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

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.