Population pharmacokinetics and dosing optimization of azlocillin in neonates with early-onset sepsis: a real-world study

Wu, Yue‐E; Wang, Tao; Yang, Hui; Tang, Bo‐Hao; Kong, Li; Li, Xin; Gao, Qi; Li, Xue; Yao, Bu‐Fan; Shi, Haiyan; Huang, Xin; Wang, Wenqi; Jacqz-Aigrain, Évelyne; Allegaert, Karel; Anker, John van den; Tian, Xiuying; Zhao, Wei

doi:10.1093/jac/dkaa468

Cited by 12 publications

(14 citation statements)

References 41 publications

(29 reference statements)

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“…In a recent phase II clinical trial of azlocillin in preterm and term infants ≤ 72 h old, Wu et al conducted Monte Carlo simulations with a desired target of 70% f T> MIC up to 32 mg/L. The authors showed that increasing the frequency (100 mg/kg every 8 h) achieved the target in 91.2% of infants compared to 63.1% of PTA with 100 mg/kg, every 12 h, both with a 0.5 h infusion ( 15 ).…”

Section: Resultsmentioning

confidence: 99%

Beta-Lactams Therapeutic Monitoring in Septic Children–What Target Are We Aiming for? A Scoping Review

et al. 2022

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The antimicrobial therapy of sepsis and septic shock should be individualized based on pharmacokinetic/pharmacodynamic (PK/PD) parameters to deliver effective and timely treatment of life-threatening infections. We conducted a literature scoping review to identify therapeutic targets of beta-lactam antibiotics in septic pediatric patients and the strategies that have been applied to overcome sepsis-related altered pharmacokinetics and increase target attainment against susceptible pathogens. A systematic search was conducted in the MEDLINE, EMBASE and Web of Science databases to select studies conducted since 2010 with therapeutic monitoring data of beta-lactams in septic children. Last searches were performed on 02 September 2021. Two independent authors selected the studies and extracted the data. A narrative and qualitative approach was used to summarize the findings. Out of the 118 identified articles, 21 met the eligibility criteria. Population pharmacokinetic modeling was performed in 12 studies, while nine studies reported data from bedside monitoring of beta-lactams. Most studies were conducted in the United States of America (n = 9) and France (n = 5) and reported PK/PD data of amoxicillin, ampicillin, azlocillin, aztreonam, cefazolin, cefepime, cefotaxime, ceftaroline, ceftazidime, doripenem, meropenem and piperacillin/tazobactam. Therapeutic targets ranged from to 40% fT> MIC to 100% fT> 6 × MIC. Prolonging the infusion time and frequency were most described strategies to increase target attainment. Monitoring beta-lactam serum concentrations in clinical practice may potentially maximize therapeutic target attainment. Further studies are required to define the therapeutic target associated with the best clinical outcomes.

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Section: Resultsmentioning

confidence: 99%

Beta-Lactams Therapeutic Monitoring in Septic Children–What Target Are We Aiming for? A Scoping Review

et al. 2022

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“…4 Although well documented in adults, PK and PD of these antibiotics are poorly explored in critically ill neonates; the sparsity of studies suggests that current dosing is frequently inadequate. [59][60][61] Therefore, there is an urgent need to characterize a population PK of commonly used beta-lactams in neonates associated with target attainment to develop evidence-based dosing schemes and TDM practices. Recently, population PK models for the penicillins, amoxicillin, piperacillin, azlocillin, and the cephalosporin cefathiamidine have been developed and used to calculate target attainment with present SmPC and local dosing schemes.…”

Section: Beta-lactam Antibioticsmentioning

confidence: 99%

Therapeutic Drug Monitoring of Antimicrobial Drugs in Neonates: An Opinion Article

Touw

Anker

2022

Therapeutic Drug Monitoring

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Background: Neonatal infections are associated with high morbidity and mortality rates. Optimal treatment of these infections requires knowledge of neonatal pharmacology and integration of neonatal developmental pharmacokinetics (PKs) of antimicrobial drugs in the design of dosing regimens for use with different gestational and postnatal ages. Population PK and pharmacodynamic models are used to personalize the use of these drugs in these fragile patients. The final step to further minimize variability in an individual patient is therapeutic drug monitoring (TDM), where the same population PK/pharmacodynamic models are used in concert with optimally drawn blood samples to further fine-tune therapy. The purpose of this article is to describe the present status and future role of model-based precision dosing and TDM of antimicrobial drugs in neonates. Methods: PubMed was searched for clinical trials or clinical studies of TDM in neonates.Results: A total of 447 articles were retrieved, of which 19 were concerned with antimicrobial drugs. Two articles (one aminoglycoside and one vancomycin) addressed the effects of TDM in neonates. We found that, in addition to aminoglycosides and vancomycin, TDM also plays a role in beta-lactam antibiotics and antifungal drugs.Conclusions: There is a growing awareness that, in addition to aminoglycosides and vancomycin, the use of beta-lactam antibiotics, such as amoxicillin and meropenem, and other classes of antimicrobial drugs, such as antifungal drugs, may benefit from TDM. However, the added value must be shown. New analytical techniques and software development may greatly support these novel developments.

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“…To ensure that the finding of this trial can comprehensively reflect PD characteristics of latamoxef in EONS treatment, 70% fT > MIC will be used as the primary outcome indicator, and efficacy and safety indexes will be employed as the secondary outcome indicators. Because there’s no clinical evaluation of latamoxef in EONS treatment, the trial design is derived from other clinical trials about cephalosporin treatment or therapeutic decision conducted in children or neonates ( Stocker et al, 2017 ; Wu et al, 2020 ). Rate of treatment failure, duration of antibiotic therapy, changes of inflammatory indicators, results of blood culture and incidence of AEs are commonly used indicators in efficacy and safety evaluation for anti-infective agents ( Molyneux et al, 2011 ; Stocker et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

“…The primary outcome will be 70% fT > MIC, which is the target rate of 70% of patients having a free antimicrobial drug concentration exceeding the MIC during 70% of the dosing interval. 70% fT > MIC is appropriate to evaluate therapeutic efficacy of time dependent antibiotics in neonates ( Craig, 1995 ; Wu et al, 2020 ). Based on PPK model of latamoxef, 70% fT > MIC will be calculated after testing plasma drug concentration at the initial stage of treatment ( Table 3 ).…”

Section: Methods and Designmentioning

confidence: 99%

Latamoxef for Neonates With Early-Onset Neonatal Sepsis: A Study Protocol for a Randomized Controlled Trial

Liu

et al. 2021

Front. Pharmacol.

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Early-onset neonatal sepsis (EONS), a bacterial infection that occurs within 72 h after birth, is associated with high likelihood of neonatal mortality. Latamoxef, a semi-synthetic oxacephem antibiotic developed in 1980s, has been brought back into empirical EONS treatment in recent years. In the preliminary work, we established a population pharmacokinetics (PPK) model for latamoxef in Chinese neonates. Moreover, in order to better guide clinical treatment, we conducted dose simulation and found that ascending administration frequency could improve the target rate of 70% of patients having a free antimicrobial drug concentration exceeding the MIC during 70% of the dosing interval (70% fT > MIC). Accordingly, this study is aimed to compare the 70% fT > MIC, efficacy and safety between conventional regimen and PPK model regimen for rational use of latamoxef in EONS treatment. A single-blind, multicenter randomized controlled trial (RCT) for latamoxef will be conducted in Chinese EONS patients. Neonates (≤3 days of age, expected number = 114) admitted to the hospital with the diagnosis of EONS and fulfilling inclusion and exclusion criteria will be randomized (ratio of 1:1) to either a conventional regimen (30 mg/kg q12h) or model regimen (20 mg/kg q8h) latamoxef treatment group for at least 3 days. Primary outcome measure will be 70% fT > MIC and secondary outcome indicators will be the latamoxef treatment failure, duration of antibiotic therapy, changes of white blood cell count (WBC), C-reactive protein (CRP) and procalcitonin (PCT), blood culture results during administration and incidence of adverse event (AE)s. Assessments will be made at baseline, initial stage of latamoxef treatment (18–72 h) and before the end of latamoxef treatment. Ethical approval of our clinical trial has been granted by the ethics committee of the Beijing Children’s Hospital (ID: 2020-13-1). Written informed consent will be obtained from the parents of the participants. This trial is registered in the Chinese Clinical Trial Registry (ChiCTR 2000040064).It is hoped that our study will provide a clinical basis for the rational clinical use of latamoxef in EONS treatment.

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Population pharmacokinetics and dosing optimization of azlocillin in neonates with early-onset sepsis: a real-world study

Cited by 12 publications

References 41 publications

Beta-Lactams Therapeutic Monitoring in Septic Children–What Target Are We Aiming for? A Scoping Review

Beta-Lactams Therapeutic Monitoring in Septic Children–What Target Are We Aiming for? A Scoping Review

Therapeutic Drug Monitoring of Antimicrobial Drugs in Neonates: An Opinion Article

Latamoxef for Neonates With Early-Onset Neonatal Sepsis: A Study Protocol for a Randomized Controlled Trial

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