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Doripenem Treatment during Continuous Renal Replacement Therapy.

ABSTRACT: Doripenem is a broad-spectrum parenteral carbapenem with enhanced activity against Pseudomonas aeruginosa. While the initial dosing recommendation for renally competent patients and patients undergoing continuous renal replacement therapy (cRRT) was 500 mg every 8 h (q8h), the dose for renally competent patients was updated to 1 g q8h in June 2012. There are no updated data for the dosing of patients on continuous renal replacement therapy. The original dosing regimen for cRRT patients was based on nonseptic patients, while newer publications chose comparatively low target concentrations for a carbapenem. Thus, there is an urgent need for updated recommendations for dosing during cRRT. In the trial presented here, we included 13 oliguric septic patients undergoing cRRT in an intensive care setting. Five patients each were treated with hemodiafiltration or hemodialysis, while three patients received hemofiltration treatment. All patients received 1 g doripenem every 8 h. Doripenem concentrations in the plasma and ultrafiltrate were measured over 48 h. The mean hemofilter clearance was 36.53 ml/min, and the mean volume of distribution was 59.26 liters. The steady-state trough levels were found at 8.5 mg/liter, with no considerable accumulation. Based on pharmacokinetic and pharmacodynamic considerations, we propose a regimen of 1 g q8h, which may be combined with a loading dose of 1.5 to 2 g for critically ill patients. (This study has been registered with EudraCT under registration no. 2009-018010-18 and at ClinicalTrials.gov under registration no. NCT02018939.).

SUBMITTER: Vossen MG

PROVIDER: S-EPMC4775919 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Doripenem Treatment during Continuous Renal Replacement Therapy.

Vossen M G MG Wenisch J M JM Maier-Salamon A A Fritsch A A Saria K K Zuba C C Jilch S S Lemmerer R R Unger M M Jaehde U U Jäger W W Thalhammer F F

Antimicrobial agents and chemotherapy 20151228 3

Doripenem is a broad-spectrum parenteral carbapenem with enhanced activity against Pseudomonas aeruginosa. While the initial dosing recommendation for renally competent patients and patients undergoing continuous renal replacement therapy (cRRT) was 500 mg every 8 h (q8h), the dose for renally competent patients was updated to 1 g q8h in June 2012. There are no updated data for the dosing of patients on continuous renal replacement therapy. The original dosing regimen for cRRT patients was based ...[more]

PMID: 26711775

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Project description:BackgroundRhabdomyolysis is a condition that is characterised by the breakdown of skeletal muscle tissue and leakage of intracellular myocyte contents into circulating blood. Rhabdomyolysis can lead to acute kidney injury (AKI) and is a potentially life-threatening condition. Studies have indicated that continuous renal replacement therapy (CRRT) may provide benefits for people with rhabdomyolysis by removing potentially damaging myoglobin and stabilising haemodynamic and metabolic status.ObjectivesWe aimed to: i) assess the efficacy of CRRT in removing myoglobin; ii) investigate the influence of CRRT on mortality and kidney-related outcomes; and iii) evaluate the safety of CRRT for the treatment of people with rhabdomyolysis.Search methodsWe searched the Cochrane Renal Group's Specialised Register to 6 January 2014 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. We also searched China National Knowledge Infrastructure (from 1 January 1979 to 16 April 2013) and the Chinese Clinical Trials Register (to 16 April 2013).Selection criteriaAll randomised controlled trials (RCTs) and quasi-RCTs that investigated clinical outcomes of CRRT for people with rhabdomyolysis were included.Data collection and analysisTwo authors independently assessed studies for inclusion and extracted data. We derived risk ratios (RR) for dichotomous data and mean differences (MD) for continuous data with 95% confidence intervals (CI). Methodological risk of bias was assessed using the Cochrane risk of bias tool.Main resultsOf the three included studies (101 participants), one evaluated continuous arteriovenous haemodialysis and two investigated continuous venovenous haemofiltration; all included conventional therapy as control.We found significant decreases in myoglobin in patients among whom CRRT therapy was initiated on days four, eight, and 10 (day 4: MD -11.00 (μg/L), 95% CI -20.65 to -1.35; Day 8: MD -23.00 (μg/L), 95% CI -30.92 to -15.08; day 10: MD -341.87 (μg/L), 95% CI -626.15 to -57.59) compared with those who underwent conventional therapy.Although CRRT was associated with improved serum creatinine, blood urea nitrogen, and potassium levels; reduced duration of the oliguria phase; and was associated with reduced time in hospital, no significant differences were found in mortality rates compared with conventional therapy (RR 0.17, 95% CI 0.02 to 1.37). The included studies did not report on long-term outcomes or prevention of AKI.Overall, we found that study quality was suboptimal: blinding and randomisation allocation were not reported by any of the included studies, leading to the possibility of selection, performance and detection bias.Authors' conclusionsAlthough CRRT may provide some benefits for people with rhabdomyolysis, the poor methodological quality of the included studies and lack of data relating to clinically important outcomes limited our findings about the effectiveness of CRRT for people with rhabdomyolysis.There was insufficient evidence to discern any likely benefits of CRRT over conventional therapy for people with rhabdomyolysis and prevention of rhabdomyolysis-induced AKI.

Project description:BackgroundThe need for continuous renal replacement therapy (CRRT) in critically ill patients with serious infections is associated with clinical failure, emergence of resistance, and excess mortality. These poor outcomes are attributable in large part to subtherapeutic antimicrobial exposure and failure to achieve target pharmacokinetic/pharmacodynamic (PK/PD) thresholds during CRRT. Cefiderocol is a novel siderophore cephalosporin with broad in vitro activity against resistant pathogens and is often used to treat critically ill patients, including those receiving CRRT, despite the lack of data to guide dosing in this population.ObjectiveThe aim of this study was to evaluate the PK and PD of cefiderocol during in vitro and in vivo CRRT and provide optimal dosing recommendations.MethodsThe PK and dialytic clearance of cefiderocol was evaluated via an established in vitro CRRT model across various modes, filter types, and effluent flow rates. These data were combined with in vivo PK data from nine patients receiving cefiderocol while receiving CRRT from phase III clinical trials. Optimal dosing regimens and their respective probability of target attainment (PTA) were assessed via an established population PK model with Bayesian estimation and 1000-subject Monte Carlo simulations at each effluent flow rate.ResultsThe overall mean sieving/saturation coefficient during in vitro CRRT was 0.90 across all modes, filter types, effluent flow rates, and points of replacement fluid dilution tested. Adsorption was negligible at 10.9%. Three-way analysis of variance (ANOVA) and multiple linear regression analyses demonstrated that effluent flow rate is the primary driver of clearance during CRRT and can be used to calculate optimal cefiderocol doses required to match the systemic exposure observed in patients with normal renal function. Bayesian estimation of these effluent flow rate-based optimal doses in nine patients receiving CRRT from the phase III clinical trials of cefiderocol revealed comparable mean (± standard deviation) area under the concentration-time curve values as patients with normal renal function (1709 ± 539 mg·h/L vs. 1494 ± 58.4 mg·h/L; p = 0.26). Monte Carlo simulations confirmed these doses achieved >90% PTA against minimum inhibitory concentrations ≤4 mg/L at effluent flow rates from 0.5 to 5 L/h.ConclusionThe optimal dosing regimens developed from this work have been incorporated into the prescribing information for cefiderocol, making it the first and only antimicrobial with labeled dosing for CRRT. Future clinical studies are warranted to confirm the efficacy and safety of these regimens.

Project description:BackgroundTo evaluate the transmembrane clearance (CLTM) of apixaban during modeled in vitro continuous renal replacement therapy (CRRT), assess protein binding and circuit adsorption, and provide initial dosing recommendations.MethodsApixaban was added to the CRRT circuit and serial pre-filter bovine blood samples were collected along with post-filter blood and effluent samples. All experiments were performed in duplicate using continuous veno-venous hemofiltration (CVVH) and hemodialysis (CVVHD) modes, with varying filter types, flow rates, and point of CVVH replacement fluid dilution. Concentrations of apixaban and urea were quantified via liquid chromatography-tandem mass spectrometry. Plasma pharmacokinetic parameters for apixaban were estimated via noncompartmental analysis. CLTM was calculated via the estimated area under the curve (AUC) and by the product of the sieving/saturation coefficient (SC/SA) and flow rate. Two and three-way analysis of variance (ANOVA) models were built to assess the effects of mode, filter type, flow rate, and point of dilution on CLTM by each method. Optimal doses were suggested by matching the AUC observed in vitro to the systemic exposure demonstrated in Phase 2/3 studies of apixaban. Linear regression was utilized to provide dosing estimations for flow rates from 0.5-5?L/h.ResultsMean adsorption to the HF1400 and M150 filters differed significantly at 38 and 13%, respectively, while mean (± standard deviation, SD) percent protein binding was 70.81?±?0.01%. Effect of CVVH point of dilution did not differ across filter types, although CLTM was consistently significantly higher during CRRT with the HF1400 filter compared to the M150. The three-way ANOVA demonstrated improved fit when CLTM values calculated by AUC were used (adjusted R2 0.87 vs. 0.52), and therefore, these values were used to generate optimal dosing recommendations. Linear regression revealed significant effects of filter type and flow rate on CLTM by AUC, suggesting doses of 2.5-7.5?mg twice daily (BID) may be needed for flow rates ranging from 0.5-5?L/h, respectively.ConclusionFor CRRT flow rates most commonly employed in clinical practice, the standard labeled 5?mg BID dose of apixaban is predicted to achieve target systemic exposure thresholds. The safety and efficacy of these proposed dosing regimens warrants further investigation in clinical studies.

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Doripenem Treatment during Continuous Renal Replacement Therapy.

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Doripenem Treatment during Continuous Renal Replacement Therapy.

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