Ceftolozane/tazobactam for the treatment of serious Pseudomonas aeruginosa infections: a multicentre nationwide clinical experience.

Augmented renal clearance (ARC) is a phenomenon in critically ill patients characterized by increased creatinine clearance and elimination of renally eliminated medications. Patients with severe neurologic injury, sepsis, trauma, and burns have been consistently identified as at risk of ARC, with mean creatinine clearances ranging from 170 ml/minute to more than 300 ml/minute. Several potential mechanisms may contribute to the occurrence of ARC including endogenous responses to increased metabolism and solute production, alterations in neurohormonal balance, and therapeutic maneuvers such as fluid resuscitation. Augmented renal clearance is associated with suboptimal exposure to critical medications, including β-lactams and vancomycin, increasing the risk of treatment failure. Although definitive screening tools are not yet known, critical care pharmacists must be vigilant in recognizing when ARC may be a contributing factor affecting expected treatment outcomes in individual patients. Optimizing dosing strategies in critically ill patients with ARC remains a goal of continued research. The current review discusses the clinical characteristics and methods of identifying patients at risk of ARC, potential mechanisms for ARC, and describes pharmacotherapy dosing considerations in patients with ARC.

Augmented Renal Clearance.

Early and appropriate antibiotic dosing is associated with improved clinical outcomes in critically ill patients, yet target attainment remains a challenge. Traditional antibiotic dosing is not suitable in critically ill patients, since these patients undergo physiological alterations that strongly affect antibiotic exposure. For beta-lactam antibiotics, the unbound plasma concentrations above at least one to four times the minimal inhibitory concentration (MIC) for 100% of the dosing interval (100%ƒT > 1–4×MIC) have been proposed as pharmacodynamic targets (PDTs) to maximize bacteriological and clinical responses. The objectives of this study are to describe the PDT attainment in critically ill patients and to identify risk factors for target non-attainment. This prospective observational study was performed in two ICUs in the Netherlands. We enrolled adult patients treated with the following beta-lactam antibiotics: amoxicillin (with or without clavulanic acid), cefotaxime, ceftazidime, ceftriaxone, cefuroxime, and meropenem. Based on five samples within a dosing interval at day 2 of therapy, the time unbound concentrations above the epidemiological cut-off (ƒT > MICECOFF and ƒT > 4×MICECOFF) were determined. Secondary endpoints were estimated multivariate binomial and binary logistic regression models, for examining the association of PDT attainment with patient characteristics and clinical outcomes. A total of 147 patients were included, of whom 63.3% achieved PDT of 100%ƒT > MICECOFF and 36.7% achieved 100%ƒT > 4×MICECOFF. Regression analysis identified male gender, estimated glomerular filtration rate (eGFR) ≥ 90 mL/min/1.73 m2, and high body mass index (BMI) as risk factors for target non-attainment. Use of continuous renal replacement therapy (CRRT) and high serum urea significantly increased the probability of target attainment. In addition, we found a significant association between the 100%ƒT > MICECOFF target attainment and ICU length of stay (LOS), but no significant correlation was found for the 30-day survival. Traditional beta-lactam dosing results in low target attainment in the majority of critically ill patients. Male gender, high BMI, and high eGFR were significant risk factors for target non-attainment. These predictors, together with therapeutic drug monitoring, may help ICU clinicians in optimizing beta-lactam dosing in critically ill patients. Netherlands Trial Registry (EXPAT trial), 
NTR 5632

. Registered on 7 December 2015.

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Failure of target attainment of beta-lactam antibiotics in critically ill patients and associated risk factors: a two-center prospective study (EXPAT)

Background Few data are reported in the literature about the outcome of patients with severe extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E) infections treated with ceftolozane/tazobactam (C/T), in empiric or definitive therapy. Methods A multicenter retrospective study was performed in Italy (June 2016-June 2019). Successful clinical outcome was defined as complete resolution of clinical signs/symptoms related to ESBL-E infection and lack of microbiological evidence of infection. The primary end point was to identify predictors of clinical failure of C/T therapy. Results C/T treatment was documented in 153 patients: pneumonia was the most common diagnosis (n = 46, 30%), followed by 34 cases of complicated urinary tract infections (22.2%). Septic shock was observed in 42 (27.5%) patients. C/T was used as empiric therapy in 46 (30%) patients and as monotherapy in 127 (83%) patients. Favorable clinical outcome was observed in 128 (83.7%) patients; 25 patients were considered to have failed C/T therapy. Overall, 30-day mortality was reported for 15 (9.8%) patients. At multivariate analysis, Charlson comorbidity index >4 (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.9-3.5; P = .02), septic shock (OR, 6.2; 95% CI, 3.8-7.9; P < .001), and continuous renal replacement therapy (OR, 3.1; 95% CI, 1.9-5.3; P = .001) were independently associated with clinical failure, whereas empiric therapy displaying in vitro activity (OR, 0.12; 95% CI, 0.01-0.34; P < .001) and adequate source control of infection (OR, 0.42; 95% CI, 0.14-0.55; P < .001) were associated with clinical success. Conclusions Data show that C/T could be a valid option in empiric and/or targeted therapy in patients with severe infections caused by ESBL-producing Enterobacterales. Clinicians should be aware of the risk of clinical failure with standard-dose C/T therapy in septic patients receiving CRRT.

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Ceftolozane/Tazobactam for Treatment of Severe ESBL-Producing Enterobacterales Infections: A Multicenter Nationwide Clinical Experience (CEFTABUSE II Study).

Augmented renal clearance (ARC) refers to the state of heightened renal filtration commonly observed in the critically ill. Its prevalence in this patient population is a consequence of the body’s natural response to serious disease, as well as the administration of fluids and pharmacologic therapies necessary to maintain sufficient blood pressure. ARC is objectively defined as a creatinine clearance of more than 130 mL/min/1.73 m2 and is thus a crucial condition to consider when administering antibiotics, many of which are cleared renally. Using conventional dosing regimens risks the possibility of subtherapeutic concentrations or clinical failure. Over the past decade, research has been conducted in patients with ARC who received a number of antibacterials frequently used in the critically ill, such as piperacillin-tazobactam or vancomycin. Strategies to contend with this condition have also been explored, though further investigations remain necessary.

Augmented Renal Clearance and How to Augment Antibiotic Dosing

Association between augmented renal clearance, antibiotic exposure and clinical outcome in critically ill septic patients receiving high doses of β-lactams administered by continuous infusion: a prospective observational study

Augmented renal clearance (ARC) is recognized as a leading cause of β-lactam subexposure when conventional dosing regimens are used. The main objective was to compare the clinical outcome of ARC patients treated by conventional or increased β-lactam dosing regimens for a first episode of hospital or ventilator-acquired pneumonia (HAP-VAP). In this single-center, retrospective study, every ARC patient treated by β-lactam for a first episode of HAP-VAP was included during two 15-month periods, before (Control period) and after (Treatment period) the modification of a local antibiotic therapy protocol. ARC was defined by a 24-h measured creatinine clearance ≥ 150 ml/min. The primary endpoint was defined as a therapeutic failure of the antimicrobial therapy or a HAP-VAP relapse within 28 days. Inverse probability of treatment weight (IPTW) was derived from a propensity score model. Cox proportional hazard models were used to evaluate the association between treatment period and clinical outcome. During the study period, 177 patients were included (control period, N = 88; treatment period, N = 89). Therapeutic failure or HAP-VAP relapse was significantly lower in the treatment period (10 vs. 23%, p = 0.019). The IPTW-adjusted hazard ratio of poor clinical outcome in the treatment period was 0.35 (95% CI 0.15–0.81), p = 0.014. No antibiotic side effect was reported during the treatment period. Higher than licensed dosing regimens of β-lactams may be safe and effective in reducing the rate of therapeutic failure and HAP-VAP recurrence in critically ill augmented renal clearance (ARC) patients.

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Increased β-Lactams dosing regimens improve clinical outcome in critically ill patients with augmented renal clearance treated for a first episode of hospital or ventilator-acquired pneumonia: a before and after study

May levosimendan be safe and effective in refractory vasospasm despite adequate treatment with repeated angiography and milrinone infusion after subarachnoid haemorrhage

Noemie Sauvage

Papers

Association between augmented renal clearance, antibiotic exposure and clinical outcome in critically ill septic patients receiving high doses of β-lactams administered by continuous infusion: a prospective observational study

Increased β-Lactams dosing regimens improve clinical outcome in critically ill patients with augmented renal clearance treated for a first episode of hospital or ventilator-acquired pneumonia: a before and after study

May levosimendan be safe and effective in refractory vasospasm despite adequate treatment with repeated angiography and milrinone infusion after subarachnoid haemorrhage