Pharmacokinetics and Dialytic Clearance of Ceftazidime-Avibactam in a Critically Ill. Patient on Continuous Venovenous Hemofiltration

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1 AAC Accepted Manuscript Posted Online 17 April 2017 Antimicrob. Agents Chemother. doi: /aac Copyright 2017 American Society for Microbiology. All Rights Reserved Pharmacokinetics and Dialytic Clearance of Ceftazidime-Avibactam in a Critically Ill Patient on Continuous Venovenous Hemofiltration Eric Wenzler 1, Kristen L. Bunnell 1, Susan C. Bleasdale 2, Scott Benken 1, Larry H. Danziger 1, 2, Keith A. Rodvold 1, 2 1 University of Illinois at Chicago, College of Pharmacy, Chicago, IL, USA, 2 University of Illinois at Chicago, College of Medicine, Chicago, Illinois, USA Key words: pharmacokinetics, ceftazidime, avibactam, dialysis, hemofiltration, renal replacement All correspondence to: Eric Wenzler, PharmD, BCPS Infectious Diseases Pharmacotherapy Fellow University of Illinois at Chicago, College of Pharmacy 833 South Wood Street, Rm 164, M/C 886 Chicago, IL Phone: Fax: wenzler@uic.edu Funding: There was no financial support for this work.

2 2 22 Potential conflicts of interest: All authors certify no potential conflicts of interest ABSTRACT Ceftazidime-avibactam 1.25 g every 8 hours was used to treat multi-drug resistant Pseudomonas aeruginosa bacteremia in a critically ill patient on continuous venovenous hemofiltration (CVVH). Pre-filter plasma drug concentrations of ceftazidime and avibactam were measured at 0, 1, 2, 4, 6, and 8 hours along with post-filter and ultrafiltrate concentrations at hours 2 and 6. Plasma pharmacokinetic parameters of ceftazidime and avibactam, respectively, were C max and mg/l, C min and 8.45 mg/l, t 1/ and 6.78 hours, V ss and liters, CL ss 2.87 and 2.95 L/h, and AUC and mg h/l. Concentrations of ceftazidime in plasma exceeded the ceftazidime-avibactam MIC (6 mg/l) throughout the 8 hour dosing interval. Mean CVVH extraction ratio % for ceftazidime and avibactam, respectively, were 14.44% and 11.53% and mean sieving coefficients were 0.96 and 0.93, respectively. The calculated mean clearance of ceftazidime by CVVH was 1.64 L/h and for avibactam it was 1.59 L/h, representing 57.1% of the total clearance of ceftazidime and 54.3% of the total clearance of avibactam. Further data including multiple patients and dialysis modes are needed to verify the optimal dosing strategy of ceftazidime-avibactam during critical illness and CVVH. INTRODUCTION Ceftazidime-avibactam is a novel oxyimino cephalosporin-diazobicyclooctane β- lactamase inhibitor combination antimicrobial approved for the treatment of complicated urinary tract and intra-abdominal infections (1, 2). Avibactam is capable of inhibiting β-lactamase enzymes from Ambler class A and C, including KPC and chromosomal Pseudomonas AmpC

3 enzymes, and displays potent in vitro activity against a variety of multi-drug resistant Gram negative pathogens when combined with ceftazidime (3). This broad in vitro activity and collective familiarity with ceftazidime has stimulated the rapid uptake and frequent off-label use of ceftazidime-avibactam (4-6). Despite this pervasive use, there are no published pharmacokinetic data to guide dosing in critically ill patients or during any form of continuous renal replacement therapy. Furthermore, the pharmacokinetics and optimal dosing scheme of ceftazidime-avibactam were the subject of significant controversy during the regulatory process (3). Therefore, real-world data are needed to guide appropriate dosing in these critically ill patients with multi-drug resistant infections and significant pathophysiological and pharmacokinetic alterations. This work details the plasma pharmacokinetics and dialytic clearance of ceftazidime-avibactam in a patient on continuous venovenous hemofiltration (CVVH) being treated for multi-drug resistant P. aeruginosa bacteremia. A 53 year old female patient with a history of a deceased-donor renal transplant was admitted to the medical intensive care unit for idiopathic liver failure. Her hospital course was complicated by toxic megacolon secondary to Clostridium difficile, polymicrobial empyema, and anuric renal failure necessitating the initiation of renal replacement therapy. Approximately three weeks into her hospitalization she developed septic shock and ascitic fluid, respiratory, and blood cultures were positive for multi-drug resistant P. aeruginosa. Antibiotic susceptibilities for the isolate cultured from ascitic fluid are displayed in Table 1. Susceptibilities to ceftazidimeavibactam and colistin were determined by Etest (BioMerieux, Durham, NC), ceftolozanetazobactam by disk diffusion (Hardy Diagnostics, Santa Maria, CA), and the remaining antimicrobials by Vitek II (BioMerieux, Durham, NC). Given the resistance profile, the patient was started on ceftazidime-avibactam 1.25 g every 8 hours as a 2 hour infusion while on CVVH

4 via a NxStage System One machine (Lawrence, MA) with a 1.6m 2 polyethersulfone membrane filter. The blood and ultrafiltration flow rate were fixed at 200 ml/min and 2 L/h, respectively, and replacement fluid was added pre-filter. There were no interruptions in CVVH during her treatment with ceftazidime-avibactam and the CVVH filter was changed 4 hours prior to the 4 th dose. This work involved the use of a marketed drug in the course of medical practice and therefore did not meet the institutional criteria for human subjects research. RESULTS The pre-filter plasma pharmacokinetic parameters of ceftazidime and avibactam from this patient receiving CVVH and reference parameters from healthy subjects receiving the same dose are displayed in Table 2 (7). Pre-filter plasma concentration-time profiles of ceftazidime and avibactam in relation to the MIC are displayed in Figure 1. Concentrations of ceftazidime in plasma exceeded the ceftazidime-avibactam MIC throughout the entire 8 hour dosing interval. The extraction ratio % for ceftazidime at 2 and 6 hours after the start of the infusion were 13.57% and 15.30% and for avibactam were 10.88% and 12.18%, respectively. Sieving coefficients at the same time points for ceftazidime were 0.88 and 1.03 and for avibactam were 0.89 and 0.97, respectively. The calculated CL CVVH for ceftazidime at 2 and 6 hours was 1.51 L/h and 1.77 L/h and for avibactam it was 1.52 L/h and 1.65 L/h. The CL CVVH thus represented 57.1% of the total clearance of ceftazidime and 54.3% of the total clearance of avibactam. DISCUSSION To our knowledge, this is the first published report of a patient receiving ceftazidime- avibactam while on any type of renal replacement therapy. Given the lack of available data and considering the severity of illness of the patient and the MIC of the pathogen, the dose of

5 ceftazidime-avibactam used in this case was extrapolated from the package insert dosing for patients with an estimated creatinine clearance of ml/min. We then prospectively measured the systemic concentrations and dialytic clearance of ceftazidime-avibactam in order to calculate patient-specific pharmacokinetic parameters and optimize dosing. Our report demonstrates significant pharmacokinetic alterations during critical illness and renal replacement therapy compared to healthy volunteers administered the same dose of ceftazidime-avibactam (Table 2). The plasma exposure in terms of AUC was approximately 3- fold larger for ceftazidime and over 4-fold larger for avibactam in our patient compared to healthy volunteers. Total clearance was reduced roughly 3- to 4-fold for ceftazidime and avibactam, respectively, and V ss was increased 1.5-fold, leading to a t 1/2 approximately 4 hours longer than that observed in healthy volunteers. The plasma pharmacokinetic parameters and dialytic clearance of ceftazidime described in this case are comparable to those previously reported in patients undergoing CVVH (8, 9). There are no published data on the removal of avibactam by CVVH or its effect on the systemic pharmacokinetics. The primary pharmacokinetic/pharmacodynamic index of efficacy for β-lactam antibiotics is the time that serum free drug concentrations remain above the MIC (ft>mic) throughout the dosing interval (10). Assuming 10% protein binding of ceftazidime, our patient achieved 100% ft>mic through the 8 hour dosing interval with the 1.25 g every 8 hour dosing regimen while on CVVH. The pharmacodynamic parameter most closely associated with efficacy of the β-lactam inhibitors, including avibactam, appears to be the time the free drug concentration is spent above a threshold concentration required to inhibit β-lactamases throughout the dosing interval. For avibactam, this threshold has been shown to be 1 mg/l for bactericidal activity and the target percent time above this threshold to be 30-50% for

6 bactericidal activity (13, 14). Using this endpoint and assuming 7% protein binding, the avibactam concentrations were also above this target for 100% of the dosing interval. The estimated free C min for ceftazidime (28.76 mg/l) was more than 4-fold above the MIC and was more than 7-fold above the 1 mg/l threshold for avibactam (7.86 mg/l) (Table 2). In retrospect, the package insert dosing for patients with an estimated creatinine clearance of ml/min (0.94 g every 12 hours), would have likely also achieved the pharmacokinetic/pharmacodynamic targets for ceftazidime and avibactam assuming dose-proportional kinetics. Ultimately, despite achieving target plasma pharmacokinetic/pharmacodynamic endpoints, the patient expired due to persistent infection and multiorgan failure. Blood cultures remained positive for 5 days despite therapy with ceftazidime-avibactam and repeated therapeutic doses of tobramycin. The data obtained herein provide clinicians using this agent off-label in critically ill patients on CVVH with some initial dosing guidance. Larger studies exploring multiple patients and dialysis modes are needed to verify the optimal dosing strategy of ceftazidime-avibactam in this patient population. The clearance reported in this case may not be representative of alternate modes and rates of renal replacement therapy or CVVH with postfilter replacement hemofiltration. The sampling period in this study covered the 8 hour dosing interval, but complete elimination phase data are need in order to more accurately quantify the plasma half-life. MATERIALS AND METHODS Serial pre-filter blood samples were collected in heparinized K 2 EDTA tubes before, during, at the end, and 4, 6, and 8 hours after the start of the fourth infusion of ceftazidime- avibactam. The sampling point at the end of the infusion accounted for overfill volume during

7 drug reconstitution and residual fluid volume in the intravenous catheter. Simultaneous postfilter and ultrafiltrate samples were obtained at the end of the infusion and 6 hour time points. Pre-filter blood samples were obtained from an indwelling arterial catheter and post-filter from a port on the blood return access line. Pre and post-filter blood samples were centrifuged at 2000 g for 10 minutes and supernatant plasma was frozen at -80 C within 30 minutes of collection. Ceftazidime and avibactam concentrations were quantified using liquid-chromatography tandem mass-spectrometry methods (Keystone Bioanalytical, North Wales, PA). The calibration range for ceftazidime and avibactam was mg/l and mg/l, respectively, with an intraand inter-assay error of ± 10%. Steady-state pharmacokinetic parameters for ceftazidime and avibactam were estimated from observed pre-filter plasma concentrations via noncompartmental analysis (WinNonlin Version 7.0, Pharsight Corp., Mountain View, CA). The following parameters were calculated: maximum plasma concentration (C max ), minimum plasma concentration (C min ), half-life (t 1/2 ), apparent volume of distribution (V ss ), total clearance (CL ss ), and the area under the concentration-time curve from 0 to 8 hours (AUC 0-8 ). AUC 0-8 was calculated via the linear uplog down method. Calculations for the estimation of removal of ceftazidime and avibactam by CVVH were as follows (11): Extraction ratio %: ((pre-filter concentration post-filter concentration)/pre-filter concentration) x Sieving coefficient (SC): ultrafiltrate concentration/(pre-filter concentration + post-filter concentration/2)

8 CL CVVH : SC x ultrafiltrate flow rate x correction factor for pre-filter fluid replacement o Correction factor: [blood flow rate/(blood flow rate + replacement fluid rate)] (12). ACKNOWLEDGEMENTS There was no outside financial support for this work. REFERENCES 1. Zasowski EJ, Rybak JM, Rybak MJ The beta-lactams Strike Back: Ceftazidime-Avibactam. Pharmacotherapy 35: Anonymous. Avycaz (ceftazidime/avibactam) Prescribing Information. Actavis, Inc. September Available at Accessed 14 September Anonymous. Food and Drug Administration Anti-Infective Drugs Advisory Committee Meeting. Ceftazidime-avibactam for injection for Treatment of Complicated Intra-Abdominal Infection (used in combination with metronidazole), Complicated Urinary Tract Infection including Acute Pyelonephritis, and Limited Use Indication: Aerobic Gram-negative Infections with Limited Treatment Options. 05 December Available from -InfectiveDrugsAdvisoryCommittee/UCM pdf. Accessed 25 August Shields RK, Chen L, Cheng S, Chavda KD, Press EG, Snyder A, Pandey R, Doi Y, Kreiswirth BN, Nguyen MH, Clancy CJ Emergence of ceftazidime-avibactam resistance due to plasmidborne blakpc-3 mutations during treatment of carbapenem-resistant Klebsiella pneumoniae infections. Antimicrob Agents Chemother doi: /aac Xipell M, Bodro M, Marco F, Losno RA, Cardozo C, Soriano A Clinical experience with ceftazidime/avibactam in patients with severe infections, including meningitis and lung abscesses, caused by extensively drug-resistant Pseudomonas aeruginosa. Int J Antimicrob Agents 49: Temkin E, Torre-Cisneros J, Beovic B, Benito N, Giannella M, Gilarranz R, Jeremiah C, Loeches B, Machuca I, Jimenez-Martin MJ, Martinez JA, Mora-Rillo M, Navas E, Osthoff M, Pozo JC, Ramos Ramos JC, Rodriguez M, Sanchez-Garcia M, Viale P, Wolff M, Carmeli Y Ceftazidime-Avibactam as Salvage Therapy for Infections Caused by Carbapenem-Resistant Organisms. Antimicrob Agents Chemother 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 35:

9 Traunmüller F, Schenk P, Mittermeyer C, Thalhammer-Scherrer R, Ratheiser K, Thalhammer F Clearance of ceftazidime during continuous venovenous haemofiltration in critically ill patients. J Antimicrob Chemother 49: Isla A, Gascon AR, Maynar J, Arzuaga A, Sanchez-Izquierdo JA, Pedraz JL In vitro AN69 and polysulphone membrane permeability to ceftazidime and in vivo pharmacokinetics during continuous renal replacement therapies. Chemotherapy 53: Ambrose PG, Bhavnani SM, Rubino CM, Louie A, Gumbo T, Forrest A, Drusano GL Pharmacokinetics-pharmacodynamics of antimicrobial therapy: it's not just for mice anymore. Clin Infect Dis 44: Golper TA, Wedel SK, Kaplan AA, Saad AM, Donta ST, Paganini EP Drug removal during continuous arteriovenous hemofiltration: theory and clinical observations. Int J Artif Organs 8: Pea F, Viale P, Pavan F, Furlanut M Pharmacokinetic considerations for antimicrobial therapy in patients receiving renal replacement therapy. Clin Pharmacokinet 46: Downloaded from on October 26, 2018 by guest

10 Table 1. Pseudomonas aeruginosa antibiotic susceptibilities Antibiotic MIC (mg/l) Interpretation a Amikacin 16 Susceptible Aztroenam >16 Resistant Cefepime >16 Resistant Ceftazidime >16 Resistant Ceftazidime-avibactam 6/4 Susceptible b Ceftolozane-tazobactam 24 c Susceptible Ciprofloxacin >2 Resistant Colistin 2 Susceptible Gentamicin 8 Intermediate Imipenem-cilastatin >8 Resistant Levofloxacin >4 Resistant Meropenem >8 Resistant Pierpacillin-tazobactam >64 Resistant Ticarcillin-clavulanate >64 Resistant Tobramycin 2 Susceptible a Interpeted according to CLSI M100-S27 b Interpreted using FDA breakpoints; Susceptible - 8/4, Resistant - 16/4 c Disk diffusion diameter of inhibition

11 Table 2. Plasma pharmacokinetic parameters of ceftazidime and avibactam in a critically ill patient receiving CVVH and healthy subjects Ceftazidime Avibactam Parameter CVVH patient a Healthy volunteers b, c CVVH patient a Healthy volunteers b, c C max (mg/l) C min (mg/l) t 1/2 (h) AUC 0-τ (mg h/l) d d CL (L/h) V ss (L) a CVVH settings: filter, 1.6m 2 polyethersulfone membrane; blood flow rate, 200 ml/min; pre-filter replacement fluid rate, 2 L/h b Healthy volunteers given a single dose of 1000 mg of ceftazidime and 250 mg avibactam (Reference 9). c Mean or median value d AUC 0-last

12 Fig 1. Pre-filter concentration-time profiles of ceftazidime (solid line, filled circles) and avibactam (dotted line, open circles) in plasma before and after the fourth dose of ceftazidimeavibactam 1.25 g in relation to the MIC of the infecting P. aeruginosa pathogen (dashed horizontal line). Shaded region represents the infusion period, accounting for reconstitution volume overfill and residual fluid volume in catheter. The y axis is in the log scale.

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