Pharmacokinetics of Ceftazidime-avibactam Among Critically-ill Patients Receiving Continuous Venovenous Hemodiafiltration
Conditions: Bacterial Infections
Sponsor: University of Pittsburgh

1 
 
 
Ceftazidime-avibactam plasma levels in critically ill patients, including those receiving 
continuous renal replacement therapy 
 
NCT04358991 
 
SIGNATURE PAGE 
 
RESPONSIBLE STUDY AUTHORS 
 
 
STUDY AUTHOR(S):   
I have read this report and confirm that to the best of my knowledge it accurately describes the conduct and 
results of the study. 
 
 
Signature:_______________________ 
Date: _April 7, 2020___________________ 
Ryan K. Shields 
Principal Investigator 
University of Pittsburgh 
3550 Terrace Street, Room S805 
Pittsburgh, PA 15621 
412-864-3745 
 
 
 
 
 
 
 
 

2 
 
 
 
Table of Contents 
SIGNATURE PAGE................................................................................................................................................ 1 
RESPONSIBLE STUDY AUTHORS...................................................................................................................... 1 
Table of Figures. ..................................................................................................................................................... 3 
Table of Tables. ...................................................................................................................................................... 3 
List of Abbreviations................................................................................................................................................ 4 
Purpose........................................................................................................................... 5 
Methods. ......................................................................................................................... 5 
Results. ........................................................................................................................... 7 
Ceftazidime Pharmacokinetics .....................................................................................................................9 
Avibactam Pharmacokinetics ..................................................................................................................... 11 
Pharmacokinetic Parameters: Patients Receiving Renally-Adjusted Doses of CAZ-AVI.................... 13 
Pharmacodynamics and Target Attainment .............................................................................................. 15 
Safety ............................................................................................................................................................. 16 
References.................................................................................................................. 177 
Appendix. .......................................................................................................................................................... 1818 
 
 
 

3 
 
Table of Figures.  
Figure 1. Chromatograms of Ceftazidime and Avibactam. .................................................................................... 6 
Figure 2. Ceftazidime Plasma Concentrations in Patients Receiving 2.5g IV q 8h............................................... 9 
Figure 3. Ceftazidime Concentration-time Profile: Patients Receiving 2.5g IV q 8h, Stratified by those with or 
without CRRT. ....................................................................................................................................................... 10 
Figure 4. Avibactam Plasma Concentrations in Patients Receiving 2.5g IV q 8h.   ............................................ 11 
Figure 5. Avibactam Concentration-time Profile: Patients Receiving 2.5g IV q 8h, Stratified by those with or 
without CRRT. ....................................................................................................................................................... 12 
Figure 6: Concentration-time profiles of Patients Receiving Non-standard Dosing. ........................................... 14 
Figure 7. Target Attainment for Ceftazidime. ....................................................................................................... 15 
Figure 8. Target Attainment for Avibactam........................................................................................................... 16 
 
Table of Tables. 
Table 1. Patient Demographics (n=20)................................................................................................................... 7 
Table 2. Renal Replacement Therapy Settings. .................................................................................................... 8 
Table 3. Calculated Ceftazidime PK parameters by Patient Group....................................................................... 9 
Table 4. Ceftazidime PK Parameters for Patients Receiving Continuous Renal Replacement Therapy. .......... 10 
Table 5. Calculated Avibactam PK Parameters by Patient Group. ..................................................................... 11 
Table 6. Avibactam PK Parameters for Patients Receiving Continuous Renal Replacement Therapy. ............ 12 
Table 7.  Measured Total Drug Values of Ceftazidime and Avibactam in Critically Ill Patients. ......................... 13 
 
 
 
 
 
 
 
 
 

4 
 
List of Abbreviations.  
AUC – area under curve 
AVI – avibactam  
CAZ – ceftazidime  
CL – observed clearance at steady state 
CLSI – Clinical and Laboratory Standards Institute 
cm – centimeter  
Cmax – predicted maximum concentration 
Cmin – predicted minimum concentration 
CrCl – creatinine clearance 
CRRT – continuous renal replacement therapy 
CVVHDF – continuous venovenous hemodiafiltration 
EDTA – ethylenediaminetetraacetic acid 
fT – time of free drug concentration  
g – gram  
HD – hemodialysis  
IBW – ideal body weight 
IQR – interquartile range 
IV – intravenous(ly)  
Ke – equilibrium constant 
kg – kilogram  
LCMS – liquid chromatography mass spectrometry 
MIC – minimum inhibitory concentration 
µg/mL – micrograms per millilter 
PD – pharmacodynamics  
PK – pharmacokinetic  
RRT – renal replacement therapy 
q 8/24/48h – every 8/24/48 hours  
t1/2 – half life 
UHPLC – ultra high performance liquid chromatography   
Vd – observed volume of distribution at steady state 
 
 
 
 
 
 
 
 

5 
 
Purpose.  
 
Ceftazidime-avibactam is a β-lactam/β-lactamase inhibitor combination used to treat multidrug-resistant gram-
negative infections. There are limited pharmacokinetic data among critically ill patients and no dosing 
recommendations for those receiving continuous renal replacement therapy (CRRT). The objective of this 
study is to describe the population pharmacokinetics of ceftazidime and avibactam among patients infected or 
being treated for multidrug-resistant gram-negative pathogens, including those on CRRT.  
 
Methods.  
 
Enrollment 
Adult patients at UPMC Presbyterian hospital who received >24 hours of ceftazidime-avibactam were eligible 
for participation. Informed consent was obtained for each subject. The study protocol was approved by the 
University of Pittsburgh institutional review board (protocol number: PRO17060377).  
 
Clinical management 
During the course of the study, we identified receipt of RRT as a risk factor for clinical failure and emergence of 
ceftazidime-avibactam resistance [1]. Given these data, our standard approach to ceftazidime-avibactam 
treatment for patients receiving CRRT was to administer 2.5g IV q 8h and enroll patients into this study. For 
each of these patients, we carefully monitored patients for any signs or symptoms of drug toxicity, including 
neurotoxicity and myelosuppression.  
 
Sampling and storage 
Whole blood samples were collected from November 2016 to March 2019 in sterile tubes containing EDTA as 
an anticoagulant. Samples were collected prior to a dose of ceftazidime-avibactam, and then at 2, 4, 6, and 8 
hours after the infusion started. Collection tubes were centrifuged at 3,000 x rpm for 5 minutes immediately 
after collection. Plasma was stored in 0.5-1mL aliquots at -80°C until analysis.   
 
 

6 
 
Simultaneous measurement of avibactam and ceftazidime with a highly-sensitive, reproducible ultra 
high performance liquid chromatography mass spectrometry (UHPLC-MS) assay.  
We developed an UHPLC-MS assay to quantify avibactam and ceftazidime on a Shimadzu Nexera XD UHPLC 
with a Shimadzu 8045 MS (Figure 1). Mobile phase A was 0.1% formic acid in water; mobile phase B was 
0.1% formic acid in acetonitrile. Samples were prepared by adding 100µL of plasma to 200µL of water and 
700µL of acetonitrile containing internal standards (ceftazidime-d5, Toronto Research Chemical, Toronto 
Canada; avibactam-H2; Alsachim, Illkirch, France). Samples were vortexed, allowed to rest on ice, then 
centrifuged at 13,000 x rpm for 5 minutes, and allowed to rest on ice again. In an LCMS vial, 100µL of 
supernatant was added to 400µL mobile phase A and samples were loaded into a 4°C autosampler. A Waters 
Atlantis T3 column (3µm, 50x2.1mm; with guard) was used. An elution gradient at 0.5mL/min started at 5% B 
increasing to 90% B, where it was held for 30 seconds before returning to 5% B. The total run time was 5.5 
minutes and the injection volume was 3µL. Transitions were monitored in positive mode for ceftazidime (m/z 
274.1 < 80.05) and negative mode for avibactam (264.00 < 95.90). The assay was reproducible and linear over 
a range of 0.1 - 20µg/mL for avibactam and 1 - 200µg/mL for ceftazidime. 
 
Figure 1. Chromatograms of Ceftazidime and Avibactam. 
 
 
Pharmacokinetic and Pharmacodynamic analysis.  
Pharmacokinetic analysis of serum concentrations was performed with WinNonlin version 8.2 (Certara, 
Princeton, NJ) for IV infusion noncompartmental model analysis. Predicted PK values were calculated for each 
patient. Descriptive statistics are provided, including mean and standard deviation for continuous variables. 
Dichotomous or continuous variables were compared by chi-squared test or Mann-Whitney U, respectively.  
 
 
Ceftazidime 
10µg/ml 
Avibactam 
1µg/ml 

7 
 
Results. 
 
A total of 20 patients (Table 1) were enrolled in the study. Fifteen patients received a standard dosing regimen 
of 2.5g ceftazidime-avibactam every 8 hours intravenously. Five patients received dose-adjustments due to 
renal insufficiency. Two received 1.25g of ceftazidime-avibactam every 8 hours intravenously, 2 received 0.94g 
every 48 hours, and 1 received 0.94g every 24 hours. For patients receiving CRRT, dialysis settings and flow 
rates are provided in Table 2. 
 
Table 1. Patient Demographics (n=20).  
Patient # 
Age 
Sex 
Race1 
Height 
(cm) 
Weight2 
(kg) 
Dose 
SCr on day 
of sampling 
Cockroft-
Gault IBW 
(kg) 
Renal 
Replacement 
Therapy 
7 
74 
F 
D 
160 
50.9 
0.94g q 24h 
2.3 
CRRT 
CRRT 
2 
64 
M 
W 
178 
66 
0.94g q 48h 
2 
HD 
HD 
5 
69 
F 
W 
173 
54.5 
0.94g q 48h 
2.1 
HD 
HD 
1 
60 
M 
W 
185 
120.8 
1.25g q 8h 
2.1 
42.0 
None 
16 
51 
F 
W 
168 
65.7 
1.25g q 8h 
1.5 
42.0 
None 
Mean (non-standard 
dosing): 
63.6 
 
 
172.8 
71.6 
 
1.93 
 
 
 
 
 
 
 
 
 
 
 
 
3 
59 
F 
W 
163 
70.1 
2.5g q 8h 
1 
52.6 
None 
4 
59 
F 
W 
163 
78.2 
2.5g q 8h 
0.6 
87.7 
None 
6 
59 
F 
W 
185 
85.8 
2.5g q 8h 
0.7 
133.5 
None 
8 
66 
M 
W 
175 
132 
2.5g q 8h 
0.4 
CRRT 
CRRT 
9 
68 
M 
W 
175 
75.6 
2.5g q 8h 
1.2 
CRRT 
CRRT 
10 
48 
F 
W 
173 
67 
2.5g q 8h 
1.5 
CRRT 
CRRT 
11 
35 
M 
W 
163 
66 
2.5g q 8h 
1 
CRRT 
CRRT 
12 
59 
M 
U 
170 
120 
2.5g q 8h 
1.5 
CRRT 
CRRT 
13 
58 
M 
W 
178 
96 
2.5g q 8h 
1.5 
CRRT 
CRRT 
14 
45 
F 
W 
163 
46.2 
2.5g q 8h 
0.4 
154.2 
None 
15 
44 
F 
W 
168 
132 
2.5g q 8h 
0.4 
168.6 
None 
17 
31 
M 
W 
193 
75.5 
2.5g q 8h 
0.7 
187.1 
None 
18 
61 
M 
W 
168 
104.6 
2.5g q 8h 
1 
70.2 
None 
19 
41 
M 
W 
171 
73.2 
2.5g q 8h 
2.5 
36.8 
None 
20 
63 
M 
W 
177 
114 
2.5g q 8h 
0.8 
96.3 
None 
Mean (standard 
dosing): 
53.1 
 
 
172.3 
89.0 
 
1.01 
 
 
Mean (overall): 
55.7 
 
 
172.4 
84.7 
 
1.21 
 
 
1White (W), declined race (D), race unknown (U) 
2Adjusted body weight was used for obese patients when >120% IBW  
 
 
 
 

8 
 
Table 2. Renal Replacement Therapy Settings. 
Patient 
CRRT 
Machine 
Type of CRRT 
Filter Model 
Blood Flow Rate 
(mL/hr) 
Replacement Fluid 
Infusion Rate 
(mL/hr) 
Dialysate Flow Rate 
(mL/hr) 
7 
Prismaflex 
CVVHDF 
M100 
250 
250 
1750 
8 
Prismaflex 
CVVHDF 
M100 
250 
250 
3000 
9 
Prismaflex 
CVVHDF 
M100 
200 
500 
2000 
10 
Prismaflex 
CVVHDF 
M100 
250 
250 
1500 
11 
Prismaflex 
CVVHDF 
M100 
250 
250 
1700 
12 
Prismaflex 
CVVHDF 
M150 
300 
250 
3500 
13 
Prismaflex 
CVVHDF 
M100 
250 
250 
2500 
 
 
 
 
 
 
 
 
 
 
 
 

9 
 
Ceftazidime Pharmacokinetics 
A total of 96 plasma samples were collected from 20 patients. Figure 2 shows total ceftazidime concentrations 
plotted for each patient. Table 3 lists PK parameters for all patients stratified by dosing strategy. There was no 
statistical difference (Mann-Whitney) between patients receiving a standard 2.5g dose q8h with normal renal 
function and patients on CRRT for Cmax, AUC, CL, and Vd. Median values were statistically different for Cmin 
(normal function 29.01 vs CRRT 46.59, p = 0.0496), t1/2  (normal function 4.478h vs CRRT 10.12h, p = 0.0496), 
and the rate elimination constant (Ke) (normal function 0.15 vs CRRT 0.07, p = 0.0496). Figure 3 compares the 
concentrations over time per patient for those with and without CRRT.  
Figure 2. Ceftazidime Plasma Concentrations in Patients Receiving 2.5g IV q 8h. 
 
 
Table 3. Calculated Ceftazidime PK parameters by Patient Group. 
Median 
(IQR) 
All patients 
(n=20) 
Standard Dose 
Other (n=5) 
All 2.5g q8h 
(n=15) 
CrCl > 50ml/min 
(n=9); 2.5g IV q8h 
CRRT (n=6);  
2.5g IV q8h 
P 
value 
Cmax (µg/ml) 
80.6 (61.2, 
104.1) 
87.0 (69.2, 108.2) 
81.3 (76.5, 88.1) 
96.3 (69.6, 
112.4) 
0.4559 
69.9 (59.3, 73.2)1 
Cmin (µg/ml) 
40.4 (28.3, 55.0) 
35.4 (27.7, 53.5) 
29.0 (20.9, 35.5) 
46.6 (37.9, 64.4) 
0.0496 
46.1 (46.0, 53.7)1 
AUC0-8h 
(hr*µg/mL)2 
456.3 (400.3 
588.1) 
456.6 (388.7, 
651.8) 
437.4 (328.2, 
550.3) 
522.2 (455.1, 
683.7) 
0.3277 
444.8 (432.7, 456.9) 
Ke (1/hr) 
0.13 (0.06, 0.16) 
0.15 (0.10, 0.16) 
0.15 (0.14, 0.19) 
0.07 (0.05, 0.14) 
0.0496 
0.04 (0.04, 0.07) 
t1/2 (hr) 
5.2 (4.3, 12.6) 
4.5 (4.2, 7.0) 
4.5 (3.7, 5.1) 
10.1 (5.5, 15.1) 
0.0496 
15.7 (8.9, 16.5) 
Vd (L) 
34.6 (22.5, 49.3) 
28.7 (20.6, 46.0) 
26.0 (16.3, 36.1) 
43.2 (31.3, 56.9) 
0.1135 
40.7 (33.1, 55.1) 
CL (L) 
3.6 (2.3, 5.2) 
4.4 (3.2, 5.5) 
5.3 (3.6, 6.2) 
4.0 (3.0, 4.7) 
0.2238  
2.3 (1.8, 2.3) 
1 See Table 6 for details. 
2 For AUC, patients with 24 or 48 hour dosing were excluded; All patients n = 17, Other n = 2  
 
 

10 
 
Figure 3. Ceftazidime Concentration-time Profile: Patients Receiving 2.5g IV q 8h, Stratified by those 
with or without CRRT. 
 
 
Table 4. Ceftazidime PK Parameters for Patients Receiving Continuous Renal Replacement Therapy. 
Patient 
Regimen 
Cmin 
(µg/ml) 
Cmax 
(µg/ml) 
AUC0-8h 
(hr*µg/mL) 
t1/2 
(hr) 
CL 
(L/hr) 
Vd 
(L) 
Blood 
Flow 
Rate 
(mL/hr) 
Replacement 
Fluid Infusion 
Rate (mL/hr) 
Dialysate 
Flow Rate 
(mL/hr) 
8 
2.5g IV q 8h 
45.73 
60.43 
456.3 
16.24 
5.92 
143.92 
250 
250 
3000 
9 
2.5g IV q 8h 
22.72 
104.95 
454.7 
4.32 
5.54 
34.43 
200 
500 
2000 
10 
2.5g IV q 8h 
80.03 
162.85 
1156.4 
16.77 
2.18 
53.24 
250 
250 
1500 
11 
2.5g IV q 8h 
45.88 
83.33 
588.1 
4.40 
4.45 
30.40 
250 
250 
1700 
12 
2.5g IV q 8h 
30.85 
70.91 
377.1 
8.60 
6.46 
76.61 
300 
250 
3500 
13 
2.5g IV q 8h 
68.26 
122.98 
715.6 
11.64 
3.48 
54.80 
250 
250 
2500 
 
 
 
 
 

11 
 
Avibactam Pharmacokinetics 
The same 96 samples were simultaneously analyzed for avibactam total drug concentrations; Figure 4 shows 
the results for each patient. Table 5 lists PK parameters for all patient groups. There was no statistical 
difference (Mann-Whitney) between patients receiving a standard 2.5g dose q8h with normal renal function 
and patients on CRRT for Cmax or Vd. Median values for Cmin, AUC, t1/2, Ke, and CL were statistically different 
(normal function vs CRRT, respectively: 4.45 vs 11.1, p = 0.0028, 73.4 vs 126.4, p = 0.0496, 3.3 vs 10.3, p = 
0.0048, 0.21 vs 0.07, p = 0.0048, 6.6 vs 4.2, p = 0.0256). Figure 5 shows the time course results for the 15 
standard dose patients.  
Figure 4. Avibactam Plasma Concentrations in Patients Receiving 2.5g IV q 8h.  
 
 
Table 5. Calculated Avibactam PK Parameters by Patient Group. 
Median 
(IQR) 
All patients 
(n=20) 
Standard Dose 
Other (n=5) 
All 2.5g q8h 
(n=15) 
CrCl > 50ml/min 
(n=9); 2.5g IV q8h 
CRRT (n=6); 2.5g 
IV q8h 
P value 
Cmax 
(µg/ml) 
15.6 (11.8, 23.0) 
15.9 (12.7, 24.3) 
13.3 (11.3, 16.3) 
21.3 (16.7, 27.1) 
0.1135 
14.1 (8.9, 
21.5)1 
Cmin 
(µg/ml) 
8.5 (4.2, 9.8) 
8.9 (3.9, 10.1) 
4.5 (2.8, 8.9) 
11.1 (9.8, 14.2) 
0.0028 
6.11 (5.8, 9.0)1 
AUC0-8h 
(hr*µg/mL)2 
98.8 (58.3, 149.4) 
99.1 (62.0, 150.2) 
73.4 (48.3, 99.1) 
126.4 (101.9, 
154.5) 
0.0496 
74.7 (66.5, 
82.9) 
Ke (1/hr) 
0.15 (0.07, 0.21) 
0.16 (0.09, 0.21) 
0.21 (0.16, 0.23) 
0.07 (0.05, 0.13) 
0.1135 
0.07 (0.05, 
0.07) 
t1/2 (hr) 
4.6 (3.3, 10.2) 
4.4 (3.3, 7.9) 
3.3 (3.0, 4.2) 
10.3 (5.6, 15.2) 
0.0048 
9.8 (9.3, 12.6) 
Vd (L) 
43.2 (23.4, 58.9) 
38.1 (22.6, 56.8) 
32.1 (20.6, 43.8) 
56.1 (35.4, 78.9) 
0.1135 
43.8 (42.6, 
57.7) 
CL (L) 
4.5 (3.3, 6.2) 
5.3 (3.4, 8.0) 
6.6 (5.6, 9.6) 
4.2 (3.3, 4.9) 
0.0256 
3.0 (1.6, 3.6) 
1 See Table 6 for details. 
2 For AUC, patients with 24 or 48 hour dosing were excluded; All patients n = 17, Other n = 2  

12 
 
 
Figure 5. Avibactam Concentration-time Profile: Patients Receiving 2.5g IV q 8h, Stratified by those 
with or without CRRT. 
 
 
 
 
Table 6. Avibactam PK Parameters for Patients Receiving Continuous Renal Replacement Therapy. 
Patient 
Regimen 
Cmin 
(µg/ml) 
Cmax 
(µg/ml) 
AUC0-8h 
(hr*µg/mL) 
t1/2 
(hr) 
CL 
(L/hr) 
Vd 
(L) 
Blood 
Flow 
Rate 
(mL/hr) 
Replacement 
Fluid Infusion 
Rate (mL/hr) 
Dialysate 
Flow Rate 
(mL/hr) 
8 
2.5g IV q 8h 
10.11 
13.43 
101.4 
16.36 
5.33 
130.64 
250 
250 
3000 
9 
2.5g IV q 8h 
5.04 
23.79 
103.4 
4.35 
4.87 
30.64 
200 
500 
2000 
10 
2.5g IV q 8h 
20.28 
38.15 
279.5 
31.83 
1.79 
84.40 
250 
250 
1500 
11 
2.5g IV q 8h 
11.66 
20.74 
149.4 
4.52 
3.49 
24.26 
250 
250 
1700 
12 
2.5g IV q 8h 
8.26 
17.97 
98.8 
8.94 
4.97 
62.56 
300 
250 
3500 
13 
2.5g IV q 8h 
14.66 
28.12 
156.2 
11.66 
3.17 
49.66 
250 
250 
2500 
 
 
 
 

13 
 
Pharmacokinetic Parameters: Patients Receiving Renally-Adjusted Doses of CAZ-AVI. 
Five patients received non-standard dosing. Table 7 details the dose received, as well as the observed 
concentrations of both ceftazidime and avibactam at specific times following start of drug infusion. Figure 6 
show the concentration-time profiles of these patients for both ceftazidime (top panels) and avibactam (bottom 
panels).  
 
Table 7.  Measured Total Drug Values of Ceftazidime and Avibactam in Critically Ill Patients.  
Patient 
Dosing  
Creatinine 
clearance or RRT 
Actual Draw Time 
(hours)1 
Ceftazidime 
(µg/mL) 
Avibactam 
(µg/mL) 
7 
0.94g IV q 24h 
CRRT 
Pre-dose 
38.563 
8.692 
2.1 
76.049 
17.473 
3.3 
66.048 
16.391 
6.1 
58.712 
14.380 
7.4 
55.094 
13.026 
2 
0.94g IV q 48h 
HD2 
Pre-dose 
4.436 
1.056 
14.5 (Pre-HD) 
18.848 
4.643 
16.5 (Mid-HD) 
8.385 
1.845 
18.4 (Post-HD) 
4.790 
1.069 
5 
0.94g IV q 48h 
HD3 
2.4 (Pre-HD) 
23.864 
7.583 
5.9 (Post-HD) 
7.049 
1.721 
24.8 
7.742 
2.265 
48.1 
6.925 
2.099 
1 
1.25g IV q 8h 
42mL/min 
4.2 
61.665 
11.960 
6.1 
52.092 
10.208 
7.9 
46.306 
9.071 
16 
1.25g IV q 8h 
42mL/min 
2.0 
59.388 
8.903 
5.3 
51.557 
7.009 
1Time relative to start of drug infusion. 
2 Patient received a full 4-hour HD session with 1L ultrafiltration. Samples were collected immediately before, during, and after HD.   
3 Patient received a 3-hour HD session with 1.5L ultrafiltration. Samples were collected immediately before and after HD, as well as 24 
and 48 hours after the dose. The latter time point represents the trough values for this patient. 
 
 
 
 
 
 
 
 
 
 

14 
 
Figure 6: Concentration-time profiles of Patients Receiving Non-standard Dosing. 
 
 
 
 

15 
 
Pharmacodynamics and Target Attainment 
Ceftazidime free drug concentration was calculated by adjusting for 10% protein binding. To determine if 
patients in the study met pre-determined PD targets, we assessed the time free drug concentrations (fT) 
remained above the MIC and 4x MIC, using the CLSI susceptibility breakpoint for ceftazidime (8 µg/mL) as the 
representative MIC value. All patients dosed every 8 hours had ceftazidime exposures of 100% fT>MIC (Figure 
7). Both patients receiving intermittent dialysis achieved targets before, but not after HD. Excluding patients on 
HD, 56% of patients achieved exposures of 100% fT>4xMIC, an exposure reported to suppress the 
emergence of resistance [2].  
 
Figure 7. Target Attainment for Ceftazidime. 
 
 
For analysis purposes, we estimated the avibactam free drug concentration using 10% protein binding as well 
[3]. Although PD targets are not as well elucidated for β-lactamase inhibitors, we used surrogate targets of 1 
and 2.5 µg/mL and evaluated free trough concentrations of avibactam. As shown in Figure 8, 95% and 90% of 
patients met targets of 100% fT>1 µg/mL and >2.5 µg/mL, respectively [2-4]. Only one patient (patient #17) 
with normal function on a standard 2.5g q8h dose did not meet targets.   
 
 
 
0%
20%
40%
60%
80%
100%
All Patients
Standard Dosing
Standard, Normal
Function
Standard, CRRT
Non Standard Dosing
% Patients
Ceftazidime Target Attainment
Above 8ug/mL
Above 32ug/mL

16 
 
Figure 8. Target Attainment for Avibactam. 
 
 
Safety 
The safety of ceftazidime-avibactam has been well-defined for patients with normal renal clearance, but not for 
patients receiving standard doses during CRRT. We assessed 6 such patients as part of this study to ensure 
exposures, which clearly met PD targets, were not associated with undue toxicity. Among the 6 patients 
receiving 2.5g IV q 8h on CRRT (Table 2), 50% died within 72 hours of sample collection due to underlying 
multi-system organ failure.  One additional patient was transitioned to HD the day after study enrollment. The 
last two patients received treatment courses of 12 and 14 days with no apparent toxicity, including 
myelosuppression, neurotoxicity, or further renal toxicity.  
 
 
 
0%
20%
40%
60%
80%
100%
All Patients
Standard Dosing
Standard, Normal
Function
Standard, CRRT
Non Standard Dosing
% Patients
Avibactam Target Attainment
Above 1ug/mL
Above 2.5ug/mL

17 
 
References.  
 
1. 
Shields, R.K., et al., Pneumonia and Renal Replacement Therapy Are Risk Factors for Ceftazidime-
Avibactam Treatment Failures and Resistance among Patients with Carbapenem-Resistant 
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18 
 
Appendix. 
Observed Drug Concentrations.  
Patient 
# hours post start of infusion 
Total Measured CAZ (µg/mL) 
Total Measured AVI (µg/mL) 
1 
4.22 
61.665 
11.960 
  
6.08 
52.092 
10.208 
  
7.92 
46.306 
9.071 
2 
-2.28 
4.436 
1.056 
  
14.50 
18.848 
4.643 
  
16.50 
8.385 
1.845 
  
18.42 
4.790 
1.069 
3 
-0.70 
69.076 
12.027 
  
2.47 
149.718 
29.957 
  
4.02 
114.670 
20.922 
  
5.85 
87.003 
14.256 
  
8.15 
57.749 
8.816 
4 
1.05 
114.512 
19.102 
  
2.13 
124.009 
19.293 
  
4.13 
59.349 
6.936 
  
5.63 
46.217 
4.894 
  
6.13 
40.060 
4.245 
  
8.63 
25.943 
2.461 
  
-0.25 
26.280 
2.302 
5 
2.42 
23.864 
7.583 
  
5.92 
7.049 
1.721 
  
24.83 
7.742 
2.265 
  
29.20 
8.935 
2.596 
  
48.07 
6.925 
2.099 
6 
2.33 
71.190 
12.212 
  
4.45 
36.178 
4.575 
  
6.40 
27.501 
3.054 
  
7.28 
23.193 
2.521 
7 
-0.12 
38.563 
8.692 
  
2.05 
76.049 
17.473 
  
3.30 
66.048 
16.391 
  
6.13 
58.712 
14.380 
  
7.35 
55.094 
13.026 
8 
0.05 
45.727 
10.111 
  
2.55 
60.427 
13.428 
  
6.30 
49.106 
10.919 
  
8.58 
47.102 
10.487 
9 
-0.17 
22.724 
5.042 
  
2.45 
104.953 
23.793 
  
3.03 
78.604 
17.805 

19 
 
  
3.93 
60.631 
13.852 
  
5.98 
41.508 
9.548 
  
7.97 
31.745 
7.291 
10 
-0.18 
80.026 
20.284 
  
0.85 
140.574 
33.392 
  
1.98 
162.853 
38.147 
  
3.87 
156.434 
36.869 
  
6.00 
138.158 
34.962 
11 
0.00 
53.859 
14.073 
  
1.12 
83.329 
20.740 
  
2.47 
75.611 
19.423 
  
4.17 
82.851 
20.739 
  
6.08 
63.154 
16.557 
  
7.92 
45.877 
11.657 
12 
-0.03 
30.852 
8.260 
  
2.25 
70.914 
17.969 
  
4.25 
47.960 
12.786 
  
6.13 
40.304 
10.379 
  
8.00 
35.450 
9.563 
13 
-0.10 
68.263 
14.656 
  
1.07 
98.623 
21.050 
  
2.08 
122.983 
28.116 
  
4.02 
88.581 
19.227 
  
6.10 
77.589 
16.771 
  
8.10 
69.466 
15.085 
14 
1.02 
66.823 
13.196 
  
2.43 
75.367 
14.827 
  
4.02 
63.294 
12.060 
  
6.10 
48.993 
9.059 
  
8.02 
35.207 
5.852 
  
-0.62 
36.211 
5.340 
  
1.12 
97.037 
17.224 
15 
-1.75 
31.124 
5.997 
  
0.83 
33.864 
6.882 
  
1.92 
61.286 
13.123 
  
4.00 
29.411 
5.797 
  
5.90 
22.595 
4.390 
  
7.10 
19.758 
3.679 
16 
1.97 
59.388 
8.903 
  
5.33 
51.557 
7.009 
17 
2.03 
95.156 
16.796 
  
4.03 
41.400 
5.188 
  
5.95 
23.634 
2.358 
  
8.03 
12.392 
0.994 
18 
5.47 
47.534 
11.478 

20 
 
  
7.87 
32.785 
8.997 
19 
-0.97 
88.724 
14.151 
  
1.20 
158.668 
30.242 
  
3.20 
128.146 
21.859 
  
5.20 
100.281 
15.687 
  
7.20 
76.658 
10.822 
20 
-0.08 
29.811 
2.762 
  
2.42 
80.068 
11.926 
  
4.25 
46.112 
5.162 
  
6.08 
33.278 
3.229 
  
8.13 
21.301 
1.792