fr-264205 and Critical-Illness

Ceftolozane/tazobactam is approved for hospital-acquired/ventilator-associated bacterial pneumonia at double the dose (i.e. 2 g/1 g) recommended for other indications. We evaluated the bronchopulmonary pharmacokinetic/pharmacodynamic profile of this 3 g ceftolozane/tazobactam regimen in ventilated pneumonia patients.. This was an open-label, multicentre, Phase 1 trial (clinicaltrials.gov: NCT02387372). Mechanically ventilated patients with proven/suspected pneumonia received four to six doses of 3 g of ceftolozane/tazobactam (adjusted for renal function) q8h. Serial plasma samples were collected after the first and last doses. One bronchoalveolar lavage sample per patient was collected at 1, 2, 4, 6 or 8 h after the last dose and epithelial lining fluid (ELF) drug concentrations were determined. Pharmacokinetic parameters were estimated by non-compartmental analysis and pharmacodynamic analyses were conducted to graphically evaluate achievement of target exposures (plasma and ELF ceftolozane concentrations >4 mg/L and tazobactam concentrations >1 mg/L; target in plasma: ≥30% and ≥20% of the dosing interval, respectively).. Twenty-six patients received four to six doses of study drug; 22 were included in the ELF analyses. Ceftolozane and tazobactam Tmax (6 and 2 h, respectively) were delayed in ELF compared with plasma (1 h). Lung penetration, expressed as the ratio of mean drug exposure (AUC) in ELF to plasma, was 50% (ceftolozane) and 62% (tazobactam). Mean ceftolozane and tazobactam ELF concentrations remained >4 mg/L and >1 mg/L, respectively, for 100% of the dosing interval. There were no deaths or adverse event-related study discontinuations.. In ventilated pneumonia patients, 3 g of ceftolozane/tazobactam q8h yielded ELF exposures considered adequate to cover ceftolozane/tazobactam-susceptible respiratory pathogens.

Topics: Anti-Bacterial Agents; Cephalosporins; Critical Illness; Humans; Lung; Pneumonia; Tazobactam

To investigate the influence of continuous renal replacement therapy (CRRT) intensity on the clearance of ceftolozane/tazobactam in critical care patients, and to evaluate if the reported doses would achieve an optimal pharmacokinetic/pharmacodynamic (PK/PD) target against Pseudomonas aeruginosa exhibiting different MICs.. The MEDLINE-PubMed database was searched from inception to January 2020 to retrieve observational studies or case reports investigating the PK behaviour of ceftolozane/tazobactam during CRRT. Relevant CRRT settings and PK variables were extracted, and the influence of CRRT intensity on ceftolozane/tazobactam total clearance (CLtot) was determined by simple linear regression. The optimal PK/PD target for the reported doses was deemed to be achieved when ceftolozane trough concentrations (Cmin) were above the MIC (less intensive target) or four times the MIC (intensive target) for P. aeruginosa.. Data from six studies including 11 patients (mean age 56.6 years) were analysed. Mean blood flow rate and effluent flow rate were 161.8 mL/min and 2383.4 mL/h, respectively. Ceftolozane Cmin ranged from 25.8 to 79.4 mg/L. A significant correlation was found for ceftolozane CLtot and effluent flow rate (P = 0.027). The intensive PK/PD target was achieved by 100% and 50% of the reported doses for MIC, respectively, up to 4 and 8 mg/L.. A significant correlation between effluent flow rate and ceftolozane clearance during CRRT could be identified. Higher dosing regimens coupled with continuous/extended infusion may be required in the case of higher CRRT intensity, deep-seated infections or poorly susceptible isolates. Larger studies assessing ceftolozane PK in different CRRT settings are warranted.

Topics: Anti-Bacterial Agents; Cephalosporins; Continuous Renal Replacement Therapy; Critical Illness; Humans; Microbial Sensitivity Tests; Middle Aged; Prospective Studies; Pseudomonas aeruginosa; Renal Replacement Therapy; Tazobactam

Extracorporeal membrane oxygenation (ECMO) is increasingly used in intensive care units and can modify drug pharmacokinetics and lead to under-exposure associated with treatment failure. Ceftolozane/tazobactam is an antibiotic combination used for complicated infections in critically ill patients. Launched in 2015, sparse data are available on the influence of ECMO on the pharmacokinetics of ceftolozane/tazobactam. The aim of the present study was to determine the influence of ECMO on the pharmacokinetics of ceftolozane-tazobactam.. An ex vivo model (closed-loop ECMO circuits primed with human whole blood) was used to study adsorption during 8-h inter-dose intervals over a 24-h period (for all three ceftolozane/tazobactam injections) with eight samples per inter-dose interval. Two different dosages of ceftolozane/tazobactam injection were studied and a control (whole blood spiked with ceftolozane/tazobactam in a glass tube) was performed. An in vivo porcine model was developed with a 1-h infusion of ceftolozane-tazobactam and concentration monitoring for 11 h. Pigs undergoing ECMO were compared with a control group. Pharmacokinetic analysis of in vivo data (non-compartmental analysis and non-linear mixed effects modelling) was performed to determine the influence of ECMO.. With the ex vivo model, variations in concentration ranged from - 5.73 to 1.26% and from - 12.95 to - 2.89% respectively for ceftolozane (concentrations ranging from 20 to 180 mg/l) and tazobactam (concentrations ranging from 10 to 75 mg/l) after 8 h. In vivo pharmacokinetic exploration showed that ECMO induces a significant decrease of 37% for tazobactam clearance without significant modification in the pharmacokinetics of ceftolozane, probably due to a small cohort size.. Considering that the influence of ECMO on the pharmacokinetics of ceftolozane/tazobactam is not clinically significant, normal ceftolozane and tazobactam dosing in critically ill patients should be effective for patients undergoing ECMO.

Topics: Animals; Anti-Bacterial Agents; Cephalosporins; Critical Illness; Extracorporeal Membrane Oxygenation; Humans; Swine; Tazobactam

Topics: Adult; Anti-Bacterial Agents; Cephalosporins; Critical Illness; Female; Hemodiafiltration; Humans; Microbial Sensitivity Tests; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pseudomonas aeruginosa; Pseudomonas Infections

Topics: Cephalosporins; Continuous Renal Replacement Therapy; Critical Illness; Humans; Tazobactam

Vitamin C is a well-documented antioxidant that reduces oxidative stress and fluid infusion in high doses; however, the association between high-dose vitamin C and reduced mortality remains unclear. This study evaluates the effect of high-dose vitamin C in severe burn patients under two varying thresholds.. We enrolled adult patients with severe burns (burn index ≥ 15) who were registered in the Japanese Diagnosis Procedure Combination national inpatient database from 2010 to 2016. Propensity score matching was performed between patients who received high-dose vitamin C within 1 day of admission (vitamin C group) and those who did not (control group). High-dose vitamin C was defined as a dosage in excess of 10 g or 24 g within 2 days of admission. The primary outcome was in-hospital mortality.. Eligible patients (n = 2713) were categorized into the vitamin C group (n = 157) or control group (n = 2556). After 1:4 propensity score matching, we compared 157 and 628 patients who were administered high-dose vitamin C (> 10-g threshold) and controls, respectively. Under this particular threshold, high-dose vitamin C therapy was associated with reduced in-hospital mortality (risk ratio, 0.79; 95% confidence interval, 0.66-0.95; p = 0.006). In contrast, in-hospital mortality did not differ between the control and high-dose vitamin C group under the > 24-g threshold (risk ratio, 0.83; 95% confidence interval, 0.68-1.02; p = 0.068).. High-dose vitamin C therapy was associated with reduced mortality in patients with severe burns when used under a minimum threshold of 10 g within the first 2 days of admission. While "high-dose" vitamin C therapy lacks a universal definition, the present study reveals that different "high-dose" regimens may yield improved outcomes.

Topics: Adult; Ascorbic Acid; Burns; Cephalosporins; Cohort Studies; Continuous Renal Replacement Therapy; Critical Illness; Humans; Tazobactam

Extended-infusion ceftolozane-tazobactam treatment at 1.5 g every 8 h was used to treat multidrug-resistant Pseudomonas aeruginosa in a critically ill patient on continuous venovenous hemofiltration. Serum drug concentrations were measured at 1, 4, 5, 6, and 8 h after the start of infusion. Prefilter levels of ceftolozane produced a maximum concentration of drug (Cmax) of 38.57 μg/ml, concentration at the end of the dosing interval (Cmin) of 31.63 μg/ml, time to Cmax (Tmax) of 4 h, area under the concentration-time curve from 0 to 8 h (AUC0-8) of 284.38 μg · h/ml, and a half-life (t1/2) of 30.7 h. The concentrations were eight times the susceptibility breakpoint for the entire dosing interval.

Topics: Anti-Bacterial Agents; Cephalosporins; Critical Illness; Drug Resistance, Multiple, Bacterial; Hemofiltration; Humans; Intensive Care Units; Male; Microbial Sensitivity Tests; Middle Aged; Penicillanic Acid; Prospective Studies; Prosthesis-Related Infections; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam