Clinical Trials Logo

Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT02962934
Other study ID # Royal_Brisbane
Secondary ID
Status Completed
Phase
First received
Last updated
Start date November 30, 2016
Est. completion date August 2019

Study information

Verified date September 2019
Source Royal Brisbane and Women's Hospital
Contact n/a
Is FDA regulated No
Health authority
Study type Observational

Clinical Trial Summary

The purpose of this study is to try to find out how critically ill patients receiving the antibiotic, ceftolozane-tazobactam, process it in their body. Investigators would like to study if the antibiotic concentrations during a dose of this antibiotic reaches the right concentrations necessary to kill the bacteria that is causing the infection. The process by which a drug travels through the body in blood, how it is broken down and removed by the body is called pharmacokinetics (PK). We can measure the PK by taking blood samples at specific times after the antibiotic is given.

Investigators would like to do the study in patients receiving dialysis and patients who are not receiving dialysis. This information about how the antibiotic is processed in the critically ill patient is unknown and it is important to know whether the doses doctors give patients to fight infection are adequate. If antibiotic concentrations are low in the blood, it gives the bacteria an opportunity to become resistant to the antibiotic which can lead to the antibiotic being less effective against bacteria potentially exposing future patients with infections to a limited range of effective antibiotics.

Patients will be consented, and given the antibiotic as prescribed. Blood samples will be taken from the drip that is already in the patients arm just as the antibiotic starts, at 15 and 45 minutes, at 1,2,3,4,5,6,7 and 8 hours. Patients who are on dialysis will have the blood samples taken from the dialysis machine before the blood reaches the dialysis filter (same blood samples as the non dialysis patients) and also bloods samples taken after the filter at 45 minutes, 2 and 6 hours. Dialysis patients will also have 5 separate samples of ultrafiltrate taken (approximately 10mls) - ultrafiltrate is the waste product of the dialysis process. The total amount of blood will be 40mls which is equal to about 2 tablespoons. The dialysis patient will have 50mls of blood taken.Information about the patients ICU stay will also be recorded.


Description:

Ceftolozane-tazobactam has recently emerged as a highly valuable option for the management of severe Gram-negative infections including those caused by multi-drug resistant (MDR) organisms, demonstrating superior antibacterial activity against the pathogens most frequently causing serious infection in the critically ill, such as Pseudomonas aeruginosa and Enterobacteriaceae spp, when compared with other commonly used beta-lactam antibiotics.

Although the continued reduction in the pathogen susceptibility to commonly used antibiotics in ICUs could be multifactorial, the potential contribution from inappropriate antibiotic exposure is undoubtedly very significant. Numerous clinical studies have reported sub-therapeutic antibiotic concentrations in ICU patients across different antibiotic classes, with conventional dosing regimens. This is due to marked changes in the pharmacokinetics (PK) and pharmacodynamics (PD) of antibiotics in the critically ill arising from disease-related physiological changes. Ceftolozane being a structural analogue of ceftazidime, shares similar PK properties of ceftazidime, and other beta-lactams, with a short half-life of about 2 hours, distribution into extracellular fluid, and predominant renal elimination, which all make it vulnerable to disease-related PK alterations in the critically ill.

Inappropriate antibiotic exposure in the ICU can also arise due to use of extracorporeal therapies such as continuous renal replacement therapy (CRRT). Many beta-lactam antibiotics share similar physicochemical and PK properties with ceftolozane and are efficiently cleared by CRRT machines. However the extent of total drug clearance during CRRT is variable not only due to the different modalities and operational settings across different institutions, but also due to the variable residual renal clearance associated with the degree of renal impairment. The traditional dosing considerations in patients undergoing CRRT mainly focus on the notion of renal impairment and generally consider low doses without giving appropriate consideration to the possibly high extracorporeal clearance, and thus risking under dosing. In a similar fashion, the product information for ceftolozane-tazobactam or the prescriber's information by the United States Food and Drug Administration (FDA), recommends a ten-fold lower-than-normal dose for use during renal replacement therapy (maintenance dose of 150mg versus 1.5g in those with normal renal function). However, to date there is limited data from clinical studies during CRRT in ICU patients to confirm if such a low dose provides appropriate antibiotic exposure. Lessons from studies on other beta-lactams suggest that ceftolozane may be subject to extensive but variable clearance during CRRT. It is therefore, essential to describe the adequacy of dosing in patients receiving CRRT, given that fact and that several additional pathophysiological factors affect the PK and PD of antibiotics even in the absence of extracorporeal circuits.

This prospective observational study will describe, firstly, the PK of ceftolozane-tazobactam in ICU patients who are not receiving CRRT, and secondly, the influence of CRRT on the PK and dosing requirements of ceftolozane-tazobactam in critically ill patients. This study will generate new PK data in ICU patients describing the exposure to ceftolozane-tazobactam from the recommended dosing regimen thereby allowing assessment of its adequacy and/or defining appropriate dosing. Further, it will provide invaluable insight into the altered dosing needs of patients receiving CRRT to enable its use in such patients through prediction of any necessary dosing corrections to account for the due effect of CRRT.


Recruitment information / eligibility

Status Completed
Enrollment 18
Est. completion date August 2019
Est. primary completion date June 30, 2019
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility Inclusion Criteria:

Group 1 Non CRRT

- Diagnosis of systemic infection known or suspected to be caused by an organism susceptible to ceftolozane-tazobactam

- Age more than 18 years

- The treating clinician considers Ceftolozane-tazobactam to be an appropriate agent to treat the infection Group 2 CRRT

- Diagnosis of systemic infection known or suspected to be caused by an organism susceptible to ceftolozane-tazobactam

- Age more than18 years

- Prescribed to receive CRRT

- The treating clinician considers Ceftolozane-tazobactam to be an appropriate agent to treat the infection

Exclusion Criteria:

Group 1 Non CRRT

- Renal dysfunction that necessitates the use of renal replacement therapy

- Known or suspected allergy to cephalosporins

- Receipt of any Pipercillin-Tazobactam for the treatment of this current infection.

- Pregnancy Group 2 CRRT

- Known or suspected allergy to cephalosporins

- Pregnancy

- Receipt of any Pipercillin-Tazobactam for the treatment of this current infection

Study Design


Related Conditions & MeSH terms


Intervention

Other:
Non CRRT group
Non CRRT group:Blood samples prior to first dose of Ceftolozane-Tazobactam and at 15, 45, 1hr, 2hr 3hr 4h 5h 6h 7h 8h.
CRRT group
CRRT group: Pre and Post dialysis filter blood samples taken prior to first dose of Ceftolozane-tazobactam and at 15min, 45min, 1h 2h 3h 4h 5h 6h 7h 8h. Ultrafiltrate samples at 1 hr,2h 4h 6h 8h

Locations

Country Name City State
Australia Royal Brisbane and Women's Hospital Brisbane Queensland

Sponsors (2)

Lead Sponsor Collaborator
Royal Brisbane and Women's Hospital The University of Queensland

Country where clinical trial is conducted

Australia, 

Outcome

Type Measure Description Time frame Safety issue
Primary Probability of Target Attainment for 40% fT>MIC The probability of attaining free concentrations above MIC for 40% of the time 24 hour period
See also
  Status Clinical Trial Phase
Completed NCT00723502 - Efficacy and Safety Study of Finafloxacin Used in Helicobacter Pylori Infected Patients Phase 2
Completed NCT00177814 - Piperacillin as a Part of Antibiotic Streamlining in the Intensive Care Unit
Suspended NCT00563134 - A Randomised Trial on the Saftely and Efficacy of GR270774 in the Treatment of Gram-negative Sepsis in Adult N/A
Active, not recruiting NCT05171257 - Quantifying Gram-negative Resistance to Empiric Therapy in the Intensive Care Unit
Completed NCT03160040 - A Retrospective Observational Study to Evaluate the Utilization, Outcomes, and Adverse Events in Participants Treated With Minocin® (Minocycline) for Infections Caused by Gram-negative Bacteria in a Real World Setting
Not yet recruiting NCT06135350 - Clinical Trial to Study the Efficacy and Safety of Fluorothiazinone (N.F. Gamaleya NRCEM) in Prophylaxis of Nosocomial Bacterial Infections With Participation of Patients on MV Phase 2
Enrolling by invitation NCT04055922 - Comparison of Solid Organ Transplant
Completed NCT00490477 - The Effects of Polymyxin-B Protects on Sepsis Induced Kidney Dysfunction: a Randomized Clinical Trial Phase 3
Recruiting NCT04861922 - Unfractioned Heparin for Treatment of Sepsis Caused by Abdominal Infection Phase 3
Completed NCT01732250 - Multicenter Open-label Randomized Controlled Trial (RCT) to Compare Colistin Alone Versus Colistin Plus Meropenem Phase 4
Completed NCT00406198 - Impact of Continuous Venovenous Haemofiltration on Organ Failure During the Early Phase of Severe Sepsis Phase 4
Recruiting NCT06086626 - A Study to Assess the Safety, Tolerability, and Pharmacokinetics of Cefiderocol in Hospitalized Neonates and Infants Phase 2
Withdrawn NCT04785924 - Imipenem/Cilastatin/Relebactam (IMI/REL) in Treatment of CRE Infections Phase 4
Completed NCT02285075 - Temocillin Pharmacokinetic in Hemodialysis Phase 4
Completed NCT03182504 - A Study to Investigate the Intrapulmonary Lung Penetration of Nacubactam in Healthy Participants Phase 1
Not yet recruiting NCT04917380 - The Clinical Character,Risk and Prognosis of Post-neurosurgical Intracranial Infection With Different Pathogens.
Terminated NCT05210387 - Seven Versus 14 Days of Antibiotic Therapy for Multidrug-resistant Gram-negative Bacilli Infections N/A
Completed NCT03397914 - Effect of Different Colistin Doses on Clinical Outcome of Pediatric Cancer Patients With Gram Negative Infections Phase 4
Completed NCT02088840 - Survey of Severe Infections by Gram Negative Bacteria in Patients Submitted to Stem Cell Transplant
Recruiting NCT01600768 - Evaluation of Extended Intravenous of Beta-lactams in the Treatment of Serious Gram-negative Infections in Critically Ill Patients N/A