A Pilot Study of Ceftolozane-Tazobactam in Conjunction With Rapid Molecular Diagnosis for Directed Treatment of Pseudomonas Aeruginosa Bacteremia and Pneumonia in Patients With Hematological Malignancies and Hematopoietic Stem Cell Transplantation
Phase: PHASE4
Conditions: Pneumonia, Hematologic Malignancy, Pseudomonas Aeruginosa Infection, Bacteremia, Hematopoietic Stem Cell Transplant (HSCT)
Sponsor: Weill Medical College of Cornell University

 
Title: A Pilot Study of Ceftolozane-Tazobactam in Conjunction with Rapid Molecular Diagnosis for 
Directed Treatment of Pseudomonas aeruginosa Bacteremia and Pneumonia in Patients with 
Hematological Malignancies and Hematopoietic Stem Cell Transplantation 
 
NCT Number: NCT04673175 
 
Document Date: 09/09/2025 

WCM Protocol No:
19-11021048 
Amendment:
AM007 
Version Date:
9/9/2025 
 
 
1 
Title: A Pilot Study of Ceftolozane-Tazobactam in Conjunction with Rapid Molecular 
Diagnosis for Directed Treatment of Pseudomonas aeruginosa Bacteremia and Pneumonia 
in Patients with Hematological Malignancies and Hematopoietic Stem Cell Transplantation 
 
Principal Investigator
Markus Plate, MD
Institution
Weill Cornell Medical College
Associate Investigators 
Catherine Small, MD 
Michael J. Satlin, MD, MS 
Tsiporah Shore, MD 
Gail Roboz, MD 
Alex Drelick, MD 
Rosy Priya Kodiyanplakkal, MD 
Matthew McCarthy, MD 
Lars Westblade, PhD
 
 
Weill Cornell Medicine of Cornell University 
New York Presbyterian Hospital 
1300 York Ave., Rm A-424A 
New York, NY 10065 
TEL: 212-746-4960 
FAX: 212-746-8675 
 
 
Précis 
Background 
 The primary empirical treatment of patients with hematological malignancies is being 
eroded by the emergence of multi-drug resistance. There is a limit to the armamentarium 
of agents that is validated for use in profoundly neutropenic or highly 
immunocompromised patients with hematological malignancies and HSCT.  
 Ceftolozane/tazobactam is an important advance in the treatment of infections caused by 
Pseudomonas aeruginosa 
 Based upon our in vitro and in vivo data as well as the current challenges of emergence 
of primary resistance, we propose instead that ceftolozane/tazobactam be used in patients 
with hematological malignancies in HSCT as frontline initial therapy for life-threating 
Pseudomonas aeruginosa infections 
 
Objectives 

 
 
2 
 To define the efficacy of ceftolozane/tazobactam in treatment of life-threatening 
pneumonias and bacteremia caused by Pseudomonas aeruginosa in patients with 
hematological malignancies and stem cell transplantation (HSCT) in the setting of 
rapid molecular diagnosis. 
 To document the in vitro activity and prevention of emergence of 
ceftolozane/tazobactam resistance during treatment of Pseudomonas aeruginosa 
bacteremia and pneumonia in this population. 
 
Eligibility 
 Presence of hematologic malignancy or HSCT. 
 Identification of Pseudomonas aeruginosa by rapid molecular diagnostic assay from a 
blood culture or from a respiratory sample in the setting of radiologically documented 
pneumonia and clinical symptoms compatible with pneumonia. 
 
Design 
 This is a prospective, single arm, open label study of ceftolozane/tazobactam (IV 3g q8h 
(or equivalent adjustment for renal dysfunction) x 10-14 days) for the primary treatment 
of culture-confirmed Pseudomonas aeruginosa bacteremia and/or pneumonia in patients 
with hematological malignancies and hematopoietic stem cell transplantation with 
contemporaneous case control matching. In patients with persistent or refractory 
bacteremia or pneumonia, duration of therapy may be extended to a total of 21 days. 
 
 

 
 
3 
1 
Introduction 
1.1 
Study Objectives 
1.1.1 Primary Objectives 
 To define the efficacy of ceftolozane/tazobactam in treatment of life-threatening 
pneumonias and bacteremia caused by Pseudomonas aeruginosa in patients with 
hematological malignancies and stem cell transplantation (HSCT) in the setting of 
rapid molecular diagnosis. 
 
1.1.2 Secondary Objective 
 To document the in vitro activity and prevention of emergence of 
ceftolozane/tazobactam resistance during treatment of Pseudomonas aeruginosa 
bacteremia and pneumonia in this population. 
1.2 
Background and Rationale 
1.2.1  Loss of effective antimicrobial agents 
The primary empirical treatment of patients with hematological malignancies is being eroded by 
the emergence of multi-drug resistance [1]. There is a limit to the armamentarium of agents that 
is validated for use in profoundly neutropenic or highly immunocompromised patients with 
hematological malignancies and HSCT [2]. These include ceftazidime, cefepime, 
piperacillin/tazobactam, imipenem, and meropenem. 
1.2.2  Rationale for primary use of C/T for treatment of Pseudomonas infections in 
hematological malignancies coupled with rapid molecular diagnosis 
Ceftolozane/tazobactam is an important advance in the treatment of infectious caused by 
Pseudomonas aeruginosa [3-5]. Positioning ceftolozane/tazobactam as the primary treatment for 
Pseudomonas aeruginosa bacteremia and pneumonia in this immunocompromised patient 
population with hematological malignancies and HSCT could have a profound effect in 
improving outcome from these life-threatening infections. Once Pseudomonas bacteremia or 
pneumonia would be documented in this population, rather than continuing conventional agents 
for which there is a high likelihood for emergence of resistance and failure, 
ceftolozane/tazobactam instead could be used as primary therapy. Using ceftolozane/tazobactam 
for these documented Pseudomonas infections could establish a paradigm shift for this new 
antimicrobial agent targeted specifically to Pseudomonas infection in our most vulnerable patient 
population. 
 
The current use of ceftolozane/tazobactam in patients with hematological malignancies and 
HSCT is relegated to salvage therapy after all other avenues have been exhausted.  
 

 
 
4 
Based upon our in vitro and in vivo data as well as the current challenges of emergence of 
primary resistance, we propose instead that ceftolozane/tazobactam be used in patients with 
hematological malignancies in HSCT as frontline initial therapy for life-threating Pseudomonas 
aeruginosa infections. Given the devastating consequences of progressive Pseudomonas 
bacteremia and pneumonia in this population, allowing for emergence of resistance creates the 
risk of increased mortality and morbidity. Using ceftolozane/tazobactam as initial therapy for 
Pseudomonas bacteremia and pneumonia in this highly vulnerable population would also be 
consistent with high standards of antimicrobial stewardship by conserving the use of 
carbapenems. 
 
The use of ceftolozane/tazobactam for primary treatment of life-threating Pseudomonas 
aeruginosa bacteremia and pneumonia in patients with hematological malignancies and HSCT 
would be a transformative advance in the management of these highly vulnerable patients. 
1.2.3 Preclinical data in support of C/T for treatment of multidrug resistant Pseudomonas 
aeruginosa infections 
We recently conducted a study of ceftolozane/tazobactam in humanized doses that simulate 3 
grams every 8 hours in the persistently neutropenic rabbit model Pseudomonas aeruginosa 
pneumonia [6]. The model closely simulates the clinical, microbiological, histological and 
radiological manifestations of Pseudomonas pneumonia in profoundly immunocompromised 
patients with the hematological malignances. This model is distinctive from that of traditional 
murine models in that (1) treatment of 12 to 14 days is achieved, (2) untreated controls have the 
duration of survival of approximately 7 days, (3) the emergence of resistance can be detected 
over the course of time, and (4) profound persistent neutropenia is achieved to the level of that 
seen in patient with hematological malignances. The data from this animal model system in 
collaboration with Merck colleagues demonstrated that ceftolozane/tazobactam when 
administered in a humanized dose simulating 3 grams every 8 hours allows for potent eradication 
of Pseudomonas aeruginosa of wild type, efflux pump expression, AmpC hyper-expression, and 
porin loss. 
 
Plasma exposure over the dosage range of TZC from 26 mg/kg//13 mg/kg to 53 mg/kg//26 
mg/kg reflected the plasma pharmacokinetic parameters observed in humans. The exposure of 
375.83 ± 23.84 hr∙µg/mL achieved by 53 mg/kg//26 mg/kg is comparable to that of the adult 
human dose of 2 g ceftolozane. Treatment with TZC resulted in 105 reduction in residual 
bacterial pulmonary burden caused by all 4 strains (p0.01). This antibacterial activity coincided 
with reduction of lung weight (p<0.05), which is a marker of organism-mediated pulmonary 
injury. CTZ was less active in ACHE-infected rabbits, while TZP had less activity in EPE, 
ACHE, and OPRDPL strains. Survival was prolonged in TZC and CTZ treatment groups in 
comparison to that of TZP and UC (p<0.001). 

 
 
5 
Ceftolozane Plasma Mean Concentrations after Multiple Dosing
0
2
4
6
8
0
100
200
300
400
Time (h)
mcg/mL
26.30 mg/kg
53.3 mg/kg
106.6 mg/kg
 
 Plasma pharmacokinetics of ceftolozane on day 6 after intravenous administration of 
ceftolozane/tazobactam at 40, 80, and 160 mg/kg Q8h to healthy New Zealand white rabbits. 
 
0
200
400
600
0
50
100
AUC (µr.ng/mL)
Dosage (mg/kg)
AUC vs Dosage Correlation
r = 0.9136 (p = 0.0001) 
0
200
400
600
0
50
100
AUC(hr.ng/mL)
Dosage (mg/kg)
Mean Dosage vs AUC
 
Dose proportionality of ceftolozane administered as ceftolozane/tazobactam across dosages of 
26.6 and 53.3 mg/kg IV. 
 
Plasma pharmacokinetic parameters of ceftolozane/tazobactam on day 6 after intravenous 
administration of ceftolozane/tazobactam Q8h to healthy NZW rabbits 
 
Ceftolozane 
Dosage (mg/kg) 
AUC(o-8) 
Cmax 
CL 
Vd 
 
(hr∙µg/mL) 
(µg/mL) 
(mL/hr/kg) 
(mL/kg) 
26 
155.87 ± 15.02 
137.56 ± 20.02 
162.23± 17.22 
173.64 ± 17.53 
53 
375.83 ± 23.84 
325.96 ± 27.62 
142.13 ± 9.01 
161.18 ± 6.29 
106 
494.06 ± 14.00 
356.74 ± 27.04 
212.29 ± 5.51 
216.58 ± 10.47 
Tazobactam 
Dose (mg/kg) 
AUC(o-8) 
Cmax 
CL 
Vd 
 
(hr∙µg/mL) 
(µg/mL) 
(mL/hr/kg) 
(mL/kg) 
13 
15.50 ± 4.73 
20.77 ± 8.16 
1199.18 ± 487.82 
248.35 ± 65.07 
26 
30.09± 4.82 
47.84 ± 9.28 
929.57 ± 127.33 
154.14 ± 16.65 
53 
25.18 ± 6.81 
33.67 ± 9.62 
2613.92 ± 747.69 
638.25 ± 167.30 
 

 
 
6 
 
 
Pulmonary bacterial burden and lung weights (markers of organism-mediated pulmonary injury) 
in rabbits with experimental Pseudomonas aeruginosa pneumonia treated with ceftolozane 
tazobactam (TZC), ceftazidime (CTZ), and piperacillin/tazobactam (TZP) according to 
mechanism of resistance. The normal lung weight for rabbits used in this study is approximately 
15 g. 
 
Pan-Susceptible Cumulative Survival Probability (%)
0
1
2
3
4
5
6
7
8
9
10
11
12
13
0
25
50
75
100
Time
Control
TZC
CTZ
TZP
 OPRD Cumulative Survival Probability (%)
0
1
2
3
4
5
6
7
8
9
10
11
12
13
0
25
50
75
100
Time
Control
TZC
CTZ
TZP
 AmpC Cumulative Survival Probability (%)
0
1
2
3
4
5
6
7
8
9
10
11
12
13
0
25
50
75
100
Time
Control
TZP
TZC
CTZ
Efflux pump expression
Cumulative Survival Probability (%)
0
1
2
3
4
5
6
7
8
9
10
11
12
13
0
25
50
75
100
Time
Control
TZC
CTZ
TZP
 
Survival in rabbits with experimental Pseudomonas aeruginosa pneumonia treated with 
ceftolozane tazobactam (TZC), ceftazidime (CTZ), and piperacillin/tazobactam (TZP) according 
to mechanism of resistance. 

 
 
7 
TZC ALL
Cumulative Survival Probability (%)
0
1
2
3
4
5
6
7
8
9
10
11
12
13
0
25
50
75
100
Time
Control
TZC
CTZ
TZP
 
 
Summary survival of rabbits with experimental Pseudomonas aeruginosa pneumonia treated 
with ceftolozane tazobactam (TZC), ceftazidime (CTZ), and piperacillin/tazobactam (TZP) 
summarized for all isolates. 
1.2.4 Clinical Implications of current preclinical studies of C/T in treatment of 
experimental Pseudomonas aeruginosa pneumonia 
Ceftolozane/tazobactam administered in humanized dosages achieved comparable plasma 
exposures in rabbits to permit detailed studies of experimental Pseudomonas aeruginosa 
pneumonia. Ceftolozane/tazobactam was highly active in treatment of experimental 
Pseudomonas aeruginosa pneumonia in persistently neutropenic rabbits, including infections 
caused by strains with the most common resistance mechanisms. 
 
The results of these preclinical studies clearly demonstrated potent activity of 
ceftolozane/tazobactam in treatment of experimental pneumonia caused by Pseudomonas 
aeruginosa expressing major resistant mechanisms. That the results were achieved with a 
humanized adult dose of 3g IV Q8h in persistently neutropenic animals over the course of 12 
days provides a solid foundation from which to develop a prospective clinical trial of 
Pseudomonas aeruginosa pneumonia and bacteremia in persistently neutropenic patients with 
hematological malignancies and HSCT recipients.  
 
The use of rapid molecular diagnostics in detection of Pseudomonas aeruginosa blood stream 
infection and/or pneumonia in this profoundly immunocompromised host population would then 
be transformative in improving survival. 
 
These findings were predictive of the recently completed phase 3 clinical trial 
(https://clinicaltrials.gov/ct2/show/NCT02070757), “A Prospective, Randomized, Double-Blind, 

 
 
8 
Multicenter, Phase 3 Study to Assess the Safety and Efficacy of Intravenous 
Ceftolozane/Tazobactam Compared With Meropenem in Adult Patients With Ventilated 
Nosocomial Pneumonia ((MK-7625A-008) (ASPECT-NP),” which demonstrated activity in 
treatment of this serious infection. In patients with positive lower respiratory tract cultures 
(70%), at baseline causative gram-negative pathogens were predominately Enterobacteriaceae 
(74%) and P aeruginosa (25%). Ceftolozane/tazobactam was found to be non-inferior to 
meropenem for the primary endpoint (28-day all-cause mortality (10% non-inferiority margin)) 
and the secondary endpoint (clinical response at test-of-cure (7-14 days after end-of-therapy; 
12.5% non-inferiority margin) in the intent-to-treat population). Mortality was higher in 
meropenem-treated patients with vHABP.  
 
These data have now led to the recently FDA-approved indication for the 3 gram Q8h dose of 
ceftolozane/tazobactam as a regimen for the treatment of ventilator-associated pneumonia. 
2 ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1 
Eligibility Criteria  
Patients are eligible for enrollment into this clinical trial if they fulfill the inclusion criteria and 
they or their medical proxy sign informed consent. 
2.1.1 Inclusion Criteria  
1. Presence of hematologic malignancy or HSCT. 
2. Identification of Pseudomonas aeruginosa by rapid molecular diagnostic assay from a 
blood culture or from a respiratory sample in the setting of radiologically documented 
pneumonia and clinical symptoms compatible with pneumonia. 
3. Age: ≥18 years 
2.1.2 Exclusion Criteria  
1. Prior non-study anti-pseudomonal therapy for >72 hours 
2. Anaphylactic hypersensitivity or allergic reaction to cephalosporins 
3. History of a strain of Pseudomonas aeruginosa with MIC > 4 g/ml to 
ceftolozane/tazobactam 
4. Polymicrobial aerobic Gram-negative infection as determined by ID research team 
5. Hemodialysis, continuous renal replacement therapy, or creatinine clearance <15 ml/min 
6. Patients with expected mortality within 48 hours of screening 
 
Patients who complete this study and who subsequently experience a separate, recurrent 
Pseudomonas aeruginosa infection (as confirmed by the Principal Investigator) may be 
consented and enrolled in this study again if all eligibility criteria are met.  
 
2.1.3 Control group: Inclusion criteria includes 1-3, and exclusion criteria includes 2-5 as 
above. Historical control patients will be alive >48 hours from initiation of anti-pseudomonal 
therapy for Pseudomonas bacteremia and/or pneumonia. 

 
 
9 
2.2 
Eligibility Evaluation  
2.2.1 General  
2.2.1.1 The following elements will be evaluated to confirm study eligibility and 
provide baseline measurements, when appropriate: 
 medical history 
 physical and laboratory examination findings 
 immune status 
 hypersensitivities  
 current medications 
2.2.1.2 These measurements may be obtained from the primary treatment team 
evaluations or from the assessment of the research team. 
2.3 
Patient Registration  
2.3.1  All patients are registered on study once consent has been obtained. Historical 
controls will have a waiver for informed consent. 
3 Study Implementation 
3.1 
Study Design 
3.1.1 Overall Trial Design 
This is a prospective, open label study of ceftolozane/tazobactam (IV 3g q8h (or 
equivalent adjustment for renal dysfunction) x 10 – 14 days with matched historical 
controls; up to 21 days will be permitted for persistent or refractory bacteremia or 
pneumonia) for the primary treatment of culture-confirmed Pseudomonas aeruginosa 
bacteremia and/or pneumonia in patients with hematological malignancies and 
hematopoietic stem cell transplantation with contemporaneous case control matching. 
Ten patients will be enrolled to receive ceftolozane/tazobactam in the first year.  
If further review demonstrates feasibility, 10 more patients will be enrolled to receive 
ceftolozane/tazobactam the in the second year. 
Patients enrolled into the study will be matched 1:3, enrolled:control. For each 
prospectively enrolled subject, there will be 3 retrospective subjects from this patient 
population identified from patients managed at NYPH over the past five years with 
culture-confirmed Pseudomonas aeruginosa bacteremia and/or pneumonia. The 
retrospective controls will be reviewed and data collected via chart review only from July  
28, 2015 to December 31, 2022, with the same data elements obtained for enrolled and 
control subjects.  
Case matching will be performed on the following variables: 
1. 
bacteremia vs no bacteremia 
2. 
neutropenic vs non-neutropenic 

 
 
10 
The standard of care will be the best available anti-pseudomonal beta-lactam (cefepime, 
ceftazidime, piperacillin/tazobactam, or meropenem) +/- aminoglycoside or 
fluoroquinolone. 

 
 
11 
3.1.2 Study Flowchart 
 
 
 
 
 

 
 
12 
Activity
Screening
Day 
1  
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 
Day 
8 
Day 
9 
Day 
10 
Days 
11-28 
End 
of 
Studya
30-day 
Assessment 
60-day 
Assessment
Visit window 
D -1 to 
D1
± 1 
day
± 1 
day
± 1 
day
± 1 
day
± 1 
day
± 1 
day
± 1 
day
± 1 
day
± 1 
day
± 2 
days
± 2 
days
N/A 
± 7 days 
± 7 days 
Informed consent  
X 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
Inclusion/Exclusion  
X 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
Medical History, Demographics 
X 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
Rapid molecular diagnostic testing 
(for eligibility)
X 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
Prospective: Limited physical exam, 
including fever, RR, HR, BP 
(highest); resolution of sepsis; and 
presence of cutaneous lesions (rash, 
black lesions, petechiae, ecthyma, 
bullae blisters) 
 
Retrospective: Review of historic 
physical exam to identify fever, RR, 
HR, BP (highest); resolution of sepsis; 
and presence of cutaneous lesions 
(rash, black lesions, petechiae, 
ecthyma, bullae blisters)
X 
X 
 
 
 
X* any day here 
 
 
X 
 
 
 
 
Sp02 (lowest) and oxygen 
requirements (highest)
X 
X 
 
X 
 
 5 AND 7 
  
  
X 
 
 
 
 
Diagnostic imaging (ex. CT scans, 
chest x-rays) if obtained as standard 
of care (SOC) only (pulmonary 
infiltrates/opacities, pulmonary 
nodules, pleural effusions, 
groundglass opacities, 
lympthadenopathy, lung abcess, 
cavitary lesion)
X 
To be recorded in EDC if collected/completed as SOC 
  
  
BAL if obtained as standard of care 
(SOC) only (Gram stain and culture, 
cell count, protein, glucose) 
X 
To be recorded in EDC if collected/completed as SOC 
  
  
Repeat blood culture, if enrolled with 
bacteremia
  
Xb 
To be recorded in EDC if collected/completed as SOC 
  
  

 
 
13 
Table 1. Schedule of Assessments  
 
 
 
 
 
 
 
 
 
 
 
a Patients will be monitored per protocol for up to 8 weeks while inpatient. End of study will be 8 weeks or discharge, whichever is first. Patients will additionally be 
monitored for up to 6 months specifically for rehospitalizations for Pseudomonas bacteremia/pneumonia, ceftolozane-tazobactam resistance, and to collect associated 
treatment and outcomes. 
b Blood culture must be positive prior to initiation of ceftolozane-tazobactam if patient enrolled with bacteremia.  
c Study drug will be extended at these time points, unless daily blood cultures are negative for two sequential days.  
 
 
 
 
 
d Global Response Assessment to be completed once, at the end of treatment.  
e Completed at Day 10, or at hospital discharge if treatment duration not completed. 
 
 
 
 
 
 
 
 
 
 
f To be assessed by chart review, or phone visit, as appropriate.
Sub-culturing of any SOC 
microbiologic isolates, for molecular 
genetic testing and whole genome 
sequencing
Completed on any SOC microbiologic isolates obtained 
  
  
Administration of ceftolozane-
tazobactam 3g IV Q8h
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xc 
 
  
  
Global Response Assessment
  
Xd 
 
X 
X 
Karnofsky Performance Status
  
X 
  
  
  
  
  
  
  
  
Xe 
  
 
  
 X 
Survival Assessmentf
  
  
  
  
  
  
  
  
  
  
  
  
 
X 
X 
Hospitalization Status Assessment
  
Recorded throughout
 
X 
X 
Concomitant antimicrobials for 
treatment of infection under study, 
chemotherapy (yes/no), prednisone 
(yes/no)* at screening and through 
study
X 
Recorded throughout 
 
X 
X 
Serious Adverse Events Assessment 
(CTCAE Grade 4 and 5 only)
X 
X 
 
X 
X 
Adverse Events of Interest 
Assessment (renal failure, allergic 
reaction, leukopenia, elevated liver 
function values, Clostridium difficile 
infection) that meet CTCAE Grade 3 
and above
Recorded throughout 

 
 
14 
3.1.3 Pre-screening 
Screening for candidate patients would be conducted through several mechanisms. 
1. All blood cultures and BAL fluid obtained from patients will be screened with rapid molecular 
diagnostic systems using two platforms, as appropriate: 
a. 
BioFire Film Array Blood Culture Identification Panel (BCID) 
(https://www.biofiredx.com/products/the-filmarray-panels/filmarraybcid/) 
b. 
BioFire Film Array Pneumonia Panel (https://www.biofiredx.com/products/the-
filmarray-panels/filmarray-pneumonia/)  
2. Clinical Microbiology logs from blood cultures and from bronchoalveolar lavage cultures. 
3. Paging system from clinical microbiology laboratory in real time to team members “Dr. Satlin, 
Dr. Plate” 
4. Twice daily discussions with clinical microbiology, and primary care team for in patients and 
intensive care unit patients. 
5. Daily discussions with the Weill Cornell Medicine, NYPH transplantation-oncology infectious 
diseases team 
3.1.4  
Screening 
1-Patients who are identified as being eligible for study will be presented with informed consent 
explaining potential benefits and risks associated with the clinical trial. 
2-A history and physical examination will be conducted as well as review of relevant 
laboratories following signed and consent.  
3-Prior to administration of study drug, repeat blood cultures will be performed. 
 
3.1.5  
Enrollment/Day 1 
1-Written and informed consent, ceftolozane/tazobactam (3gIV q8h or renal equivalent) will be 
administered urgently from the NYPH pharmacy. 
 
3.4 
On Study Evaluation  
3.4.1 
General 
1. 
During the course of study, patients will be followed in the intensive care unit or 
the hematology oncology, HSCT floors under meticulous observation of the 
Transplantation Oncology Infectious Diseases staff. 
2. 
Protocol defined follow-up visits will be conducted thrice weekly. 
3. 
Blood cultures, diagnostic imaging, a CT scan, vital signs, and resolution of any 
cutaneous lesions (ecthyma gangrenous) will be monitored and obtained as 
standards of care. 
4. 
All clinical microbiological isolates including baseline and available follow-up 
isolates of Pseudomonas aeruginosa will be sub-cultured and preserved on agar 
slants for further assessment of antimicrobial susceptibility. Isolates will be 
further characterized for susceptibility to ceftolozane/tazobactam, as well as other 
advanced antimicrobial agents by reference broth microdilution methods.  

 
 
15 
5. 
Molecular genetic screening will also be performed for the presence of KPC, 
NDM, VIM, IMP and OXA-48 genes. Whole genome sequencing will be 
conducted on all baseline isolates and any isolates recovered at end of therapy. 
 
3.4.2. Outcome Parameters 
1. Primary outcome variable: Clinical success at day 30 from collection of the index 
culture (Shields et al. Lancet Inf Dis 2025), defined as meeting all of the following 
criteria: 
a) Survival 
b) Resolution or near resolution of baseline clinical manifestations, including 
fever, hypoxia, and signs or symptoms of sepsis  
c) Absence of recurrent infection due to P. aeruginosa or persistent infection 
despite >7 days of anti-pseudomonal therapy 
2. Secondary outcome variables: 
a) survival at 30 and 60 days (from time of initiation of anti-pseudomonal 
therapy), assessed by chart review or phone visit, as appropriate 
b) time to resolution of bacteremia, obtained from blood cultures 
c) length of stay, obtained from Hospitalization Status Assessment 
d) emergence of resistant isolates 
e) time to appropriate therapy, obtained from assessing concomitant medications 
f) resolution of baseline clinical manifestations, obtained from physical exam 
assessments 
g) modifications to initial antimicrobial therapy, obtained from assessing 
concomitant medications 
h) the emergence of other bacteria during the course of therapy, obtained from 
blood cultures 
i) number of days on ventilator, as measured by the Ordinal Scale, Assessment 
of Clinical Status 
j) ICU length of stay, obtained from Hospitalization Status Assessment 
3.4.3. Study Duration 
The study will last one year, during which time, we anticipate enrollment of 10 patients with 
Pseudomonas aeruginosa infection. If the study enters a second phase, then another 10 patients 
will be enrolled in the following year. 
Patients will be followed throughout their hospitalization for a minimum of three scheduled 
visits per week during treatment with ceftolozane/tazobactam. 
3.5 
Concurrent Therapies  
3.5.1  
Combination therapy 
Combination antimicrobial therapy is permitted on this protocol for treatment of 
Gram-positive bacterial infections, anaerobic infections with metronidazole, 
invasive fungal infections, and viral infections.  

 
 
16 
 
3.6 
Off Study Criteria 
3.6.1 Criteria for removal from protocol 
 Persistent elevation of hepatic transaminases >10x ULN for > 72 hours. 
 Discretion of the primary physician. 
 Patient desires to discontinue study. 
 Patient expires. 
 MIC of C/T is found to be > 4 μg/mL for the infecting pathogen. 
3.6.2 End of treatment 
Patients will be monitored per protocol for up to 8 weeks while inpatient. End of study will be 8 
weeks or discharge, whichever is first. Patients will additionally be monitored for up to 6 months 
specifically for rehospitalizations for Pseudomonas bacteremia/pneumonia, ceftolozane-
tazobactam resistance, and to collect associated treatment and outcomes. 
 
4 
SUPPORTIVE CARE  
Supportive care will be provided through the patient’s primary treatment protocol.  
5  
DATA COLLECTION AND EVALUATION 
5.1 
Data Collection 
The principal investigators will be responsible for the collection, maintenance, and quality 
control of the study data. C/T treated patient data will be prospectively collected and recorded by 
individual AIs responsible for study data. Toxicity and response data will be entered into the 
database at least once every 2 weeks.  
5.1.1 Data Elements 
5.1.1.1 
H&P data: signs and symptoms of toxicity 
5.1.1.2 
Karnofsky Performance Status (Appendix B) 
5.1.1.3 
Laboratory microbiological data 
5.1.1.4 
Results of scans and radiographs 
5.2 
Response criteria 
The primary endpoint of clinical success at day 30 includes  
a) Survival and 
b) Resolution of baseline clinical manifestations, including fever, hypoxia, and signs or 
symptoms of sepsis 
c) Absence of recurrent infection due to P. aeruginosa or persistent infection despite >7 
days of anti-pseudomonal therapy 

 
 
17 
 
The secondary outcome variables: 
a) survival at 30 and 60 days (from time of initiation of anti-pseudomonal therapy) 
b) time to resolution of bacteremia 
c) length of stay 
d) emergence of resistant isolates 
e) time to appropriate therapy 
f) resolution of baseline clinical manifestations 
g) modifications to initial antimicrobial therapy 
h) the emergence of other bacteria during the course of therapy 
 
5.3 
Toxicity Criteria 
This study will utilize the Cancer Therapy Evaluation Program Common Toxicity Criteria 
Adverse Event Reporting (CTCAE) Version 5.0 for classification of the SAE by type and grade. 
A copy of the CTCAE version 5.0 can be downloaded from the CTEP home page 
(http://ctep.info.nih.gov). All appropriate treatment areas should have access to a copy of the 
CTCAE version 5.0 
5.4 
Statistical Considerations 
5.4.1 
Subject Accrual 
Subjects of both genders, from all racial and ethnic groups are eligible for this 
trial if they meet the criteria outlined in Section 2.1.  
5.4.2 
Statistics and Feasibility 
As this clinical trial is a pilot study, sample size determination is based on 
feasibility of enrollment of 10 eligible patients within a one year period.  
The retrospective analysis will consist of a 5-year review of patients with 
hematological malignancy and/or HSCT with Pseudomonas aeruginosa 
bacteremia and/or pneumonia. While the control arm may have limitations in its 
retrospective nature, the objective character of the different variables studied will 
assure an informative analysis. 
An analysis of outcome variables will be performed in comparison to controls 
matched for underlying hematological malignancy or HSCT. Further statistical 
analysis will include descriptive statistics of mean standard error of the mean 
and 95% confidence intervals for the differences in response. Differences in 
continuous variable will be analyzed by Wilcoxon rank-sum test. Differences in 
categorical variables will be assessed by Chi-square or Fisher’s exact test. Kaplan 
Meier analysis will be used to plot survival and Mantel-Haenszel chi square will 
be utilized for analysis of differences in survival. All P values are two-tailed and a 
threshold of 0.05 is designated statistically significant. 
 

 
 
18 
In univariate analysis, categorical variables were compared by either Chi-squared 
or Fisher’s exact tests and continuous variables were compared by the Wilcoxon 
rank-sum test. For determining factors independently associated with outcome, 
we will use multivariate logistic regression. All variables with a P value ≤0.1 in 
univariate analysis are initially entered into the multivariate model. Backward 
selection is then applied until only variables with P values ≤0.1 remain in the final 
model. For determining factors independently associated with survival, a Cox 
proportional hazards model is applied. Prism 8 will be used for data analysis 
(/www.graphpad.com/scientific-software/prism/).  
 
If the analysis for the outcome is favorable for the first 10 patients enrolled into 
the study, then consideration will be given to revising the protocol to include an 
additional 10 patients. 
A review of the demographics of Pseudomonas aeruginosa infections in patients 
with hematological malignancies and HSCT at our institution anticipates that we 
could enroll 20 to 30 patients with life-threatening Pseudomonas aeruginosa 
bacteremia and/or pneumonia in a two-year period. 
 
5.4.3  
Accrual Ceiling  
Target enrollment is 10 evaluable patients with a total of 20 patients who may be 
enrolled.  
6 
DATA REPORTING 
6.1 
Safety Reporting 
6.1.1 Adverse Events 
As ceftolozane/tazobactam has been approved by FDA, its safety profile is well characterized. 
We will therefore not collect adverse events. 
 
Serious adverse events (SAEs) other than hospital readmission will be monitored and reported to 
the IRB. As patients undergoing chemotherapy and hematopoietic stem cell transplantation are 
commonly readmitted to hospital reporting these events would be unlikely to be meaningful. 
 
Adverse Events of Interest that meet CTCAE Grade 3 and above will also be assessed, and 
include the following: renal failure, allergic reaction, leukopenia, elevated liver function values, 
Clostridium difficile infection. 
 
 
Serious Adverse Event Reporting Requirements.  
The principal investigator of the coordinating center will report to the IRB  
 All deaths 

 
 
19 
 All serious adverse events (SAEs) that are not listed in the consent form, but are 
possibly, probably, or definitely related to the research.  
 
An SAE is defined as an untoward medical occurrence that: 
 Resulted in death 
 Was life-threatening 
 Required or prolonged hospitalization 
 Caused persistent or significant disability/incapacity 
 Resulted in congenital anomalies or birth defects 
 Required intervention to prevent permanent impairment or death 
Reports must be received by the IRB within 7 days of notification of the event. 
 
6.2 
Withdrawal from Study  
In the event that a patient withdraws from the study, the reason will be recorded in the CRF. 
Withdrawal occurs when an enrolled patients ceases to participate in the study, prior to 
completion of the protocol. The investigator will record the cause for study withdrawal and 
would arrange for appropriate follow-up if required. 
 
6.3 
Record Keeping  
The PI will maintain a copy of all signed informed consent documents as well as the Study 
Samples Log sheets documenting the receipt and distribution of samples. The PI will maintain all 
relevant data in locked files. Coded data within the RedCap database will be securely maintained 
and password protected, to which only study investigators will have access.  
 
 
6.4 
Data Sharing  
The de-identified, coded data from this study and study results will be shared with the sponsor. 
 
  

 
 
20 
7. 
REFERENCES 
1. 
Satlin MJ and Walsh TJ: Multidrug-resistant Enterobacteriaceae, Pseudomonas 
aeruginosa, and Vancomycin-resistant enterococci: three major threats to hematopoietic 
stem cell transplant recipients. Transplant Infect Dis. Dec;19(6). doi: 10.1111/tid.12762; 
2017. 
2. 
Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, Raad II, Rolston 
KV, Young JA, Wingard JR; Infectious Diseases Society of America. ‘Clinical practice 
guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 
update by the Infectious Diseases Society of America. Clin Infect Dis. 2011 Feb 
15;52(4):e56-93. doi: 10.1093/cid/cir073. 
3. 
Nguyen L, Garcia J, Gruenberg K, MacDougall C. Multidrug-Resistant Pseudomonas 
Infections: Hard to Treat, But Hope on the Horizon? Curr Infect Dis Rep. 2018 Jun 
6;20(8):23. doi: 10.1007/s11908-018-0629-6. 
4. 
Kaye KS, Pogue JM. Infections caused by resistant Gram-negative bacteria: 
epidemiology and management. Pharmacotherapy. 2015 Oct;35(10):949-62. doi: 
10.1002/phar.1636. 
5. 
Munita JM, Aitken SL, Miller WR, Perez F, Rosa R, Shimose LA, Lichtenberger PN, 
Abbo LM, Jain R, Nigo M, Wanger A, Araos R, Tran TT, Adachi J, Rakita R, Shelburne 
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infections caused by carbapenem-resistant Pseudomonas aeruginosa.  Clin Infect Dis. 
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Gallagher JC, Satlin MJ, Elabor A, Saraiya N, McCreary EK, Molnar E, El-Beyrouty C, 
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Ceftolozane-Tazobactam for the Treatment of Multidrug-Resistant Pseudomonas 
aeruginosa Infections: A Multicenter Study.  Open Forum Infect Dis. 2018 Oct 
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7.   
Petraitis V, Petraitiene R, Naing E, Aung T, Wai Phyo T, Kavaliauskas P, DeRyke CA, 
Culshaw DL, Caro L, Satlin MG, Walsh TJ: Pharmacokinetics and efficacy of 
ceftolozane/tazobactam in the treatment of experimental Pseudomonas aeruginosa 
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Appendix A 
Karnofsky Performance Status