Ex vivo Ceftolozane/Tazobactam Clearance during Continuous Renal Replacement Therapy

Chaijamorn, Weerachai; Shaw, Alexander R.; Lewis, Susan J.; Mueller, Bruce A.

doi:10.1159/000455897

Cited by 26 publications

(40 citation statements)

References 38 publications

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“…This is the first report describing the unbound population pharmacokinetics of ceftolozane and tazobactam in critically ill patients undergoing CVVHDF. We observed sieving coefficients that are consistent with previous findings for continuous hemofiltration and dialysis (14). The observed extraction ratios for unbound ceftolozane (0.76 Ϯ 0.08) and tazobactam (0.73 Ϯ 0.1) were comparable to the values of 0.86 and 0.85, respectively, in a previous case report using continuous hemofiltration (11).…”

Section: Discussionsupporting

confidence: 91%

“…In addition, it achieves previously recommended tazobactam exposures of 20% fT Ͼ1mg/liter and 50% fT Ͼ2mg/liter (14, 15) (see Table S1 in the supplemental material). These results are concordant with an in silico simulation study based on ex vivo data that recommended 0.75 g q8h dosing as an optimal regimen for continuous hemofiltration and dialysis (14).…”

Section: Discussionsupporting

confidence: 86%

“…Second, there was a lack of a well-defined target exposure, particularly for tazobactam. We used previously recommended targets of 20% fT Ͼ1mg/liter and 50% fT Ͼ2mg/liter (14,15). However, these exposures are not concordant with the in vitro susceptibility testing protocol for beta-lactam/tazobactam combination antibiotics, where the tazobactam concentration is fixed at 4 mg/liter.…”

Section: Discussionmentioning

confidence: 99%

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A Population Pharmacokinetic Model-Guided Evaluation of Ceftolozane-Tazobactam Dosing in Critically Ill Patients Undergoing Continuous Venovenous Hemodiafiltration

Sime

Lassig-Smith

Starr

et al. 2019

Antimicrob Agents Chemother

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The aim of this work was to describe optimized dosing regimens of ceftolozane-tazobactam for critically ill patients receiving continuous venovenous hemodiafiltration (CVVHDF). We conducted a prospective observational pharmacokinetic study in adult critically ill patients with clinical indications for ceftolozane-tazobactam and CVVHDF. Unbound drug concentrations were measured from serial prefilter blood, postfilter blood, and ultrafiltrate samples by a chromatographic assay. Population pharmacokinetic modeling and dosing simulations were performed using Pmetrics. A four-compartment pharmacokinetic model adequately described the data from six patients. The mean (± standard deviation [SD]) extraction ratios for ceftolozane and tazobactam were 0.76 ± 0.08 and 0.73 ± 0.1, respectively. The mean ± SD sieving coefficients were 0.94 ± 0.24 and 1.08 ± 0.30, respectively. Model-estimated CVVHDF clearance rates were 2.7 ± 0.8 and 3.0 ± 0.6 liters/h, respectively. Residual non-CVVHDF clearance rates were 0.6 ± 0.5 and 3.3 ± 0.9 liters/h, respectively. In the initial 24 h, doses as low as 0.75 g every 8 h enabled cumulative fractional response of ≥85% for empirical coverage against Pseudomonas aeruginosa, considering a 40% fT>MIC (percentage of time the free drug concentration was above the MIC) target. For 100% fT>MIC, doses of at least 1.5 g every 8 h were required. The median (interquartile range) steady-state trough ceftolozane concentrations for simulated regimens of 1.5 g and 3.0 g every 8 h were 28 (21 to 42) and 56 (42 to 84) mg/liter, respectively. The corresponding tazobactam concentrations were 6.1 (5.5 to 6.7) and 12.1 (11.0 to 13.4) mg/liter, respectively. We suggest a front-loaded regimen with a single 3.0-g loading dose followed by 0.75 g every 8 h for critically ill patients undergoing CVVHDF with study blood and dialysate flow rates.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

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A Population Pharmacokinetic Model-Guided Evaluation of Ceftolozane-Tazobactam Dosing in Critically Ill Patients Undergoing Continuous Venovenous Hemodiafiltration

Sime

Lassig-Smith

Starr

et al. 2019

Antimicrob Agents Chemother

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“…The procedures for the CVVH study were similar to those described in our previous ex vivo studies [14, 15]. The CL TM of urea and rezafungin were evaluated with different blood flow rates, Q uf and hemodiafilters (Table 1).…”

Section: Methodsmentioning

confidence: 99%

“…Six experiments were conducted for each hemodiafilter, and new hemodiafilters and CRRT apparatus were used for each experiment. Sieving coefficient (S C ) and CL TM for post-filter replacement were calculated as follows [15]:…”

Section: Methodsmentioning

confidence: 99%

Ex vivo Rezafungin Adsorption and Clearance During Continuous Renal Replacement Therapy

2018

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Background/Aims: To determine adsorption and transmembrane clearances (CL_TM) of rezafungin, a novel long-acting echinocandin, in continuous venovenous hemofiltration (CVVH). Methods: A validated ex vivo bovine blood CVVH model using polysulfone and AN69 hemodiafilters was used to evaluate urea and rezafungin CL_TM at 3 different ultrafiltrate flow rates. Rezafungin adsorption to the CRRT apparatus was determined for each hemodiafilter. Results: The sieving coefficient (S_C) from CVVH with 3 different ultrafiltrate flow rates was 0 for both HF1400 and Multiflow-150 hemodiafilters, while urea S_C was approximately 1 at all flow rates. Hemodiafilter type and ultrafiltrate flow rate did not influence CL_TM. Rezafungin adsorption to the CVVH apparatus was not observed for either hemodiafilter. Conclusion: Rezafungin is not removed by CVVH by membrane adsorption or via CL_TM. Ultrafiltrate flow rates and hemodiafilter types are unlikely to influence rezafungin CL_TM. No dosage adjustment of rezafungin is likely required for critically ill patients receiving CVVH.

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Practical considerations for individualizing drug dosing in critically ill adults receiving renal replacement therapy

et al. 2023

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Critically ill patients with sepsis admitted to the intensive care unit (ICU) often present with or develop renal dysfunction requiring renal replacement therapy (RRT) in addition to antimicrobial therapy. While early and appropriate antimicrobials for sepsis have been associated with an increased probability of survival, adequate dosing is also required in these patients. Adequate dosing of antimicrobials refers to dosing strategies that achieve serum drug levels at the site of infection that are able to provide a microbiological and/or clinical response while avoiding toxicity from excessive antibiotic exposure. Therapeutic drug monitoring (TDM) is the recommended strategy to achieve this goal, however, TDM is not routinely available in all ICUs and for all antimicrobials. In the absence of TDM, clinicians are therefore required to make dosing decisions based on the clinical condition of the patient, the causative organism, the characteristics of RRT, and an understanding of the physicochemical properties of the antimicrobial. Pharmacokinetics (PK) of antimicrobials can be highly variable between critically ill patients and also within the same patient over the course of their ICU stay. The initiation of RRT, which can be in the form of intermittent hemodialysis, continuous, or prolonged intermittent therapy, further complicates the predictability of drug disposition. This variability highlights the need for individualized dosing. This review highlights the practical considerations for the clinician for antimicrobial dosing in critically ill patients receiving RRT.

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Ex vivo Ceftolozane/Tazobactam Clearance during Continuous Renal Replacement Therapy

Cited by 26 publications

References 38 publications

A Population Pharmacokinetic Model-Guided Evaluation of Ceftolozane-Tazobactam Dosing in Critically Ill Patients Undergoing Continuous Venovenous Hemodiafiltration

A Population Pharmacokinetic Model-Guided Evaluation of Ceftolozane-Tazobactam Dosing in Critically Ill Patients Undergoing Continuous Venovenous Hemodiafiltration

Ex vivo Rezafungin Adsorption and Clearance During Continuous Renal Replacement Therapy

Practical considerations for individualizing drug dosing in critically ill adults receiving renal replacement therapy

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