806. Pharmacokinetics of Ceftazidime/Avibactam following Intravenous Administration in Rabbits: Developing the Preclinical Foundation for Treatment of KPC-Kp Pneumonia in Immunocompromised Patients
Session: Poster Abstract Session: Use of PK/PD to optimize existing antibiotics and antifungals
Thursday, October 5, 2017
Room: Poster Hall CD

Background: CRE have been identified by the CDC as one of three urgent antibiotic resistance threats. The international emergence of these pathogens has largely been driven by the dissemination of carbapenemase-producing Klebsiella pneumoniae (KPC-Kp), through enzymes that hydrolyze carbapenems and all other beta-lactam agents.

Ceftazidime/avibactam (CAZ-AVB) represents a promising alternative for the treatment of KPC-Kp pneumonia and bacteremia. However, little is known about the efficacy of CAZ-AVB in immunocompromised hosts. We therefore studied its plasma pharmacokinetics in order to establish humanized dosages for preclinical investigation of CAZ-AVB in treatment of KPC-Kp pneumonia.

Methods: Three groups of four NZW rabbits received a single dose of ceftazidime/avibactam at 60, 90, and 120 mg/kg as an IV infusion.  During the second stage, ceftazidime/avibactam was administered Q8h for 6 days with serial plasma sampling on day 7. Pharmacokinetic parameters were estimated using non-compartmental methods.

Results:

Single dose

Ceftazidime Dose (mg/kg)

AUC(o-8)

(hr∙ug/mL)

Cmax

(ug/mL)

CL

(L/hr/kg)

Vss

(L/kg)

60

287.3 ± 40.1

321.8 ± 33.56

222.1 ± 33.4

224.5 ± 56.2

90

454.7 ± 55.9

477.4 ± 43.6

206.6 ± 27.6

173.4 ± 14.4

120

608.6 ± 70.8

581.1 ± 39.4

204.0 ± 22.1

193.5 ± 25.9

Avibactam

Dose (mg/kg)

AUC(o-8)

(hr∙ug/mL)

Cmax

(ug/mL)

CL

(L/hr/kg)

Vss

(L/kg)

15

21.8 ± 2.41

38.9 ± 5.09

696.8 ± 66.1

329.8 ± 58.9

22.5

35.9 ± 3.98

56.0 ± 3.50

626.8 ± 78.0

276.1 ± 13.7

30

48.5 ± 5.26

63.4 ± 4.31

613.3 ± 54.3

349.0 ± 11.1

Multi-dose

Ceftazidime Dose (mg/kg)

AUC(o-8)

(hr∙ug/mL)

Cmax

(ug/mL)

CL

(L/hr/kg)

Vss

(L/kg)

60

300.7 ± 111.8

415.5 ± 234.4

253.1 ± 75.0

271.3 ± 76.9

90

498.6 ± 161.1

564.3 ± 85.5

263.3 ± 87.8

262.4 ± 49.5

120

781.3 ± 181.9

817.9 ± 84.2

181.9 ± 42.1

228.6 ± 58.9

Avibactam

Dose (mg/kg)

AUC(o-8)

(hr∙ug/mL)

Cmax

(ug/mL)

CL

(L/hr/kg)

Vss

(L/kg)

15

26.8 ± 3.07

48.1 ± 19.0

569.5 ± 66.1

275.2 ± 85.9

22.5

32.9 ± 2.40

58.7 ± 4.15

674.2 ± 50.3

331.7 ± 19.4

30

48.9 ± 6.49

77.8 ± 12.5

611.4 ± 60.9

375.4 ± 38.9

Conclusion: This study demonstrates that CAZ-AVB displays linear dose proportional exposures simulating those of human plasma pharmacokinetics profiles and further establishes the preclinical foundation for treatment of immunocompromised patients.

Vidmantas Petraitis, MD1, Ruta Petraitiene, MD1, Michael Satlin, MD, MS2, Bo Bo Win Maung, MD1, Farehin Khan, BS1, Chase Mazur, BS3, Benjamin Georgiades, PharmD4, Joshua A Hayden, PhD3 and Thomas J Walsh, MD1, (1)Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine of Cornell University, New York, NY, (2)Weill Cornell Medicine, New York, NY, (3)Department of Pathology and Laboratory Medicine, Weill Cornell Medicine of Cornell University, New York, NY, (4)Allergan, Irvine, CA

Disclosures:

V. Petraitis, None

R. Petraitiene, None

M. Satlin, Hardy Diagnostics: Investigator , Research support
Allergan: Grant Investigator , Research grant
Merck: Grant Investigator , Grant recipient

B. B. W. Maung, None

F. Khan, None

C. Mazur, None

B. Georgiades, Allergan: Employee , Salary

J. A. Hayden, None

T. J. Walsh, Astellas, Actavis, Contrafect, Drais, iCo, Novartis, Methylgene, Pfizer, Sigma-Tau: Consultant , Consulting fee
Astellas, Actavis, Merck, Novartis, Phizer, Sctnexis, Tetraphase, The Medicines Company, Theravance: Grant Investigator , Research grant

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