An Observational Pharmacokinetic Sudy of Ceftolozane-Tazobactam in Intensive Care Unit in Patients With and Without CRRT

NCT ID: NCT02962934

Last Updated: 2019-10-02

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 18 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2016-11-30
• Study Completion Date: 2019-08-31

Brief 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.

Detailed 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.

Conditions

Gram-Negative Bacterial Infections

Study Design

• Observational Model Type: CASE_ONLY
• Study Time Perspective: PROSPECTIVE

Study Groups

Non CRRT group

Critically ill patients receiving Ceftolozane-Tazobactam not receiving continuous renal replacement therapy

Non CRRT group

Intervention Type: OTHER

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

Critically ill patients receiving Ceftolozane-Tazobactam who require continuous renal replacement therapy

CRRT group

Intervention Type: OTHER

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

Interventions

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.

Intervention Type: OTHER

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

Intervention Type: OTHER

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

The University of Queensland

OTHER

Sponsor Role: collaborator

Royal Brisbane and Women's Hospital

OTHER_GOV

Sponsor Role: lead

Responsible Party

Jason Roberts

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jason A Roberts, Professor

Role: PRINCIPAL_INVESTIGATOR

Royal Brisbane and Womens Hospital

Locations

Royal Brisbane and Women's Hospital

Brisbane, Queensland, Australia

Countries

Australia

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

Royal_Brisbane

Identifier Type: -

Identifier Source: org_study_id