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Objective:To explore the effect of augmented renal clearance(ARC)on 24-hour area under the concentration-time curve to minimum inhibitory concentration ratio(AUC 24/MIC)of vancomycin and prognosis in critical children, thus to provide proposal for individual dosage regimen. Methods:Sixty-five critical children treated with vancomycin, who suffered from sepsis/septic shock, were brought into this retrospective cohort study.According to estimate glomerular filtration rate, these children were divided into ARC group ( n=27) and normal group ( n=38). The influencing factor of AUC 24/MIC of vancomycin and therapy prognosis for two groups were detected and analyzed. Results:There were no significant differences between two groups in basic setting (age, sex, weight), scores of pediatric sequential organ failure assessment and pediatric risk of mortality Ⅲ, infection markers (C-reactive protein and procalcitonin), glutamic-pyruvic transaminase, hypoproteinemia, usage of diuretic and vasoactive agent( P>0.05). The patients from ARC group showed lower levels than those from normal group in AUC 24/MIC of vancomycin[375.2(300.8, 489.4) vs. 443.6(412.3, 593.2), Z=2.263, P=0.024] and it′s target achievement ratio (TAR)(40.7% vs. 76.3%, χ2=8.440, P=0.005). When usage of diuretic and vasoactive agent, the AUC 24/MIC of ARC group was lower than that of normal group( P<0.05). But there was no significant difference between ARC group and normal group regarding hypoproteinemia( P>0.05). The days of body temperature steady at least 48 hours[7.0(5.5, 9.0)d vs. 6.0(5.0, 8.0)d], the length of hospital stay[39.0(21.0, 58.0)d vs. 20.5(16.0, 28.0)d], the length of PICU stay[14.0(9.0, 31.5)d vs. 10.0(5.0, 15.0)d] were longer than those in normal group( P<0.05). There were no significant differences between ARC group and normal group regarding days of ventilation and infectious markers decreased at least 50%, as well as 28-days mortality( P>0.05). The multivariable analysis showed that the presence of ARC, hypoproteinemia, use of diuretics and vasoactive agent were significantly associated with AUC 24/MIC of vancomycin( P<0.05). Conclusion:ARC may down regulate levels of AUC 24/MIC and TAR of vancomycin.During ARC period, the usage of diuretic and vasoactive agent could affect the AUC 24/MIC of vancomycin.Individual dosage regimen should be employed for critical children suffered with ARC.
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Augmented renal clearance （ARC）refers to the significant enhancement of patients ’renal function ，which is manifested by the significant increase of glomerular filtration rate ，which increases the clearance of drugs ，and the effective blood drug concentration cannot be achieved under the conventional dose. The efficacy of antibiotics is closely related to the concentration. The influence of renal dysfunction on drug metabolism is an important factor that clinicians should consider when determining the dosage. This article reviews the definition ，risk factors ，occurrence mechanism ，evaluation methods of ARC ，as well as its impact on the pharmacokinetics/pharmacodynamics of antibiotics and administration methods. It is found that ARC widely exists in critically ill patients ，and the risk factors include age （≤50 years old ），brain trauma ，sepsis，multiple trauma ， etc. When using antibiotics in ARC patients ，the therapeutic effect of drugs can be improved by increasing the dosage ，prolonging the duration of administration and increasing the frequency of administration. However ，in order to prevent adverse reactions caused by high concentration accumulation of drugs ，it is recommended to try to combine treatment drug monitoring.
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OBJECTIVE：To study the effects of augmented renal clearance （ARC）on blood trough concentration of patients receiving high-dose regimen of teicoplanin. METHODS ：Patients who received high-dose regimen of teicoplanin in the ICU were prospectively collected from the Affiliated Suzhou Hospital of Nanjing Medical University/Suzhou Municipal Hospital during Jul. 2018-Jun. 2020. They were divided into ARC group and normal renal function group according to corrected creatinine clearance. The dosage regimen of teicoplanin in the two groups were loading dose of 600 mg，q12 h×3 doses，maintenance dose of 6-10 mg/kg，qd，and the dosage was adjusted in combination with creatinine clearance rate and blood trough concentration. The trough concentration of blood samples which were collected 30 min before the 4th and 8th-10th dosage of teicoplanin were determined by HPLC. Trough concentration ，clinical efficacy ，Gram-positive bacterial clearance rate and the occurrence of ADR were compared between 2 groups. RESULTS ：A total of 56 patients were included and divided into ARC group （18 cases）and normal renal function group （38 cases）. ARC group had younger age （P＜0.001）and lower serum albumin level （P＝0.025）than normal renal function group. The trough concentrations before administration of the 4th and 8th-10th dosage in ARC group were lower than normal renal function group （P＝0.034；P＝0.035）. The trough concentrations in the ARC group and normal renal function group before 8th-10th dosage were all higher than 30 min before the 4th dosage （P＝0.003；P＜0.001）. The clinical efficacy rate and the clearance rate of Gram-positive bacteria in ARC group were 77.8％ and 76.2％，which were lower than those of the normal renal function group ，but there was no statistical difference （P＝0.195；P＝0.223）. There was no liver function damage ，hemocytopenia and allergic reaction in both groups ，but in the normal renal function group ，the causal relationship between acute renal damage and teicoplanin was assessed as “very likely ”in one patient. CONCLUSIONS ：ARC patients are younger ，most of them have hypoproteinemia，and the blood trough concentrations of teicoplanin in high-dose regimen are significantly lower than those of normal renal function patients. For critical ill ARC patients ，it is advisable to increase the loading dose of teicoplanin to make the trough concentration reach the target concentration range quickly.
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Adding to the complexity of caring for critically ill patients is the fact that many of them have a creatinine clearance that exceeds 130 mL/min/1.73 m². This phenomenon, termed augmented renal clearance (ARC), has only recently been widely recognized and its pathogenesis remains incompletely understood. However, ARC has been shown to result in increased dose requirements for drugs that are primarily eliminated by renal excretion, including many antimicrobial agents and enoxaparin. Recognition of ARC is hampered by the fact that the standard creatinine-based equations used to estimate renal function are not accurate in this clinical setting and the diagnosis is best established using both serum and urine creatinine measurements to calculate clearance. So a high index of clinical suspicion and awareness is usually required before this step is taken to confirm the diagnosis of ARC.
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Humans , Anti-Infective Agents , Creatinine , Critical Illness , Diagnosis , Enoxaparin , Renal EliminationABSTRACT
Objective To evaluate the predictive value and to verify the clinical effect of JPKD-vancomycin for the trough concentration of vancomycin in patients with augmented renal clearance (ARC), and to provide a reference for clinical individualized drug therapy. Methods A retrospective analysis was conducted. The clinical data of 48 adult patients with ARC using vancomycin and monitoring steady-state trough concentration of vancomycin admitted to Suzhou Hospital Affiliated to Nanjing Medical University from July 2013 to July 2017 were collected. A combination of classical Vancomycin Calculator software and JPKD-vancomycin software was used. Based on the individual conditions of patients [gender, age, height, weight, serum creatinine (SCr), disease status], Vancomycin Calculator software was used to obtain the recommended regimen and its steady-state trough concentration, and then JPKD-vancomycin software was used to predict the steady-state trough concentration of initial regimen. If the regimen was adjusted during the treatment, JPKD-vancomycin software was used to predict the steady-state trough concentration of the adjusted regimen. The measured values of steady-state trough concentration were recorded. The weight deviation between predicted concentration and measured concentration (WRES) was calculated. WRES < 30% was considered as good prediction, and the predictive value of JPKD-vancomycin software was evaluated for vancomycin trough concentration. Results Forty-eight patients with ARC were enrolled, of whom 24 patients had adjusted the dosing regimen during the treatment. The initial concentration of blood samples was 48, after adjusting the dosage regimen, 24 blood samples were collected. The initial and adjusted daily dose of vancomycin was (2 000±500) mg/d and (2 500±600) mg/d, respectively, and the initial trough concentrations and adjusted trough concentrations was (8.4±7.3) mg/L and (9.1±4.3) mg/L, respectively. Only 14.6% and 25.0% of initial and adjusted trough concentrations reached the target range (10-20 mg/L) without significant difference (P > 0.05). The WRES value of adjusted trough concentrations predicted by JPKD-vancomycin software was significantly lower than that of initial regimen [10.6% (3.0%, 16.4%) vs. 14.3% (10.5%, 38.2%), P < 0.05], and the percentage of WRES < 30% also tended to increase [95.8% (23/24) vs. 70.8% (34/48), P < 0.05]. The well predictive rate of JPKD-vancomycin software for vancomycin trough concentration was 79.2% (57/72), but there were 15 patients with WRES > 30%. Conclusions JPKD-vancomycin software has good predictive value for the vancomycin trough concentration of ARC patients, especially for the trough concentration after adjusting the treatment regimen. JPKD-vancomycin can provide a reference for the design of clinical individualized application of vancomycin.
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Objective To compare the clinical efficacy and safety of meropenem administered by standard 30-minute infusion or prolonged 3-hour infusion regimen in treatment of hospital acquired pneumonia (HAP) in elderly patients,and evaluate the effect of augmented renal clearance on clinical efficacy.Methods An open-label randomized controlled clinical trial was conducted.A total of 40 elderly patients (≥65 years of age) with HAP requiring meropenem therapy were enrolled from September 1,2015 to August 31,2016.The patients were randomly assigned to receive meropenem 1.0 g in 100 mL ot 0.9％ NaCl solution by constant-rate continuous intravenous infusion over 3 hours (study group,n=20) or by constant-rate intravenous infusion over 30 minutes (control group,n=20),every 8 hours,for at least 7 days.Clinical efficacy and safety were compared between groups.According to the level of creatinine clearance (Ccr),the 40 patients were further divided into group A1 [Ccr ≥ 130 (mL/min)/1.73 m2] and A2 [Ccr＜ 130 (mL/min)/1.73 m2].The patients with Ccr≥ 130 (mL/min)/1.73 m2 in control group belonged to group B1,and those in study group belonged to group B2.Clinical efficacy was compared between group A1 and A2,and between group B1 and B2.Results The clinical cure rate was 70.00％ (14/20) in study group and 50.00％ (10/20) in control group (P＜0.05).The 28-day survival rate was 85.00％ (17/20) in study group and 65.00％ (13/20) in control group (P＜0.05).The clinical pulmonary infection score (CPIS) was improved significantly in study group (reduction of 2.88±2.51) than in control group (reduction of 1.25 ± 1.67) (P＜ 0.05).Procalcitonin (PCT) level was more improved in study group [reduction of (2.43± 0.68) μg/L] than in control group [reduction of (1.05±0.27) μg/L] (P＜0.05).The duration of meropenem treatment and days of hospital stay did not show significant difference between study group and control group (P＞0.05).The common adverse reactions were transient elevation of serum transaminases and diarrhea in both groups.The incidence of adverse reactions did not show significant difference between groups (P＞0.05).Further analysis indicated that the clinical cure rate was 44.44％ (4/9) in group A1 and 64.52％ (20/31) in group A2 (P＜0.05).The 28-day survival rate was 66.67％ (6/9) in group A1 and 77.42％ (24/31) in group A2 (P＜0.05).CPIS reduction was 1.62±1.61 in group A1 and 2.19±2.2 in group A2 (P＜0.05).The reduction of PCT level was (1.41 ±0.39) μg/L in group A1 and (1.84±0.5) μg/L in group A2 (P＜0.05).The duration of meropenem treatment and days of hospital stay did not show significant difference between group A1 and group A2.The clinical cure rate was 1/4 in group B1 and 3/5 in group B2 (P＜0.05).The 28-day survival rate was 2/4 in group B1 and 4/5 in group B2 (P＜0.05).CPIS reduction was 0.68±0.93 in group B1 and 2.56±2.29 in group B2 (P＜ 0.05).The reduction of PCT level was (0.61 ±0.15) μg/L in group B 1 and (2.21 ± 0.63) μg/L in group B2 (P＜0.05).The duration of meropenem treatment and days of hospital stay did not show significant difference between group B1 and group B2 (P＞0.05).Conclusions Prolonged intravenous infusion of meropenem over 3 hours provides better clinical efficacy than the standard 30-minute infusion of meropenem in the treatment of HAP in elderly patients without increase of adverse reactions.Augmented renal clearance may reduce the clinical efficacy of meropenem,which can be improved by 3-hour prolonged infusion ofmeropenem.
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Objective To investigate the role of clinical pharmacist in anti-infection therapy for patients with augmented renal clearance (ARC).Methods A case with multi-site severe infection after traffic accident was treated with anti-infection therapy.According to the characteristics of infection and pharmacokinetics,clinical pharmacist discussed the intervention by clinical pharmacist in terms of formulating anti-infection program and adjustment of individual dose.Results After consultation and evaluation by clinical pharmacist,the patient was diagnosed as ARC.According to pharmacokinetics characteristics reported by literature,vancomycin was adjusted to 1 g (once per 8 h).Based on detection result of pathogenic bacteria,meropenem was replaced by cefoperazone/sulbactam,and the dose was increased to 3 g (once per 6 h).And then,vancomycin concentration was detected again,and it reached ＞ 10 μg· mL-1;pathogenic bacteria culture result was negative.This patient obtained good therapeutic effect.Conclusion Clinical pharmacist could assist physician on anti-infection treatment and dose adjustment of ARC patient,and improve ARC patient's therapeutic effect.
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Objective To evaluate the serum trough concentration and the pharmacokinetics/pharmacodynamics (PK/PD)of vancomycin in patients with severe acute pancreatitis (SAP), and analyze the effect of vancomycin continuous infusion for optimizing the characteristics of its PK/PD.Methods The inhospital patients with SAP received vancomycin treatment and admitted to emergency intensive care unit (EICU) of Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine from January 2011 to December 2016 were enrolled. Steady-state trough concentrations of vancomycin from patients were collected retrospectively. The SAP patients were divided into augmented renal clearance (ARC) and non-ARC groups, as well as systemic inflammatory response syndrome (SIRS) and non-SIRS groups according to the patients with or without symptom above. Adjustments of increased dosage or 24-hour continuous infusion or increase vancomycin dose were made for patients if the steady-state trough concentrations fell below the target level. Steady state trough concentration for vancomycin intermittent infusion or steady state concentration for vancomycin continuous infusion was determined by the fluorescence polarization immunoassay method. PK parameters of vancomycin were calculated using the Bayesian estimator and the area under the serum drug concentration-time curve (AUCc-t), the minimum inhibitory concentration (MIC) and AUCc-t/MIC was recorded and calculated.Results The steady state trough concentration or steady state concentration from 61 patients with SAP were collected with mean steady state trough concentration of vancomycin of (7.7±4.4) mg/L, which was significantly lower than standard concentration (15 mg/L,P < 0.001). Apparent volume of distribution (Vd) and clearance of vancomycin was (1.06±0.26) L/kg and (8.9±2.8) L/h. The serum steady state trough concentration of vancomycin in ARC group (n = 33) was significantly lower than that in non-ARC group (n = 28; mg/L: 6.7±3.5 vs. 8.2±4.1, P < 0.01), clearance was significantly increased (L/h: 9.8±2.9 vs. 7.7±2.2,P < 0.01). Compared with non-SIRS group (n = 31), the serum steady state trough concentration of vancomycin in SIRS group (n= 30) was significantly lowered (mg/L: 6.1±3.2 vs. 13.0±4.2,P < 0.01), and clearance was significantly increased (L/h: 9.4±2.0 vs. 7.1±2.1,P < 0.05). Compared with the only increasing vancomycin dose group (n = 29), vancomycin continuous infusion for 24 hours (n = 21) could significantly reduce daily dosage (mg/kg: 13.6±3.9 vs. 19.1±3.5,P < 0.01), increase the serum trough concentration (mg/L: 18.1±7.0 vs. 12.6±5.3,P < 0.01), and improve the AUCc-t/MIC.Conclusions The serum trough concentration of vancomycin was significantly reduced in SAP patients with ARC. The more serious of the SIRS is, the lower the vancomycin trough concentration is. Vancomycin 24-hour continuous infusion could optimize the PK/PD parameters, decrease the daily dose, increase the clinical effect, and reduce the bacterial resistance.