A Study of Avycaz (Ceftazidime/Avibactam) Pharmacokinetics/Pharmacodynamics (PK/PD) in Critically Ill Patients
Phase: PHASE1
Conditions: Pharmacokinetics of Avycaz in ICU Patients
Sponsor: Michigan State University

Study Title:   
 
A study of Avycaz (ceftazidime/avibactam)  
Pharmacokinetics/Pharmacodynamics (PK/PD) in Critically Ill  
Patients 
 
Protocol Version Date:  
Revised April 4, 2016  
 
Primary Investigator Name: 
Gary E. Stein, PharmD 
 
Primary Investigator Address: Professor of Medicine and Pharmacology 
Michigan State University 
B320 Life Science Building 
East Lansing, MI 48824 
 
 
1 
STUDY RATIONALE/BACKGROUND 
Avycaz is a new cephalosporin (ceftazidine)/beta-lactamase (avibactam) inhibitor combination antibiotic 
which has been approved by the FDA for treatment of complicated UTI and IA infections.  Ceftazidime is 
a third generation cephalosporin with good activity against gram-negative rods (GNR) and has been 
marketed in the U.S. since 1985 for a variety of bacterial infections (1).  Avibactam is a new non-beta-
lactam/beta-lactamase inhibitor.     
The addition of avibactam improves ceftazidime’s activity against Pseudomonas aeruginosa and many 
extended-spectrum beta-lactamase (ESBL)-producing gram-negative pathogens.  Ceftazidime/avibactam 
is the first beta-lactam/beta-lactamase inhibitor combination to have activity against some carbapenem-
resistant Enterobacteriaceae, including those that produce Klebsiella pneumoniae carbapenemase (KPC), 
the most common carbapenemase in the U.S.(2). 
A PK/PD analysis of Avycaz in patients with medical or post-surgical infections in the ICU has not been 
conducted.  These studies are critical to understanding appropriate dosing of beta-lactams in critically ill 
patients and important for comparison against other newer agents. 
2 
 STUDY HYPOTHESIS 
Failure with emerging antibiotics in critically ill patients is an ongoing challenge.  Effective antibiotic 
therapy is crucial for improving outcomes in these patients.  Compared to healthy volunteers, both the 
volume of distribution and clearance of antibiotics can be altered in critically ill patients (3).  Moreover, 
altered protein binding can also occur in severely ill patients (4).  These variations in PK can affect the 
antimicrobial activity of antibiotics in patients in the ICU (5).  Several studies have shown altered PK for 
beta-lactams in critically ill patients (6).  Most recently, the Vd of doripenem in ICU patients was found 
to be significantly higher (2-times) than in healthy subjects (7).  This finding is similar to our study of 
doripenem in neutropenic patients (8).  
Obtaining only PK parameters is useful for comparison to healthy subjects but does not provide 
documentation on microbiologic efficacy.  The use of serum to analyze PD efficacy has been shown to be 
a better estimate of activity compared to in vitro studies, because one uses actual serum antibiotic 
levels with serum factors to determine microbiological activity (9).  Monte-Carlo simulations using PK 
parameters are also useful to define appropriate dosing schedules in patients with altered PK (8).   

2.1 
PRELIMINARY DATA  
A study of ceftazidime in acutely ill hospitalized elderly patients found that clearance was 
reduced, T ½ increased, and the volume of distribution was reduced (10).  In surgical patients 
with IA infection, the disposition of ceftazidime was dependent on CrCl and Vd and not altered 
by surgery or infectious process (11).  The higher dose and longer dosing administration of 
Avycaz may enhance its activity against MDR pathogens in critically ill patients. 
3 
STUDY OBJECTIVE AND ENDPOINTS 
3.1 
STUDY OBJECTIVE 
To analyze the PK/PD of AvyCaz in critically ill patients in the Intensive Care Unit (12). This study 
will include medical and post-surgical patients who develop an infection where Avycaz can be 
utilized.  Since these patients will have variable PK parameters, we will also analyze (time-kill) 
these serum concentrations (ex vivo) against relevant clinical isolates (e.g. GNR with ESBL or 
KPC) from the ICU to determine microbiologic activity of Avycaz in critically ill patients with 
variable characteristics. Monte-Carlo simulations will also be conducted against clinical ICU 
isolates (JMI labs) to help determine appropriate dosing schedules based upon these PK 
parameters. 
3.2 
STUDY ENDPOINTS 
3.2.1 
PRIMARY ENDPOINT:   
A pharmacokinetic analysis of Avycaz in critically ill patients.  
3.2.1.1 PRIMARY ENDPOINT DEFINITION:   
PK parameters such as Vd, Cl and T½. 
3.2.2 
SECONDARY ENDPOINT(S):   
A pharmacodynamic (time-kill) analysis of Avycaz against selected organisms in critically 
ill patients as well as Monte-Carlo simulations using these PK parameters for dosing of 
MDR pathogens. 
3.2.2.1 SECONDARY ENDPOINT DEFINITION(S):   
Time-kill curves and Monte-Carlo simulations against selected GN bacteria using 
obtained sera. 
4 
STUDY DESIGN 
4.1 
CLINICAL STUDIES (INCLUDING STEWARDSHIP GRANTS) 
4.1.1 
SITES  
This study will be conducted at Sparrow Hospital, Lansing, MI (Level 1 trauma center) by 
the investigators listed below, including John Kepros, MD, chief of Trauma Surgery and 
Daniel Havlichek MD, ID Division Chief.  This hospital is affiliated with Michigan State 
University and the Mayo Clinics.  Patients in the Medical/Surgical ICU commonly 

develop infections such as skin/soft tissue infections, urinary infections, IA infections 
and pneumonia (including VAP).  Ceftazidime has been used clinically for these 
infections for the past 30 years.  Samples for this investigation will be obtained from 
medical and post-surgical infected patients in the ICU.  High volumes of antibiotics are 
used in these patients. 
4.1.2 
INCLUSION CRITERIA 
 
• 
Adult (≥18y/o) patients with a medical or post-surgical infection such as 
skin/soft tissue infections, urinary infections, IA infections and pneumonia 
(including VAP) 
 
       Patients  requiring intensive care (critically ill patients) in the med/surg ICU    
              (APACHE II score ≥ 15) 10 with a mean ≥15 for these patients) 
• 
Patients prescribed Avycaz for their infection will receive FDA recommended 
dosages and times of administration 
• 
Written informed consent 
 
4.1.3 
EXCLUSION CRITERIA 
 
• 
Pregnant Patients, patients older than 90 y/o, those with CrCl < 30 mL/min, 
patients with a BMI > 45 Kg/m2, patients unable to provide serum samples, and 
those with the risk of imminent death during the study 
 
4.1.4 
SAMPLE SIZE AND DETERMINATION 
12 patients is sufficient for PK analysis [similar to other PK studies] 
4.1.5 
RANDOMIZATION 
Prospective, open-label, non-randomized study  
4.1.6 
TREATMENT 
Avycaz 2500 mg (1250 mg for CrCl 31-50 mL/min) IV over 120 minutes, every 8 hours 
[other antibiotics can also be administered as needed].  Patients will receive at least 3 
doses (steady-state) of Avycaz prior to obtaining serum samples. 
4.1.7 
INTERVENTION 
The only treatment intervention will be the use of Avycaz when empirically or directly 
needed to treat a medical or post-surgical infection.  The duration of treatment and the 
use of other antibiotics, such as vancomycin, will be determined by the attending 
physician(s). 
Blood samples (after at least 3rd dose) will be obtained at 2, 4, 6, 8 hours after starting 
the 2h IV infusion.  These four collection times will allow for determination of serum PK 
and provide concentrations relevant for PD (time-kill) and Monte-Carlo determinations. 
4.2 
NON-CLINICAL STUDIES 
4.2.1 
SITES  

See above (single site study) 
4.2.2 
PRIMARY METHODS  
Patient serum at each collection time point will be used to determine time-kill curves 
against strains of Avycaz-susceptible GNR.  These ex vivo PD experiments will be helpful 
to determine the effectiveness of Avycaz to inhibit the replication of GN bacteria in 
serum.  These experiments have enhanced value compared to in vitro studies because 
they test actual clinical levels, including protein binding, of Avycaz against relevant 
pathogens.  These investigations will be conducted in the ID lab at Michigan State 
University (Dr. Stein).  Monte-Carlo simulations will be determined using the PK 
parameters obtained against various MDR pathogens (MIC90) such as P. aeruginosa (MIC 
= 4 mg/L) and CRE (eg. KPC = 4mg/L) (Dr. Nicolau, co-investigator).   
4.2.3 
SAMPLE SIZE AND DETERMINATION 
See above  
4.2.4 
TREATMENT 
See above  
5 
DATA COLLECTION AND ANALYSIS 
5.1 
DATA COLLECTION 
Patients 
• 
Patient demographic data (Ht, Wt, Age, BMI) as well as renal/liver function tests will be 
collected for each patient.  Medical co-morbidities as well as APACHE II scores will also 
be recorded.  Serum will be collected from subjects as stated above and frozen at -70°C 
until analysis. 
• 
Ceftazidime and avibactam concentrations will be determined by LC-MS/MS analysis per 
Dr. Nicolau (co-investigator). 
• 
PK parameters (mean ± SD) will be calculated from serum samples per Dr. Smith (co- 
Investigator).  
Serum drug concentrations from study patients will be used to develop a 
pharmacokinetic model for critically ill patients with infections.   
 
 
Ex Vivo: 
• 
Antimicrobial activity for selected GNR (ESBL + KPC isolates) will be determined and 
tested against each patient serum at each collection time. 
• 
The geometric mean changes in bacterial density at each time point (n=12 patients) will 
be used to construct time-kill curves of Avycaz against selected GNR pathogens. The 
MIC90 for Avycaz against selected ICU clinical isolates (eg., KPC, ESBL E. coli) obtained 
from JMI labs (National Database) will be used in these time-kill experiments:  
 
CTX-M-15 MIC = 1.0 mg/L 
 
ESBL E. coli MIC = 0.25 mg/L 
 
ESBL K. pneumoniae MIC = 1.0 mg/L 
 
KPC MIC = 4.0 mg/L 

● 
Monte-Carlo simulations will also be conducted against these selected ICU pathogens. 
These simulations will be performed using the PK model derived from patient data.  The 
MIC data for the Monte Carlo simulations will be obtained from a national database and 
targets for Monte Carlo simulations will be %fT>MIC for ceftazidime and %fT>threshold 
concentrations for avibactam. 
 
5.2 
DATA / STATISTICAL ANALYSIS 
The PK analysis will be conducted with standard software (Phoenix WinNonLin Version 6.3) by 
Dr. Curtis Smith.  The mean ± SD will be calculated for each PK parameter.  Time-kill curve data 
will be determined as the geometric mean kill at each time point (n=12) for each tested GN 
isolate (Dr. Stein).  Monte-Carlo analyses will be conducted using 5000-patient simulations 
(Crystal Ball 2000 Professional Edition) against various (see above) isolates (Dr. Nicolau). 
6 
PUBLICATION 
 
• 
A summary report will be sent to Allergan following all data analysis. 
• 
An abstract will be sent to a local meeting (MIDS) as well as to a National meeting such 
as ICAAC or ID-week. 
• 
A paper for publication will be written and sent to a pharmacy or antibiotic journal (eg. 
AAC, JAC, Pharmacotherapy) 
• 
The investigators have conducted and published several PK/PD papers on newer 
antibiotics as well as Monte-Carlo simulations including a study of Teflaro in 
neurosurgical patients (8,13,14).   
 
7 
TIMELINE 
IRB/Contract Approval and Study Initiation  
 
3 months 
 
Patient Enrollment/Sample Procurement 
 
6 months 
 
Data Analysis/Study Report/Publication  
 
3 months 
 
 
 
 
 
Total   
 
12 months 
8 
 REFERENCES 
1.  Med Letter. 1985;27:85. 
2.  Med Letter. 2015;57:79. 
3.  Nandy et al.  AAC. 2010;54:2354. 
4.  Liebchen et al.  JAC. 2014;69:3108. 
5.  Udy et al.  Intern J Antimicrob Agents 2012;39:455. 
6.  Roberts et al.  IJAA. 2012;39:187.  
7.  Abdul-Aziz et al.  AAC. 2016;60:206. 
8.  Stein et al.  Ann Pharmacother. 2012;46:1281. 

9.  Leggett et al.  AAC. 1989;33:35. 
10.  Jonssan et al.  EJCMID. 1992;11:15. 
11.  Heim-Duthoy et al.  AAC. 1988;32:1845. 
12.  Roberts et al.  JAC. 2015;70:1495. 
13.  Stein et al.  JAC. 2013;68:2852. 
14.  Stein et al.  Surg Infections. 2015;16:169.