Correction to: Effect of therapeutic drug monitoring-based dose optimization of piperacillin/tazobactam on sepsis-related organ dysfunction in patients with sepsis: a randomized controlled trial.
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ABSTRACT:
SUBMITTER: Hagel S
PROVIDER: S-EPMC9050772 | biostudies-literature | 2022 May
REPOSITORIES: biostudies-literature
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Correction to: Effect of therapeutic drug monitoring-based dose optimization of piperacillin/tazobactam on sepsis-related organ dysfunction in patients with sepsis: a randomized controlled trial.
Hagel Stefan S Bach Friedhelm F Brenner Thorsten T Bracht Hendrik H Brinkmann Alexander A Annecke Thorsten T Hohn Andreas A Weigand Markus Alexander MA Michels Guido G Kluge Stefan S Nierhaus Axel A Jarczak Dominik D König Christina C Weismann Dirk D Frey Otto O Witzke Dominic D Müller Carsten C Bauer Michael M Kiehntopf Michael M Neugebauer Sophie S Lehmann Thomas T Roberts Jason A JA Pletz Mathias W MW
Intensive care medicine 20220501 5
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Project description:PurposeInsufficient antimicrobial exposure is associated with worse outcomes in sepsis. We evaluated whether therapeutic drug monitoring (TDM)-guided antibiotic therapy improves outcomes.MethodsRandomized, multicenter, controlled trial from January 2017 to December 2019. Adult patients (n = 254) with sepsis or septic shock were randomly assigned 1:1 to receive continuous infusion of piperacillin/tazobactam with dosing guided by daily TDM of piperacillin or continuous infusion with a fixed dose (13.5 g/24 h if eGFR ≥ 20 mL/min). Target plasma concentration was four times the minimal inhibitory concentration (range ± 20%) of the underlying pathogen, respectively, of Pseudomonas aeruginosa in empiric situation. Primary outcome was the mean of daily total Sequential Organ Failure Assessment (SOFA) score up to day 10.ResultsAmong 249 evaluable patients (66.3 ± 13.7 years; female, 30.9%), there was no significant difference in mean SOFA score between patients with TDM (7.9 points; 95% CI 7.1-8.7) and without TDM (8.2 points; 95% CI 7.5-9.0) (p = 0.39). Patients with TDM-guided therapy showed a lower 28-day mortality (21.6% vs. 25.8%, RR 0.8, 95% CI 0.5-1.3, p = 0.44) and a higher rate of clinical (OR 1.9; 95% CI 0.5-6.2, p = 0.30) and microbiological cure (OR 2.4; 95% CI 0.7-7.4, p = 0.12), but these differences did not reach statistical significance. Attainment of target concentration was more common in patients with TDM (37.3% vs. 14.6%, OR 4.5, CI 95%, 2.9-6.9, p < 0.001).ConclusionTDM-guided therapy showed no beneficial effect in patients with sepsis and continuous infusion of piperacillin/tazobactam with regard to the mean SOFA score. Larger studies with strategies to ensure optimization of antimicrobial exposure are needed to definitively answer the question.
| S-EPMC8866359 | biostudies-literature
Project description:BackgroundSepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection with a hospital mortality in excess of 40%. Along with insufficient and delayed empirical antimicrobial therapy, inappropriate antimicrobial exposure has been identified to negatively affect patient outcomes. Receipt of prolonged infusion (i.e. extended or continuous infusion) of piperacillin/tazobactam (TZP) improves antimicrobial exposure and is associated with reduced mortality in patients with sepsis. Using therapeutic drug monitoring (TDM) with dosing tailored to the altered pharmacokinetics of the individual patient to avoid under- and overdosing may be a further strategy to improve patient outcomes. This current trial will address the question whether a TDM-guided therapy with TZP administered by continuous infusion will result in a greater resolution of organ dysfunction and hence better clinical outcome compared to continuous infusion of the total daily dose of TZP without TDM.MethodsThe study is an investigator-initiated, multi-centre, parallel-group, single-blinded, randomised controlled trial. The trial will be conducted in several centres across Germany. Adult patients (aged ≥ 18 years) with severe sepsis or septic shock will be eligible for study participation. Participants will be randomly assigned to receive either TZP by continuous infusion guided by daily TDM of piperacillin (experimental group) or by continuous infusion without TDM guidance (total daily dose in normal renal function 13.5 g TZP) (control group). The pharmacokinetic (PK)/pharmacodynamic (PD) target will be 100% f T>4MIC (percentage of time during a dosing interval that the free [f] drug concentration exceeds 4 times the minimum inhibitory concentration). The primary efficacy endpoint is the change in mean total Sequential Organ Failure Assessment score from day 1 after randomisation until day 10 or discharge from the intensive care unit or death, whichever comes first. Secondary outcomes include mortality, clinical cure, microbiological cure, overall antibiotic use, individual components of the primary outcome, adverse events and analysis of PK and (PD) indices.DiscussionThis trial will assess for the first time whether continuous infusion of TZP guided by daily TDM in patients with sepsis will result in a greater resolution of organ dysfunction and hence better clinical outcome compared to continuous infusion without TDM.Trial registrationGerman Clinical Trials Register (GermanCTR), DRKS00011159 . Registered on 10 October 2016.
| S-EPMC6554958 | biostudies-literature
Project description:Piperacillin/tazobactam (PTZ) is frequently prescribed during the perioperative period as prophylaxis in critically ill patients. Current international guidelines recommend that the pediatric intraoperative dosing regimen for PTZ be 90-112.5 mg/kg (80-100 mg/kg as piperacillin [PIP]) administered every 2 hours (Q2H). Concerns have been raised not only about the risk of nephrotoxicity due to elevated PIP exposure but also regarding the practicality of adhering to a 2-h dosing interval in clinical settings. To address these concerns, we employed population pharmacokinetic (PK) modeling and simulation approaches to optimize PTZ dosing regimens in pediatric intraoperative patients. PIP plasma concentration data were obtained from 34 patients using an opportunistic sampling strategy. A two-compartment model was found to adequately describe the PK data. Creatinine clearance was identified as a significant covariate on clearance. The inclusion of inter-occasion variability significantly improved model fit. Simulations across body weights of 10-70 kg and creatinine clearance of 20-130 mL/min/1.73 m2 demonstrated that 6-15 mg/kg Q2H, or a 10 mg/kg loading dose followed by 1.0-2.75 mg/kg/h continuous infusion would achieve free PIP concentrations being above the minimum inhibitory concentration (MIC) for 100% of the dosing interval (100% fT >1× MIC). For achieving 100% fT >4× MIC, 25-55 mg/kg Q2H or a 20 mg/kg loading dose followed by 3.25-9.25 mg/kg/h continuous infusion was derived. The model-informed simulations indicated that both lower Q2H doses and continuous infusion methods are clinically viable options and potentially resolve current clinical challenges during intraoperative dosing.
| S-EPMC11881557 | biostudies-literature
Project description:Background and objectiveStandard piperacillin-tazobactam (P-T) dosing may be suboptimal in obesity, but high-dose regimens have not been studied. We prospectively evaluated the pharmacokinetics and pharmacodynamics of standard- and high-dose P-T in obese adult inpatients.MethodsThose receiving standard-dose P-T with BMI ≥ 30 kg/m2 weighing 105-139 kg or ≥ 140 kg were given up to 6.75 g or 9 g every 6 h, respectively. Patients were monitored closely for safety. Elimination phase blood samples were drawn for 28 patients on standard and high doses to calculate the pharmacokinetic values using a one-compartment model. The likelihood of pharmacodynamic target attainment (100% fT > 16/4 mg/L) on various P-T regimens was calculated using each patient's own pharmacokinetic values.ResultsPiperacillin and tazobactam half-lives ranged from 0.5-10.6 to 0.9-15.0 h, while volumes of distribution ranged from 13.6-54.8 to 11.5-60.1 L, respectively. Predicted dose requirements for target attainment ranged from 2.25 g every 6 h in hemodialysis patients to a 27 g/24-h continuous infusion in a patient with a short P-T half-life. An amount of 4.5 g every 6 h would have met the target for only 1/12 (8%) patients with creatinine clearance ≥ 80 mL/min and 13/28 (46%) for all enrolled patients. One patient (3%) experienced an adverse event deemed probably related to high-dose P-T.ConclusionSome patients required high P-T doses for target attainment, but dosing requirements were highly variable. Doses up to 6.75 g or 9 g every 6 h may be tolerable; however, studies are needed to see if high dosing, prolonged infusions, or real-time therapeutic drug monitoring improves outcomes in obese patients. CLINICAL TRIAL REGISTRATION (CLINICALTRIALS.GOV): NCT01923363.
| S-EPMC8093170 | biostudies-literature
Project description: Not available
| S-EPMC11837518 | biostudies-literature
Project description:BackgroundPiperacillin/tazobactam, a commonly used antibiotic, is associated with acute kidney injury (AKI). The relationship between piperacillin concentrations and AKI remains unknown.ObjectiveEstimate piperacillin exposures in critically ill children and young adults administered piperacillin/tazobactam to identify concentrations and clinical factors associated with piperacillin-associated AKI.Patients and methodsWe assessed piperacillin pharmacokinetics in 107 patients admitted to the paediatric ICU who received at least one dose of piperacillin/tazobactam. Piperacillin AUC, highest peak (Cmax) and highest trough (Cmin) in the first 24 hours of therapy were estimated. Piperacillin-associated AKI was defined as Kidney Disease: Improving Global Outcomes (KDIGO) Stage 2/3 AKI present >24 hours after initial piperacillin/tazobactam dose. Likelihood of piperacillin-associated AKI was rated using the Naranjo Adverse Drug Reaction Probability Scale. Multivariable logistic regression was performed to identify patient and clinical predictors of piperacillin-associated AKI.ResultsOut of 107 patients, 16 (15%) were rated as possibly or probably having piperacillin-associated AKI. Estimated AUC and highest Cmin in the first 24 hours were higher in patients with piperacillin-associated AKI (2042 versus 1445 mg*h/L, P = 0.03; 50.1 versus 10.7 mg/L, P < 0.001). Logistic regression showed predictors of piperacillin-associated AKI included higher Cmin (OR: 5.4, 95% CI: 1.7-23) and age (OR: 1.13, 95% CI: 1.05-1.25).ConclusionsWe show a relationship between estimated piperacillin AUC and highest Cmin in the first 24 hours of piperacillin/tazobactam therapy and piperacillin-associated AKI, suggesting total piperacillin exposure early in the course is associated with AKI development. These data could serve as the foundation for implementation of model-informed precision dosing to reduce AKI incidence in patients given piperacillin/tazobactam.
| S-EPMC10169424 | biostudies-literature
Project description:Piperacillin and Tazobactam Injection is a combination product consisting of a penicillin-class antibacterial, piperacillin, and a beta-lactamase inhibitor, tazobactam, indicated for the treatment of patients with moderate to severe infections caused by susceptible isolates of bacteria. In the past decade some quality problems have been noted by the US Food and Drug Administration (FDA) with the Apotex Corp. manufacturing. Intra-lot and inter-lot variability in the spectra of Piperacillin and Tazobactam Injection 3.375 g was detected in the Drug Quality Study (DQS) using Fourier transform near-infrared spectrometry (FTNIR). One vial of 6 (17%) sampled from lot AD103008F3 appeared 14.4 multidimensional SDs from the other vials, suggesting that it represents a different material. Spectra of 132 vials from 19 lots in the spectral library contained 4 vials that were outside the group (21.0 SDs using a subcluster detection test), suggesting that the 4 library vials (3%) also contain differing materials.
| S-EPMC9060210 | biostudies-literature
Project description:Sepsis is a dysregulated immune response to an infection that leads to organ dysfunction. Sepsis-associated organ dysfunction involves multiple inflammatory mechanisms and complex metabolic reprogramming of cellular function. These mechanisms cooperate through multiple organs and systems according to a complex set of long-distance communications mediated by cellular pathways, solutes, and neurohormonal actions. In sepsis, the concept of organ crosstalk involves the dysregulation of one system, which triggers compensatory mechanisms in other systems that can induce further damage. Despite the abundance of studies published on organ crosstalk in the last decade, there is a need to formulate a more comprehensive framework involving all organs to create a more detailed picture of sepsis. In this paper, we review the literature published on organ crosstalk in the last 10 years and explore how these relationships affect the progression of organ failure in patients with septic shock. We explored these relationships in terms of the heart-kidney-lung, gut-microbiome-liver-brain, and adipose tissue-muscle-bone crosstalk in sepsis patients. A deep connection exists among these organs based on crosstalk. We also review how multiple therapeutic interventions administered in intensive care units, such as mechanical ventilation, antibiotics, anesthesia, nutrition, and proton pump inhibitors, affect these systems and must be carefully considered when managing septic patients. The progression to multiple organ dysfunction syndrome in sepsis patients is still one of the most frequent causes of death in critically ill patients. A better understanding and monitoring of the mechanics of organ crosstalk will enable the anticipation of organ damage and the development of individualized therapeutic strategies.
| S-EPMC11413314 | biostudies-literature
Project description:Continuous infusion of beta-lactam antibiotics has emerged as an alternative for the treatment of sepsis because of the favourable pharmacokinetics of continuous infusion. This study aimed to evaluate the survival benefits of continuous vs. intermittent infusion of piperacillin-tazobactam in critically ill patients with sepsis. We retrospectively conducted a single-centre study of continuous infusion vs. intermittent infusion of piperacillin-tazobactam for adult patients who met the Sepsis-3 criteria and were treated at a medical ICU within 48 h after hospitalisation between 1 May 2018 and 30 April 2020. The primary outcome was mortality at 28 days. A total of 157 patients (47 in the continuous group and 110 in the intermittent group) met the inclusion criteria for evaluation. The 28-day mortality rates were 12.8% in the continuous group and 27.3% in the intermittent group (p = 0.07). However, after adjustment for potential covariables, patients in the continuous group (12.8%) showed significantly lower mortality at 28 days than those in the intermittent group (27.3%; adjusted hazard ratio (HR), 0.31; 95% confidence interval (CI), 0.13-0.79; p = 0.013). In sepsis patients, continuous infusion of piperacillin-tazobactam may confer a benefit regarding the avoidance of mortality at 28 days compared with intermittent infusion.
| S-EPMC9686508 | biostudies-literature
Project description:Piperacillin-tazobactam resistance in Klebsiella pneumoniae is often mediated by blaSHV amplification in a widespread plasmid
| PRJEB88171 | ENA