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Trial registered on ANZCTR

Registration number

ACTRN12625000544471

Ethics application status

Approved

Date submitted

28/04/2025

Date registered

29/05/2025

Date last updated

29/05/2025

Date data sharing statement initially provided

29/05/2025

Type of registration

Prospectively registered

Titles & IDs

Public title

Defining Antibiotic Levels in Intensive care patients 2 (DALI-2) - A multi-national pharmacokinetic/pharmacodynamic cohort study to determine whether contemporary antibiotic dosing for critically ill patients
achieves therapeutic exposures.

Scientific title

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

U1111-1321-9885

Trial acronym

DALI-2

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Serious infection

Critical Illness

Condition category

Condition code

Infection

Studies of infection and infectious agents

Intervention/exposure

Study type

Observational

Patient registry

False

Target follow-up duration

Target follow-up type

Description of intervention(s) / exposure

The DALI-2 study does not have a study intervention. Treatment of infection will be conducted according to standard of care by the treating physician. This includes antibiotic dose, frequency, infusion time and duration of therapy and all microbiological cultures. The specific antibiotics includes are (beta-lactams: amoxicillin-clavulanate; amoxicillin; ampicillin; ampicillin/sulbactam; piperacillin-tazobactam; penicillin-G (benzylpenicillin); flucloxacillin; cloxacillin; cephazolin; cefiderocol; cefotaxime; ceftazidime; ceftazidime/avibactam; ceftolozane/tazobactam; ceftriaxone; cefepime; aztreonam; meropenem; imipenem/cilastatin; doripenem; ertapenem; meropenem/vaborbactam; imipenem/cilastin/relebactam; glycopeptides: Vancomycin; teicoplanin, other antibiotics: linezolid; daptomycin; tigecycline; colistin; amikacin; fosfomycin; gentamicin; tobramycin; ciprofloxacin; levofloxacin; trimethoprim/ sulfamethoxazole; metronidazole). Enrolled patients will have two to three blood samples collected over one dosing interval on the selected day of sampling, which is between 24 and 96 hours after starting the study antibiotic. For beta-lactam antibiotics, teicoplanin, and linezolid, two blood samples will be taken, with sample 1 taken mid-way through the dosing interval, and sample 2 taken within 30 minutes of the next dose. For vancomycin, daptomycin, tigecycline, fosfomycin, gentamicin, tobramycin, amikacin, ciprofloxacin, trimethoprim/sulfamethoxazole, and metronidazole, three blood samples will be required to determine the area under of the curve. Sample 1 will be taken 30 minutes after starting the infusion, sample 2 taken mid-way through the dosing interval, and sample 3 taken within 30 minutes of the next dose.
All blood samples will be taken between 24 and 96 hours of antibiotic therapy, At Day 14 after initiation of the study antibiotic, vital status (alive or deceased), and if deceased, was the patient’s death related to infection will be recorded. Emergence of antibiotic resistance is recorded when subsequent cultures collected within 14 days of commencing the study antibiotic identify a resistant organism to the study antibiotic. At Day 30 after initiation of the study antibiotic, vital status (alive or deceased), and if deceased, was the patient’s death related to infection will be recorded. ICU free days at day 30 after initiation of the study antibiotic will be recorded, with deceased patients assigned a penalized value of zero days. Data collection is still required if the patient is transferred from the ICU to the ward or discharged.

Intervention code [1]

Not applicable

Comparator / control treatment

No control group

Control group

Uncontrolled

Outcomes

Primary outcome [1]

Number of critically ill patients who achieve pre-defined therapeutic antibiotic exposures (concentrations)

Timepoint [1]

During one dosing interval between 24 and 96 hours after starting study antibiotic.

Secondary outcome [1]

Number of critically ill patients who achieve beta-lactam exposures of: 50% free time at or above the MIC,

Timepoint [1]

During one dosing interval between 24 and 96 hours after starting study antibiotic.

Secondary outcome [2]

Number of participants with a positive clinical outcome.

Timepoint [2]

Positive clinical outcome - 48 hours after cessation of antibiotic

Secondary outcome [3]

Number of participants who surpass the pre-defined values associated with toxicity

Timepoint [3]

During one dosing interval between 24 and 96 hours after starting study antibiotic.

Secondary outcome [4]

Adverse drug events

Timepoint [4]

During the antibiotic course and followed up for 48-hours post-antibiotic cessation.

Secondary outcome [5]

Pharmacokinetics of antibiotics (e.g. volume of distribution, and clearance)

Timepoint [5]

All blood samples collected during one dosing interval between 24 and 96 hours of antibiotic therapy will be used to assess the pharmacokinetics of antibiotics. For BETA-LACTAMS, teicoplanin and linezolid, two blood samples are required, with sample 1 taken mid-way through the dosing interval, and sample 2 taken within 30 minutes of the next dose. For vancomycin, daptomycin, tigecycline, fosfomycin, gentamicin, tobramycin, amikacin, ciprofloxacin, trimethoprim/sulfamethoxazole, and metronidazole, three blood samples are required with samples one taken 30 minutes after starting the infusion, sample 2 taken midway through the same dosing interval, and sample 3 taken within 3o minutes of the next dose.

Secondary outcome [6]

To systematically evaluate the feasibility for implementation of the DALI-2 study across intensive care units globally.

Timepoint [6]

Feasibility assessed at the conclusion of the study at each site.

Secondary outcome [7]

In adults administered vancomycin, the number of participants who achieve a trough concentration of 15 mg/L or greater when administered via intermittent infusion.

Timepoint [7]

During one dosing interval between 24 and 96 hours after starting study antibiotic.

Secondary outcome [8]

In children administered vancomycin, the number of participants achieving a trough concentration range of 15 to 20 mg/L for methicillin-resistant Staphylococcus aureus (MRSA)

Timepoint [8]

During one dosing interval between 24 and 96 hours after starting study antibiotic.

Secondary outcome [9]

In children administered vancomycin, the number of participants achieving a trough concentration range of 10 to 15 mg/L for non- methicillin-resistant Staphylococcus aureus (MRSA)

Timepoint [9]

During one dosing interval between 24 and 96 hours after starting study antibiotic.

Secondary outcome [10]

In adults administered vancomycin, the number of participants who achieve a steady state concentration of 15 to 25 mg/L when administered as a continuous infusions.

Timepoint [10]

During one dosing interval between 24 and 96 hours after starting study antibiotic.

Secondary outcome [11]

Number of critically ill patients who achieve beta-lactam exposures of 50% free time at or above 4 times the MIC,

Timepoint [11]

During one dosing interval between 24 and 96 hours after starting study antibiotic.

Secondary outcome [12]

Number of critically ill patients who achieve beta-lactam exposures of 100% free time at or above MIC

Timepoint [12]

During one dosing interval between 24 and 96 hours after starting study antibiotic.

Secondary outcome [13]

Number of critically ill patients who achieve beta-lactam exposures of 100% free time at or above 4 times the MIC.

Timepoint [13]

During one dosing interval between 24 and 96 hours after starting study antibiotic.

Secondary outcome [14]

Number of participants with a Negative clinical outcome.

Timepoint [14]

Negative clinical outcome - 48 hours after cessation of antibiotic

Secondary outcome [15]

Infection related mortality

Timepoint [15]

Mortality - day 14 and day 30 after initiation of the study antibiotic

Secondary outcome [16]

ICU free days at day 30 after initiation of the study antibiotic.

Timepoint [16]

at day 30 after initiation of the study antibiotic.

Secondary outcome [17]

Emergence of antibiotic resistance

Timepoint [17]

Emergence of antibiotic resistance - at day 14

Secondary outcome [18]

To systematically evaluate the site readiness for implementation of the DALI-2 study across intensive care units globally.

Timepoint [18]

Site readiness assessed at the conclusion of the study at each site.

Eligibility

Key inclusion criteria

Patients are eligible for inclusion in the DALI-2 study if all the following inclusion criteria are met:

1. Patient is admitted to an ICU.
2. Patient receiving one of the specified intravenous antibiotics (including beta-lactams, glycopeptides, aminoglycosides and others) for the treatment of infection (i).
3. Suitable intravenous/intra-arterial access to facilitate sample collection. Capillary samples can be used in children if required. (arterial line preferred for sample collection).
4. Corrected gestational age of patient of 1 month or greater.
5. The patient must have been administered the study antibiotic for at least 24 hours.

(i). Treatment is defined as either: empiric therapy (a clinical syndrome that may be due to infection is being treated) e.g. empiric antibiotics for aspiration pneumonitis/pneumonia, or directed therapy (treating an infection where a causative organism is identified). Please note that post-operative prophylactic antibiotics are not included.

Minimum age

1 Months

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

1. Patient’s death is deemed imminent and inevitable.
2. Patients who have received the study antibiotic for a duration exceeding 96 hours without accompanying blood sample collection.

Study design

Purpose

Duration

Selection

Timing

Statistical methods / analysis

Recruitment

Recruitment status

Not yet recruiting

Date of first participant enrolment

Anticipated

1/07/2025

Actual

Date of last participant enrolment

Anticipated

30/06/2027

Actual

Date of last data collection

Anticipated

31/07/2027

Actual

Sample size

Target

1250

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW,NT,QLD,SA,WA,VIC

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Country [2]

China

State/province [2]

Country [3]

France

State/province [3]

Country [4]

United Kingdom

State/province [4]

Country [5]

Taiwan, Province Of China

State/province [5]

Country [6]

Belgium

State/province [6]

Country [7]

Greece

State/province [7]

Country [8]

Sweden

State/province [8]

Country [9]

Spain

State/province [9]

Country [10]

Portugal

State/province [10]

Country [11]

Turkey

State/province [11]

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

Australian National Health and Medical Research Council (NHMRC) Centre of Research Excellence RESPOND (APP2007007)

Address [1]

Country [1]

Australia

Funding source category [2]

Government body

Name [2]

NHMRC Investigator Grant (APP2009736)

Address [2]

Country [2]

Australia

Primary sponsor type

University

Name

University of Queensland

Address

Country

Australia

Secondary sponsor category [1]

Hospital

Name [1]

CHU Nimes

Address [1]

Country [1]

France

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Children’s Health Queensland Hospital and Health Service Human Research Ethics Committee

Ethics committee address [1]

http://www.childrens.health.qld.gov.au/research/human-research-ethics-committee

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

06/09/2024

Approval date [1]

12/02/2025

Ethics approval number [1]

HREC/2024/QCHQ/111399

Summary

Brief summary

The primary purpose of the DALI-2 study is to describe the achievement of therapeutic antibiotic exposures (concentrations) in critically ill patients. Our HYPOTHESIS is that failing to achieve therapeutic antibiotic exposures (concentrations) in critically ill patients is an independent determinant of clinical outcomes, including clinical failure, mortality, ICU-free days, and the emergence of antimicrobial resistance, across diverse patient populations.
Our VISION for DALI-2 is to pioneer a new era in the management of severe infections by providing definitive evidence that will reshape antibiotic dosing strategies for critically ill patients globally, irrespective of age. We aim to set a new benchmark for treatment efficacy and safety.

Trial website

Trial related presentations / publications

Public notes

Pre-defined exposures determined by either expert consensus opinion and the following references: 1. Sy SKB, Zhuang L, Sy S, Derendorf H. Clinical Pharmacokinetics and Pharmacodynamics of Ceftazidime–Avibactam Combination: A Model-Informed Strategy for its Clinical Development. Clinical pharmacokinetics. 2019;58(5):545-64. 2. Monogue ML, Nicolau DP. Pharmacokinetics-pharmacodynamics of ß-lactamase inhibitors: are we missing the target? Expert Review of Anti-infective Therapy. 2019;17(8):571-82. 3. Roberts JA, Joynt GM, Lee A, Choi G, Bellomo R, Kanji S, et al. The Effect of Renal Replacement Therapy and Antibiotic Dose on Antibiotic Concentrations in Critically Ill Patients: Data from the Multinational Sampling Antibiotics in Renal Replacement Therapy Study. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2021;72(8):1369-78. 4. Gatti M, Rinaldi M, Gaibani P, Siniscalchi A, Tonetti T, Viale P, et al. A descriptive pharmacokinetic/pharmacodynamic analysis of continuous infusion meropenem/vaborbactam in the treatment of critically ill patients with documented KPC-producing Klebsiella pneumoniae ventilator-associated pneumonia. International Journal of Antimicrobial Agents. 2023;62(5):106992. 5. Child J, Chen X, Mistry RD, Somme S, MacBrayne C, Anderson PL, et al. Pharmacokinetic and Pharmacodynamic Properties of Metronidazole in Pediatric Patients With Acute Appendicitis: A Prospective Study. Journal of the Pediatric Infectious Diseases Society. 2018;8(4):297-302. 6. Lau WK, Young LS. Trimethoprim-sulfamethoxazole treatment of Pneumocystis carinii pneumonia in adults. The New England journal of medicine. 1976;295(13):716-8. 7. Yang X, Jin L, Luo X, An S, Wang M, Zhu H, et al. Pharmacokinetic/Pharmacodynamic Target Attainment of Tigecycline in Patients with Hepatic Impairment in a Real-World Setting. Ther Drug Monit. 2023;45(6):786-91. 8. Yang X, Jin L, Luo X, Wang M, Zhu H, Zhou Y, et al. Serum concentration as a predictor of tigecycline-induced hypofibrinogenemia in critically ill patients: A retrospective cohort study. International Journal of Infectious Diseases. 2022;123:136-42. 9. Abdul-Aziz MH, Alffenaar J-WC, Bassetti M, Bracht H, Dimopoulos G, Marriott D, et al. Antimicrobial therapeutic drug monitoring in critically ill adult patients: a Position Paper#. Intensive Care Medicine. 2020;46(6):1127-53.

Contacts

Principal investigator

Name

Prof Jason Roberts

Address

UQ Centre for Clinical Research, Level 8, UQCCR building 71/918 RBWH Campus, Herston QLD 4029

Country

Australia

Phone

+61 7 3346 5032

Fax

[email protected]

Contact person for public queries

Name

Paul Williams

Address

UQ Centre for Clinical Research, Level 8, UQCCR building 71/918 RBWH Campus, Herston QLD 4029

Country

Australia

Phone

+61 7 3346 5032

Fax

[email protected]

Contact person for scientific queries

Name

Paul Williams

Address

UQ Centre for Clinical Research, Level 8, UQCCR building 71/918 RBWH Campus, Herston QLD 4029

Country

Australia

Phone

+61 7 3346 5032

Fax

[email protected]

Data sharing statement

Will the study consider sharing individual participant data?

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

No additional documents have been identified.

Trial Review

Documents added manually

Documents added automatically