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Augmented renal clearance implies a need for increased amoxicillin-clavulanic acid dosing in critically ill children.

ABSTRACT: There is little data available to guide amoxicillin-clavulanic acid dosing in critically ill children. The primary objective of this study was to investigate the pharmacokinetics of both compounds in this pediatric subpopulation. Patients admitted to the pediatric intensive care unit (ICU) in whom intravenous amoxicillin-clavulanic acid was indicated (25 to 35 mg/kg of body weight every 6 h) were enrolled. Population pharmacokinetic analysis was conducted, and the clinical outcome was documented. A total of 325 and 151 blood samples were collected from 50 patients (median age, 2.58 years; age range, 1 month to 15 years) treated with amoxicillin and clavulanic acid, respectively. A three-compartment model for amoxicillin and a two-compartment model for clavulanic acid best described the data, in which allometric weight scaling and maturation functions were added a priori to scale for size and age. In addition, plasma cystatin C and concomitant treatment with vasopressors were identified to have a significant influence on amoxicillin clearance. The typical population values of clearance for amoxicillin and clavulanic acid were 17.97 liters/h/70 kg and 12.20 liters/h/70 kg, respectively. In 32% of the treated patients, amoxicillin-clavulanic acid therapy was stopped prematurely due to clinical failure, and the patient was switched to broader-spectrum antibiotic treatment. Monte Carlo simulations demonstrated that four-hourly dosing of 25 mg/kg was required to achieve the therapeutic target for both amoxicillin and clavulanic acid. For patients with augmented renal function, a 1-h infusion was preferable to bolus dosing. Current published dosing regimens result in subtherapeutic concentrations in the early period of sepsis due to augmented renal clearance, which risks clinical failure in critically ill children, and therefore need to be updated. (This study has been registered at Clinicaltrials.gov as an observational study [NCT02456974].).

SUBMITTER: De Cock PA

PROVIDER: S-EPMC4604416 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Augmented renal clearance implies a need for increased amoxicillin-clavulanic acid dosing in critically ill children.

De Cock Pieter A J G PA Standing Joseph F JF Barker Charlotte I S CI de Jaeger Annick A Dhont Evelyn E Carlier Mieke M Verstraete Alain G AG Delanghe Joris R JR Robays Hugo H De Paepe Peter P

Antimicrobial agents and chemotherapy 20150908 11

There is little data available to guide amoxicillin-clavulanic acid dosing in critically ill children. The primary objective of this study was to investigate the pharmacokinetics of both compounds in this pediatric subpopulation. Patients admitted to the pediatric intensive care unit (ICU) in whom intravenous amoxicillin-clavulanic acid was indicated (25 to 35 mg/kg of body weight every 6 h) were enrolled. Population pharmacokinetic analysis was conducted, and the clinical outcome was documented ...[more]

PMID: 26349821

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Project description:Background: Data regarding antimicrobial pharmacokinetics (PK) in critically ill dogs are lacking and likely differ from those of healthy dogs. The aim of this work is to describe a population PK model for intravenous (IV) amoxicillin-clavulanic acid (AMC) in both healthy and sick dogs and to simulate a range of clinical dosing scenarios to compute PK/PD cutoffs for both populations. Methods: This study used a prospective clinical trial in normal and critically ill dogs. Twelve client-owned dogs hospitalized in the intensive care unit (ICU) received IV AMC 20 mg/kg every 8 h (0.5-h infusion) during at least 48 h. Eight blood samples were collected at predetermined times, including four trough samples before the next administration. Clinical covariates and outcome were recorded, including survival to discharge and bacteriologic clinical failure. Satellite PK data were obtained de novo from a group of 12 healthy research dogs that were dosed with a single AMC 20 mg/kg IV. Non-linear mixed-effects model was used to estimate the PK parameters (and the effect of health upon them) together with variability within and between subjects. Monte Carlo simulations were performed with seven dosage regimens (standard and increased doses). The correlation between model-derived drug exposure and clinical covariates was tested with Spearman's non-parametric correlation analysis. Outcome was recorded including survival to discharge and bacteriologic clinical failure. Results: A total of 218 amoxicillin concentrations in plasma were available for healthy and sick dogs. A tricompartmental model best described the data. Amoxicillin clearance was reduced by 56% in sick dogs (0.147 L/kg/h) compared with healthy dogs (0.336 L/kg/h); intercompartmental clearance was also decreased (p <0.01). None of the clinical data covariates were significantly correlated with individual exposure. Monte Carlo simulations showed that higher PK/PD cutoff values of 8 mg/L could be reached in sick dogs by extending the infusion to 3 h or doubling the dose. Conclusions: The PK of AMC is profoundly different in critically ill dogs compared with normal dogs, with much higher interindividual variability and a lower systemic clearance. Our study allows to generate hypotheses with regard to higher AMC exposure in clinical dogs and provides supporting data to revise current AMC clinical breakpoint for IV administration.

Project description:BackgroundBroad-spectrum antibiotics are commonly prescribed in critically ill patients. While it is commonly believed that only patients with impaired renal function need dose adjustment, augmented renal clearance (ARC) is a phenomenon that warrants dose adjustment as well. In critically ill patients ARC is often undetectable because it is associated with a normal or decreased serum creatinine concentration (SCr). This study's objective was to assess pharmacists' knowledge about ARC identification, risk factors, affected antimicrobials, and dosing of antibiotics in patients with ARC.MethodsIn January 2020, we carried out a cross-sectional study by sending out an online survey to the Saudi Pharmaceutical Society, Kuwait Pharmaceutical Association, and Oman Pharmaceutical Society. Due to the expected low response rate, we administered an electronic questionnaire to pharmacists attending Dubai International Pharmaceuticals and Technologies Conference and Exhibition 2020 (DUPHAT).ResultsData were collected from 288 respondents. However, only 134 were included in the final analysis following the exclusion of incomplete responses, no experience working in in-patient settings, and respondents who chose "no" universal ARC definition. Those who chose "yes" or "I do not know" regarding the universal definition of ARC were asked about SCr status in ARC. Elevation in SCr was chosen by 67/134 (50%) compared to those who chose decreased or normal (48/134, 35.8%). Regarding risk factors, only 1/134 (0.7%) respondent selected all risk factors. Two/134 (1.4%) respondents chose all hydrophilic antibiotics that are likely to be affected by ARC. Concerning the appropriate dose and frequency of piperacillin-tazobactam and meropenem, they were selected by 60.4% and 30.5%, respectively.ConclusionPharmacists' knowledge about ARC was limited. Implementation of educational programs targeting hospital pharmacists, especially those practicing in critical care settings, and developing antimicrobial institutional guidelines are important.

Project description:Fluconazole is frequently used for the treatment of invasive Candida infections in critically ill patients. However, alterations in renal functions might influence fluconazole clearance. Therefore, our objective was to study the impact of renal function on the population pharmacokinetics of fluconazole in critically ill patients with various degrees of renal function or undergoing continuous renal replacement therapy (CRRT). This was an open-label, multicenter observational study. Critically ill patients receiving fluconazole were included. Baseline and clinical data were collected. At days 3 and 7 of enrollment, blood samples were drawn for pharmacokinetic curves. Additionally, daily trough samples were taken. A nonlinear mixed-effects model was built, followed by Monte Carlo simulations for assessment of exposure to various dosages of fluconazole. Nineteen patients were included with a median age of 64.4 (range, 23 to 81) years and median weight of 82.0 (range, 44.0 to 119.5) kg. A linear two-compartment model best described fluconazole pharmacokinetics and demonstrated higher clearance than expected in critically ill patients. Simulations showed that daily dosages of 600 mg and 800 mg are needed for intensive care unit (ICU) patients with normal renal function and patients on CRRT, respectively, to achieve the EUCAST-recommended target fAUC (area under the concentration-time curve for the free, unbound fraction of the drug)/MIC ratio of 100. In conclusion, fluconazole clearance is highly variable in ICU patients and is strongly dependent on renal function and CRRT. Trough concentrations correlated well with the AUC, opening up opportunities for tailored dosing using therapeutic drug monitoring. We recommend doses of 400 mg for patients with poor to moderate renal function, 600 mg for patients with adequate renal function, and 800 mg for patients treated with CRRT. (This study has been registered at ClinicalTrials.gov under identifier NCT02666716.).

Project description:Amoxicillin-clavulanic acid (AMC) is one of the most frequently prescribed antibiotic formulations in the Western world. Extensive oral use of this antimicrobial combination influences the gut microbiota. One of the most abundant early colonizers of the human gut microbiota is represented by different taxa of the Bifidobacterium genus, which include many members that are considered to bestow beneficial effects upon their host. In the current study, we investigated the impact of AMC administration on the gut microbiota composition, comparing the gut microbiota of 23 children that had undergone AMC antibiotic therapy to that of 19 children that had not been treated with antibiotics during the preceding 6 months. Moreover, we evaluated AMC sensitivity by MIC test of 261 bifidobacterial strains, including reference strains for the currently recognized 64 bifidobacterial (sub)species, as well as 197 bifidobacterial isolates of human origin. These assessments allowed the identification of four bifidobacterial strains that exhibit a high level of AMC insensitivity, which were subjected to genomic and transcriptomic analyses to identify the putative genetic determinants responsible for this AMC insensitivity. Furthermore, we investigated the ecological role of AMC-resistant bifidobacterial strains by in vitro batch cultures.IMPORTANCE Based on our results, we observed a drastic reduction in gut microbiota diversity of children treated with antibiotics, which also affected the abundance of Bifidobacterium, a bacterial genus commonly found in the infant gut. MIC experiments revealed that more than 98% of bifidobacterial strains tested were shown to be inhibited by the AMC antibiotic. Isolation of four insensitive strains and sequencing of their genomes revealed the identity of possible genes involved in AMC resistance mechanisms. Moreover, gut-simulating in vitro experiments revealed that one strain, i.e., Bifidobacterium breve PRL2020, is able to persist in the presence of a complex microbiota combined with AMC antibiotic.

Project description:Dose optimization of novel β-lactam antibiotics (NBLA) has become necessary given the increased prevalence of multidrug-resistant infections in intensive care units coupled with the limited number of available treatment options. Unfortunately, recommended dose regimens of NBLA based on PK/PD indices are not well-defined for critically ill patients presenting with special situations (i.e., obesity, extracorporeal membrane oxygenation (ECMO), augmented renal clearance (ARC), and renal replacement therapies (RRT)). This review aimed to discuss and summarize the available literature on the PK/PD attained indices of NBLA among critically ill patients with special circumstances. PubMed, MEDLINE, Scopus, Google Scholar, and Embase databases were searched for studies published between January 2011 and May 2022. Articles relevant to NBLA (i.e., ceftolozane/tazobactam, ceftazidime/avibactam, cefiderocol, ceftobiprole, imipenem/relebactam, and meropenem/vaborbactam) were selected. The MeSH terms of "obesity", "augmented renal clearance", "renal replacement therapy", "extracorporeal membrane oxygenation", "pharmacokinetic", "pharmacodynamic" "critically ill", and "intensive care" were used for identification of articles. The search was limited to adult humans' studies that were published in English. A narrative synthesis of included studies was then conducted accordingly. Available evidence surrounding the use of NBLA among critically ill patients presenting with special situations was limited by the small sample size of the included studies coupled with high heterogeneity. The PK/PD target attainments of NBLA were reported to be minimally affected by obesity and/or ECMO, whereas the effect of renal functionality (in the form of either ARC or RRT) was more substantial. Critically ill patients presenting with special circumstances might be at risk of altered NBLA pharmacokinetics, particularly in the settings of ARC and RRT. More robust, well-designed trials are still required to define effective dose regimens able to attain therapeutic PK/PD indices of NBLA when utilized in those special scenarios, and thus aid in improving the patients' outcomes.

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Augmented renal clearance implies a need for increased amoxicillin-clavulanic acid dosing in critically ill children.

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Augmented renal clearance implies a need for increased amoxicillin-clavulanic acid dosing in critically ill children.

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