Intensive Care Med. 2017;32(1):25–37.

    Article  PubMed  Google Scholar 

  15. Livermore DM. beta-Lactamases in laboratory and clinical resistance. Clin Microbiol Rev. 1995;8(4):557–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cheng Q, Park JT. Substrate specificity of the AmpG permease required for recycling of cell wall anhydro-muropeptides. J Bacteriol. 2002;184(23):6434–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Livermore DM. Interplay of impermeability and chromosomal beta-lactamase activity in imipenem-resistant Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1992;36(9):2046–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Jacobs C, Frere JM, Normark S. Cytosolic intermediates for cell wall biosynthesis and degradation control inducible beta-lactam resistance in gram-negative bacteria. Cell. 1997;88(6):823–32.

    Article  CAS  PubMed  Google Scholar 

  19. Vollmer W, Holtje JV. Morphogenesis of Escherichia coli. Curr Opin Microbiol. 2001;4(6):625–33.

    Article  CAS  PubMed  Google Scholar 

  20. Higashino M, Murata M, Morinaga Y, Akamatsu N, Matsuda J, Takeda K, et al. Fluoroquinolone resistance in extended-spectrum beta-lactamase-producing Klebsiella pneumoniae in a Japanese tertiary hospital: silent shifting to CTX-M-15-producing K. pneumoniae. J Med Microbiol. 2017;66(10):1476–82.

    Article  CAS  PubMed  Google Scholar 

  21. Albiero J, Sy SK, Mazucheli J, Caparroz-Assef SM, Costa BB, Alves JL, et al. Pharmacodynamic evaluation of the potential clinical utility of fosfomycin and meropenem in combination therapy against KPC-2-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2016;60(7):4128–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bush K, Jacoby GA. Updated functional classification of beta-lactamases. Antimicrob Agents Chemother. 2010;54(3):969–76.

    Article  CAS  PubMed  Google Scholar 

  23. Bebrone C, Lassaux P, Vercheval L, Sohier JS, Jehaes A, Sauvage E, et al. Current challenges in antimicrobial chemotherapy: focus on β-lactamase inhibition. Drugs. 2010;70(6):651–79.

    Article  CAS  PubMed  Google Scholar 

  24. Lahiri SD, Mangani S, Durand-Reville T, Benvenuti M, De Luca F, Sanyal G, et al. Structural insight into potent broad-spectrum inhibition with reversible recyclization mechanism: avibactam in complex with CTX-M-15 and Pseudomonas aeruginosa AmpC beta-lactamases. Antimicrob Agents Chemother. 2013;57(6):2496–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sideraki V, Huang W, Palzkill T, Gilbert HF. A secondary drug resistance mutation of TEM-1 beta-lactamase that suppresses misfolding and aggregation. Proc Natl Acad Sci USA. 2001;98(1):283–8.

    CAS  PubMed  Google Scholar 

  26. Avycaz. Ceftazidime–avibactam prescribing information. Irvine: Allergan; 2018.

    Google Scholar 

  27. European Medicines Agency. Zavicefta summary of product characteristics; 2016. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004027/WC500210234.pdf. Accessed 24 July 2018.

  28. Coleman K. Diazabicyclooctanes (DBOs): a potent new class of non-beta-lactam beta-lactamase inhibitors. Curr Opin Microbiol. 2011;14(5):550–5.

    Article  CAS  PubMed  Google Scholar 

  29. Stachyra T, Levasseur P, Pechereau MC, Girard AM, Claudon M, Miossec C, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Stachyra T, Pechereau MC, Bruneau JM, Claudon M, Frere JM, Miossec C, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Citron DM, Tyrrell KL, Merriam V, Goldstein EJ. In vitro activity of ceftazidime-NXL104 against 396 strains of beta-lactamase-producing anaerobes. Antimicrob Agents Chemother. 2011;55(7):3616–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Walkty A, DeCorby M, Lagace-Wiens PR, Karlowsky JA, Hoban DJ, Zhanel GG. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Levasseur P, Girard AM, Miossec C, Pace J, Coleman K. In vitro antibacterial activity of the ceftazidime–avibactam combination against enterobacteriaceae, including strains with well-characterized beta-lactamases. Antimicrob Agents Chemother. 2015;59(4):1931–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Flamm RK, Farrell DJ, Sader HS, Jones RN. Ceftazidime/avibactam activity tested against Gram-negative bacteria isolated from bloodstream, pneumonia, intra-abdominal and urinary tract infections in US medical centres (2012). J Antimicrob Chemother. 2014;69(6):1589–98.

    Article  CAS  PubMed  Google Scholar 

  35. 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.

    Article  CAS  PubMed  Google Scholar 

  36. Berkhout J, Melchers MJ, van Mil AC, Nichols WW, Mouton JW. In vitro activity of ceftazidime–avibactam combination in in vitro checkerboard assays. Antimicrob Agents Chemother. 2015;59(2):1138–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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.

    Article  CAS  PubMed  Google Scholar 

  38. Levasseur P, Girard AM, Claudon M, Goossens H, Black MT, Coleman K, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Livermore DM, Mushtaq S, Warner M, Miossec C, Woodford N. NXL104 combinations versus Enterobacteriaceae with CTX-M extended-spectrum beta-lactamases and carbapenemases. J Antimicrob Chemother. 2008;62(5):1053–6.

    Article  CAS  PubMed  Google Scholar 

  40. US FDA. Ceftazidime–avibactam medical review, Silver Spring. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206494Orig1s000MedR.pdf. Accessed 24 July 2018.

  41. Flamm RK, Stone GG, Sader HS, Jones RN, Nichols WW. Avibactam reverts the ceftazidime MIC90 of European Gram-negative bacterial clinical isolates to the epidemiological cut-off value. J Chemother. 2014;26(6):333–8.

    Article  CAS  PubMed  Google Scholar 

  42. Sader HS, Castanheira M, Flamm RK, Farrell DJ, Jones RN. Antimicrobial activity of ceftazidime–avibactam against Gram-negative organisms collected from U.S. medical centers in 2012. Antimicrob Agents Chemother. 2014;58(3):1684–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Nichols WW, de Jonge BL, Kazmierczak KM, Karlowsky JA, Sahm DF. In vitro susceptibility of global surveillance isolates of Pseudomonas aeruginosa to ceftazidime–avibactam (INFORM 2012 to 2014). Antimicrob Agents Chemother. 2016;60(8):4743–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Castanheira M, Farrell SE, Krause KM, Jones RN, Sader HS. Contemporary diversity of beta-lactamases among Enterobacteriaceae in the nine U.S. census regions and ceftazidime–avibactam activity tested against isolates producing the most prevalent beta-lactamase groups. Antimicrob Agents Chemother. 2014;58(2):833–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wang X, Zhang F, Zhao C, Wang Z, Nichols WW, Testa R, et al. In vitro activities of ceftazidime–avibactam and aztreonam–avibactam against 372 Gram-negative bacilli collected in 2011 and 2012 from 11 teaching hospitals in China. Antimicrob Agents Chemother. 2014;58(3):1774–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zasowski EJ, Rybak JM, Rybak MJ. The beta-lactams strike back: ceftazidime–avibactam. Pharmacotherapy. 2015;35(8):755–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wu B, Sy SK, Derendorf H. Principles of applied pharmacokinetic–pharmacodynamic modeling. In: Vinks AA, Derendorf H, Mouton JW, editors. Fundamentals of antimicrobial pharmacokinetics and pharmacodynamics. New York: Springer; 2014. p. 63–79.

    Chapter  Google Scholar 

  48. Ambrose PG, Bhavnani SM, Rubino CM, Louie A, Gumbo T, Forrest A, et al. Pharmacokinetics-pharmacodynamics of antimicrobial therapy: it’s not just for mice anymore. Clin Infect Dis. 2007;44(1):79–86.

    Article  CAS  PubMed  Google Scholar 

  49. Mouton JW, Brown DF, Apfalter P, Canton R, Giske CG, Ivanova M, et al. The role of pharmacokinetics/pharmacodynamics in setting clinical MIC breakpoints: the EUCAST approach. Clin Microbiol Infect. 2012;18(3):E37–45.

    Article  CAS  PubMed  Google Scholar 

  50. Muller AE, Punt N, Mouton JW. Optimal exposures of ceftazidime predict the probability of microbiological and clinical outcome in the treatment of nosocomial pneumonia. J Antimicrob Chemother. 2013;68(4):900–6.

    Article  CAS  PubMed  Google Scholar 

  51. Sy SK, Zhuang L, Derendorf H. Pharmacokinetics and pharmacodynamics in antibiotic dose optimization. Expert Opin Drug Metab Toxicol. 2016;12(1):93–114.

    Article  CAS  PubMed  Google Scholar 

  52. Sy SK, Derendorf H. Pharmacometrics in bacterial infections. In: Schmidt S, Derendorf H, editors. Applied pharmacometrics. 1st ed. New York: Springer; 2014. p. 229–58.

    Chapter  Google Scholar 

  53. Andes D, Craig WA. Animal model pharmacokinetics and pharmacodynamics: a critical review. Int J Antimicrob Agents. 2002;19(4):261–8.

    Article  CAS  PubMed  Google Scholar 

  54. Nichols WW, Newell P, Critchley I, Riccobene T, Das S. Avibactam pharmacokinetic/pharmacodynamic targets. Antimicrob Agents Chemother. 2018;62(6):e02446-17.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Dudley MN. Combination beta-lactam and beta-lactamase-inhibitor therapy: pharmacokinetic and pharmacodynamic considerations. Am J Health Syst Pharm. 1995;52(6 Suppl 2):S23–8.

    Article  CAS  PubMed  Google Scholar 

  56. Coleman K, Levasseur P, Girard AM, Borgonovi M, Miossec C, Merdjan H, et al. Activities of ceftazidime and avibactam against beta-lactamase-producing Enterobacteriaceae in a hollow-fiber pharmacodynamic model. Antimicrob Agents Chemother. 2014;58(6):3366–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Berkhout J, Melchers MJ, Van Mil CH, Seyedmousavi S, Lagarde CM, Schuck V, et al. Exposure response relationships of ceftazidime and avibactam in neutropenic thigh model. In: 53rd Interscience conference on antimicrobial agents and chemotherapy; 10–13 Sep 2013, Denver.

  58. Berkhout J, Melchers MJ, van Mil AC, Seyedmousavi S, Lagarde CM, Schuck VJ, et al. Pharmacodynamics of ceftazidime and avibactam in neutropenic mice with thigh or lung infection. Antimicrob Agents Chemother. 2016;60(1):368–75.

    Article  CAS  PubMed  Google Scholar 

  59. Mouton JW, Punt N, Vinks AA. Concentration-effect relationship of ceftazidime explains why the time above the MIC is 40 percent for a static effect in vivo. Antimicrob Agents Chemother. 2007;51(9):3449–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Mouton JW, Vinks AA. Pharmacokinetic/pharmacodynamic modelling of antibacterials in vitro and in vivo using bacterial growth and kill kinetics: the minimum inhibitory concentration versus stationary concentration. Clin Pharmacokinet. 2005;44(2):201–10.

    Article  CAS  PubMed  Google Scholar 

  61. Merdjan H, Rangaraju M, Tarral A. Safety and pharmacokinetics of single and multiple ascending doses of avibactam alone and in combination with ceftazidime in healthy male volunteers: results of two randomized, placebo-controlled studies. Clin Drug Investig. 2015;35(5):307–17.

    Article  CAS  PubMed  Google Scholar 

  62. Tarral A, Merdjan H. Effect of age and sex on the pharmacokinetics and safety of avibactam in healthy volunteers. Clin Ther. 2015;37(4):877–86.

    Article  CAS  PubMed  Google Scholar 

  63. Fortaz. Ceftazidime prescribing information. Research Triange Park: GlaxoSmithKline; 2007.

    Google Scholar 

  64. Mawal Y, Critchley IA, Riccobene TA, Talley AK. Ceftazidime–avibactam for the treatment of complicated urinary tract infections and complicated intra-abdominal infections. Expert Rev Clin Pharmacol. 2015;8(6):691–707.

    Article  CAS  PubMed  Google Scholar 

  65. Vishwanathan K, Mair S, Gupta A, Atherton J, Clarkson-Jones J, Edeki T, et al. Assessment of the mass balance recovery and metabolite profile of avibactam in humans and in vitro drug-drug interaction potential. Drug Metab Dispos. 2014;42(5):932–42.

    Article  CAS  PubMed  Google Scholar 

  66. Bulitta JB, Landersdorfer CB, Huttner SJ, Drusano GL, Kinzig M, Holzgrabe U, et al. Population pharmacokinetic comparison and pharmacodynamic breakpoints of ceftazidime in cystic fibrosis patients and healthy volunteers. Antimicrob Agents Chemother. 2010;54(3):1275–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Merdjan H, Tarral A, Das S, Li J. Phase 1 study assessing the pharmacokinetic profile and safety of avibactam in patients with renal impairment. J Clin Pharmacol. 2017;57(2):211–8.

    Article  CAS  PubMed  Google Scholar 

  68. Sy SK, Derendorf H. Pharmacokinetics I: PK-PD approach, the case of antibiotic drug development. In: Müller M, editor. Clinical pharmacology: current topics and case studies. New York: Springer; 2016. p. 185–217.

    Chapter  Google Scholar 

  69. Nicolau DP, Siew L, Armstrong J, Li J, Edeki T, Learoyd M, et al. Phase 1 study assessing the steady-state concentration of ceftazidime and avibactam in plasma and epithelial lining fluid following two dosing regimens. J Antimicrob Chemother. 2015;70(10):2862–9.

    Article  CAS  PubMed  Google Scholar 

  70. Bradley JS, Armstrong J, Arrieta A, Bishai R, Das S, Delair S, et al. Phase I study assessing the pharmacokinetic profile, safety, and tolerability of a single dose of ceftazidime–avibactam in hospitalized pediatric patients. Antimicrob Agents Chemother. 2016;60(10):6252–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Das S, Li J, Armstrong J, Learoyd M, Edeki T. Randomized pharmacokinetic and drug-drug interaction studies of ceftazidime, avibactam, and metronidazole in healthy subjects. Pharmacol Res Perspect. 2015;3(5):e00172.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Carrothers TJ, Green M, Chiu J, Riccobene T, Lovern M. Population pharmacokinetic modeling of combination treatment of intravenous ceftazidime and avibactam, abstract T-071. In: 5th American conference on pharmacometrics; 12–15 Oct 2014, Las Vegas.

  73. Cerexa. Briefing document and addendum. NDA 206494. Anti-Infective Drugs Advisory Committee. 2014. https://www.pharmamedtechbi.com/~/media/Supporting%20Documents/The%20Pink%20Sheet%20DAILY/2014/December/12314%20FDA%20briefing%20docs.pdf. Accessed 24 July 2018.

  74. Sy SKB, Zhuang L, Xia H, Beaudoin ME, Schuck VJ, Nichols WW, et al. A mathematical model-based analysis of the time-kill kinetics of ceftazidime/avibactam against Pseudomonas aeruginosa. J Antimicrob Chemother. 2018;73(5):1295–304.

    Article  CAS  PubMed  Google Scholar 

  75. Sy SK, Zhuang L, Beaudoin ME, Kircher P, Tabosa MA, Cavalcanti NC, et al. Potentiation of ceftazidime by avibactam against beta-lactam-resistant Pseudomonas aeruginosa in an in vitro infection model. J Antimicrob Chemother. 2017;72(4):1109–17.

    CAS  PubMed  Google Scholar 

  76. Sy SK, Beaudoin ME, Zhuang L, Loblein KI, Lux C, Kissel M, et al. In vitro pharmacokinetics/pharmacodynamics of the combination of avibactam and aztreonam against MDR organisms. J Antimicrob Chemother. 2016;71(7):1866–80.

    Article  CAS  PubMed  Google Scholar 

  77. Sy S, Zhuang L, Xia H, Beaudoin ME, Schuck VJ, Derendorf H. Prediction of in vivo and in vitro infection model results using a semimechanistic model of avibactam and aztreonam combination against multidrug resistant organisms. CPT. 2017;6(3):197–207.

    CAS  Google Scholar 

  78. Crandon JL, Schuck VJ, Banevicius MA, Beaudoin ME, Nichols WW, Tanudra MA, et al. Comparative in vitro and in vivo efficacies of human simulated doses of ceftazidime and ceftazidime–avibactam against Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2012;56(12):6137–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Housman ST, Crandon JL, Nichols WW, Nicolau DP. Efficacies of ceftazidime–avibactam and ceftazidime against Pseudomonas aeruginosa in a murine lung infection model. Antimicrob Agents Chemother. 2014;58(3):1365–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Mazuski JE, Gasink LB, Armstrong J, Broadhurst H, Stone GG, Rank D, et al. Efficacy and safety of ceftazidime–avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infection: results from a randomized, controlled, double-blind, phase 3 program. Clin Infect Dis. 2016;62(11):1380–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Carmeli Y, Armstrong J, Laud PJ, Newell P, Stone G, Wardman A, et al. Ceftazidime–avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): a randomised, pathogen-directed, phase 3 study. Lancet Infect Dis. 2016;16(6):661–73.

    Article  CAS  PubMed  Google Scholar 

  82. Torres A, Zhong N, Pachl J, Timsit JF, Kollef M, Chen Z, et al. Ceftazidime–avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial. Lancet Infect Dis. 2018;18(3):285–95.

    Article  CAS  PubMed  Google Scholar 

  83. Qin X, Tran BG, Kim MJ, Wang L, Nguyen DA, Chen Q, et al. A randomised, double-blind, phase 3 study comparing the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem for complicated intra-abdominal infections in hospitalised adults in Asia. Int J Antimicrob Agents. 2017;49(5):579–88.

    Article  CAS  PubMed  Google Scholar 

  84. Mendes RE, Castanheira M, Woosley LN, Stone GG, Bradford PA, Flamm RK. Molecular beta-lactamase characterization of aerobic gram-negative pathogens recovered from patients enrolled in the ceftazidime–avibactam phase 3 trials for complicated intra-abdominal infections, with efficacies analyzed against susceptible and resistant subsets. Antimicrob Agents Chemother. 2017;61(6):e02447-16.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Center for Drug Evaluation and Research. Application Number: 206494Orig1s000. Clinical pharmacology and biopharmaceutics reviews; 2015. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206494Orig1s000CllinPharmR.pdf. Accessed 24 July 2018.

  86. Das S, Armstrong J, Mathews D, Li J, Edeki T. Randomized, placebo-controlled study to assess the impact on QT/QTc interval of supratherapeutic doses of ceftazidime–avibactam or ceftaroline fosamil-avibactam. J Clin Pharmacol. 2014;54(3):331–40.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA

    Sherwin K. B. Sy, Luning Zhuang & Hartmut Derendorf

  2. Department of Chemical Engineering, University of Waterloo, Waterloo, ON, Canada

    Serubbabel Sy

Authors
  1. Sherwin K. B. Sy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luning Zhuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Serubbabel Sy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hartmut Derendorf
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sherwin K. B. Sy.

Ethics declarations

Conflict of interest

Hartmut Derendorf received research grants from AstraZeneca. Sherwin K. B. Sy, Luning Zhuang, and Serubbabel Sy have no conflicts of interest to declare.

Funding

No funding was provided to the authors for the preparation of this review.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 32 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sy, S.K.B., Zhuang, L., Sy, S. et al. Clinical Pharmacokinetics and Pharmacodynamics of Ceftazidime–Avibactam Combination: A Model-Informed Strategy for its Clinical Development. Clin Pharmacokinet 58, 545–564 (2019). https://doi.org/10.1007/s40262-018-0705-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40262-018-0705-y

Search

Navigation