Pharmacokinetic and Pharmacodynamic Characteristics of Vancomycin and Meropenem in Critically Ill Patients Receiving Sustained Low-efficiency Dialysis

PurposeAntibiotic dosing is challenge in critically ill patients undergoing renal replacement therapy. Our aim was to evaluate the pharmacokinetic and pharmacodynamic (PK/PD) characteristics of meropenem and vancomycin in patients undergoing SLED.MethodsConsecutive ICU patients undergoing SLED and receiving meropenem and/or vancomycin were prospectively evaluated. Serial blood samples were collected before, during, and at the end of SLED sessions. Antimicrobial concentrations were determined using a validated HPLC method. Noncompartmental PK analysis was performed. AUC was determined for vancomycin. For meropenem, time above MIC was calculated.FindingsA total of 24 patients receiving vancomycin and 21 receiving meropenem were included; 170 plasma samples were obtained. Median serum vancomycin and meropenem concentrations before SLED were 24.5 and 28.0 μg/mL, respectively; after SLED, 14 and 6 μg/mL. Mean removal was 42% with vancomycin and 78% with meropenem. With vancomycin, 19 (83%), 16 (70%), and 15 (65%) patients would have achieved the target (AUC_0–24 >400) considering MICs of 1, 2, and 4 mg/L, respectively. With meropenem, 17 (85%), 14 (70%), and 10 (50%) patients would have achieved the target (100% of time above MIC) if infected with isolates with MICs of 1, 4, and 8 mg/L, respectively.ImplicationsSLED clearances of meropenem and vancomycin were 3-fold higher than the clearance described by continuous methods. Despite this finding, overall high PK/PD target attainments were obtained, except for at higher MICs. We suggest a maintenance dose of 1 g TID or BID of meropenem. With vancomycin, a more individualized approach using therapeutic drug monitoring should be used, as commercial assays are available     

万古霉素在持续性静-静脉血液滤过时的药代动力学研究

目的：研究持续性静-静脉血液滤过（CVVH）时万古霉素的药代动力学特点，指导临床合理用药。方法：应用荧光偏振免疫分析仪测定万古霉素应用不同阶段的血药浓度，计算其药代动力学参数。结果：万古霉素在该患者体内的药代动力学符合开放型二室模型。用药3d主要药代参数：峰浓度（Cmax)=22.18mg/l，谷浓度（Cmin)=5.82mg/L，半衰期（T1/2）=5.75h，总体分布容积（Vd)=21.92,L,总体清除率（CL）=3.49L/h。用药16d主要药代参数；Cmax=38.70mg/L,Cmin=16.50mg/L,T1/2=33.32h,Vd=12.92L,CL=0.38L/h。结论：CVVH可以清除万古霉素，用药时应考虑多种影响因素，并监测血药浓度以提高疗效，减少药物对肾脏的损伤。     

Absence of "red man syndrome" in patients being treated with vancomycin or high-dose teicoplanin.

Twenty-five febrile patients with a history of intravenous drug use who were receiving either vancomycin (15 patients) or teicoplanin (10 patients) as part of a multicenter, double-blind, randomized, clinical efficacy trial were enrolled, upon receipt of their first dose of antibiotic, into a study to evaluate the effect of 1 g of vancomycin and high-dose teicoplanin (30 mg/kg of body weight) on histamine release and the occurrence of "red man syndrome" (RMS). In addition, 10 healthy volunteer subjects (HVS) were randomized to receive either 1 g of vancomycin intravenously or a saline infusion in a double-blind, crossover design study. Patients and HVS were observed for the presence of erythema, flushing, pruritus, and hypotension during and for up to 1 h postinfusion by a blinded investigator. Histamine concentrations in plasma were measured at baseline and during and after drug infusion. No significant differences were noted in baseline temperature between patients (vancomycin recipients, 102.3 degrees F [39.1 degrees C]; teicoplanin recipients, 102.4 degrees F [39.1 degrees C]) or incidence of bacteremia (7 of 15 vancomycin recipients; 5 of 10 teicoplanin recipients). There were no significant differences in peak vancomycin concentrations in the sera of patients (40.8 micrograms/ml) and HVS (49.9 micrograms/ml). There were no reactions consistent with RMS in any patient who received teicoplanin (0 of 10); there was a significant difference in the occurrence of RMS in patients in comparison with that in HVS (0 of 15 patients, 9 of 10 HVS; P less than 0.001) who received vancomycin. The predominant reaction was erythema and pruritus. Histamine concentrations in plasma and the area under the histamine plasma concentration-time curve were highly variable within groups and were not statistically different between patients and HVS. The incidence of RMS secondary to vancomycin or teicoplanin in our patient population appears to be low and consistent with clinical observations. Similar to previous investigations, RMS secondary to vancomycin in HVS was high (90%). However, we found no relationship between the histamine concentration in plasma or the area under the plasma histamine concentration-time curve and the severity of RMS in HVS. The reason for the discrepancy of RMS in patients versus that in HVS in unknown, but it may be related to a blunted effect of glycopeptides to produce the reaction in the presence of infection or it may be specific to our patient population.     

High dose vancomycin for osteomyelitis: continuous vs. intermittent infusion

OBJECTIVES: To compare the efficacy, ease of use and safety of intermittent vancomycin infusion (IVI) and continuous vancomycin infusion (CVI) in high-dose therapy of osteomyelitis. Methods: Forty-four patients with an osteomyelitis requiring vancomycin for more than 4 weeks were prospectively included, 21 receiving IVI and 23, CVI. The target serum concentration of vancomycin was 20-25 mg/L. Pharmacokinetics, adverse effects, and clinical efficacy were recorded. RESULTS: The mean daily vancomycin dosing was the same in the two groups, but the serum vancomycin concentrations (trough or plateau) were lower in the IVI group than the CVI group (21.7 +/- 9.3 and 26.0 +/- 6.1 mg/L, respectively; P < 0.0001). The target concentrations were achieved quicker with CVI, and daily dosing was changed more frequently in the IVI group. After reaching the target, variability of vancomycin serum concentration (trough or plateau concentrations) was higher in the IVI group than in CVI group (standard deviation 7.9 mg/L vs. 5.6 mg/L, respectively; P = 0.001). CVI did not show clinical superiority, but adverse drug effects were more frequent in the IVI group as compared with the CVI group, 9 (42.9%) and 2 (8.7%), respectively (P = 0.03). Survival multiple regression using Cox's proportional hazard model showed that IVI (RR = 5.9, P = 0.03) and osteomyelitis of the foot (RR = 5.2, P = 0.01) were the only factors associated with adverse drug reactions leading to treatment termination. CONCLUSIONS: CVI is practical and effective, and may be a good alternative for patients requiring prolonged treatment with high vancomycin serum levels.     

Dose Optimization of Vancomycin Using a Mechanism-based Exposure–Response Model in Pediatric Infectious Disease Patients

PurposeThis study aimed to determine the appropriate vancomycin dosage, considering patient size and organ maturation, by simulating the bacterial count and biomarker level for drug administration in pediatric patients with gram-positive bacterial (GPB) infections.MethodsNatural language processing for n-gram analysis was used to detect appropriate pharmacodynamic (PD) markers in infectious disease patients. In addition, a mechanism-based model was established to describe the systemic exposure and evaluate the PD marker simultaneously in pediatric patients. A simulation study was then conducted by using a mechanism-based model to evaluate the optimal dose of vancomycin in pediatric patients.Findings: C-reactive protein (CRP) was selected as a PD marker from an analysis of ~270,000 abstracts in PubMed. In addition, clinical results, including the vancomycin plasma concentrations and CRP levels of pediatric patients (n = 93), were collected from electronic medical records. The vancomycin pharmacokinetic model with allometric scaling and a maturation function was built as a one-compartment model, with an additional compartment for bacteria. Both the effects of vancomycin plasma concentrations on the destruction of bacteria and those of bacteria on CRP production rates were represented by using a maximum achievable effect model (E_max model). Simulation for dose optimization was conducted not only by using the final model but also by exploring the possibility of therapeutic failure based on the MICs of vancomycin for GPB. Clinical cure was defined as when the CRP level fell below the upper limit of the normal range. Our dose optimization simulations suggested a vancomycin dosage of 10 mg/kg every 8 h as the optimal maintenance dose for pediatric patients with a postconceptual age <30 weeks and 10 mg/kg every 6 h for older children, aged up to 12 years. In addition, the MIC of 3 μg/mL was assessed as the upper concentration limit associated with successful vancomycin treatment of GPB infections.ImplicationsThis study confirmed that the changes in bacterial counts and CRP levels were well described with mechanistic exposure–response modeling of vancomycin. This model can be used to determine optimal empiric doses of vancomycin and to improve therapeutic outcomes in pediatric patients with GPB.     

The characteristics and impact indicator of vancomycin pharmacokinetics in cancer patients complicated with severe pneumonia

ObjectiveThis study was designed to investigate the characteristics and impact indicator of vancomycin pharmacokinetics in cancer patients complicated with severe pneumonia.MethodsFifty-seven cancer patients complicated with severe pneumonia were included in this research. Vancomycin serum trough concentrations were measured using the fluorescence polarization immunoassay (FPIA) method. The Bayesian estimator was used to calculate the pharmacokinetic parameters.ResultsThe average initial therapeutic dose of vancomycin was 15.18 ± 3.29 mg/kg (q12 h). Our study shows that vancomycin initial trough concentrations measured in cancer patients are significantly reduced (6.54 ± 3.11 mg/L; p < 0.0001) compared with the recommended standard vancomycin trough concentration (10–15 or 15–20 mg/L). Meanwhile, the clearance (CL) and volume of distribution (Vd) of vancomycin was increased significantly in cancer patients. Multivariate linear regression analysis revealed that Cys-C was the most important variable for vancomycin trough concentration (r² = 0.439). The relationships between vancomycin trough concentrations and Cys-C were further evaluated after the 57 patients were grouped by cut-off point (1.44 mg/L) of the serum Cys- C levels before vancomycin was administered. Compared with group Early group (Cys-C>1.44 mg/L), Delayed group (Cys-C≤1.44 mg/L) had much lower trough concentrations. Meanwhile, CL and CLcr were significantly increased in Delayed group (Cys-C≤1.44 mg/L). Although the clinical outcomes were similar between two groups, the duration of vasoactive agent in Early group was considerably shorter compared with Delayed group (χ² = 4.213; p < 0.05).ConclusionsThe serum trough concentration of vancomycin was significantly reduced in cancer patients complicated with severe pneumonia. Higher dosage regimen is needed to ensure clinical effectiveness. The Cys-C level measured prior to administration of vancomycin is suggested to be the most suitable parameter to predict whether vancomycin trough concentration is up to standard dosage. Especially for patients with baseline Cys-c less than 1.44 mg/L, it is more likely to need higher dosage algorithm.     

Impaired target site penetration of vancomycin in diabetic patients following cardiac surgery

Soft tissue infections constitute a serious complication following surgery in diabetic patients and frequently require the administration of vancomycin. However, despite antibiotic treatment, mortality of patients with postoperative infections remains high and might be related to an impaired penetration of anti-infective agents to target tissues. Therefore, the present study was designed to measure vancomycin tissue concentrations in six diabetic and six nondiabetic patients after cardiac surgery. Vancomycin was administered as a continuous intravenous infusion at an infusion rate of 80 to 120 mg/h. Vancomycin concentrations in soft tissues and plasma were measured in all patients during steady state as "therapeutic window" concentrations in plasma by microdialysis on day 8+/-4 after initiation of vancomycin treatment. Vancomycin tissue concentrations in diabetic patients were significantly lower than in nondiabetics (3.7 mg/liter versus 11.9 mg/liter; P=0.002). The median vancomycintissue/vancomycinplasma concentration ratio was 0.1 in diabetic patients and 0.3 in nondiabetics (P=0.002). Our study demonstrated that vancomycin penetration into target tissues is substantially impaired in diabetic patients versus nondiabetics. Insufficient tissue concentrations could therefore possibly contribute to failure of antibiotic treatment and the development of antimicrobial resistance in diabetic patients.     

Suboptimal vancomycin levels in critically ill children with sickle cell disease and acute chest syndrome

ObjectivesThis is a pilot retrospective study to assess the effect of glomerular hyper-filtration (GHF) related to sickle cell disease (SCD) on vancomycin clearance and ultimately on therapeutic drug levels in children admitted to the pediatric intensive care unit (PICU) with acute chest syndrome (ACS).MethodThe patients’ steady-state vancomycin trough levels (VTL) and the area under the curve (AUC) were compared with those of age- and gender-matched control group; matching was made at a 1:3 ratio.ResultsTwelve SCD patients with ACS and treated with vancomycin were compared with 36 non-SCD patients (control group). Compared with the control patients, the ACS patients had significantly lower initial serum VTL (median = 6.00 mcg/mL vs. 9.75 mcg/mL) (p = 0.007), and their average VTL were still lower (median = 6.65 mcg/mL vs. 10.00 mcg/mL) post vancomycin dose adjustment (p = 0.039). The time to achieve the therapeutic vancomycin level was significantly longer for the ACS patients (median = 4.75 days) than for the control group (median = 1 day) (p = 0.009). The AUC was also significantly lower in the ACS patients (median = 293 mg*h/L) than in the control group (median = 405.5 mg*h/L) (p = 0.007). The AUC was negatively associated with creatinine clearance (Beta Coefficient = ?0.366, p-value=<0.001) even when adjusted for receiving loading dose, standard dose per weight, and severity of critical illness.ConclusionThese findings support the attributed role of the GHF associated with SCD leading to lower vancomycin level in ACS cases. Therefore, the standard dosing approach for vancomycin in ACS patients may be ineffective. We thus advocate for individualized dosing with careful monitoring of drug levels to account for GHF.     

Vancomycin-induced thrombocytopenia in endocarditis: A case report and review of literature

BACKGROUNDThrombocytopenia is a serious complication in the medical practice of numerous drugs. Vancomycin is frequently used for the prophylaxis and treatment of suspected or identified methicillin-resistant positive infections. Several cases with vancomycin-induced thrombocytopenia (VIT) have been reported. However, these have rarely been extensively reviewed. The present report describes a case of VIT in endocarditis, and reviews all VIT cases reported in the literature.CASE SUMMARYA 26-year-old male diagnosed with infective endocarditis was admitted. The patient was treated with multiple drugs, including vancomycin, which was initially intravenously given at 1000 mg every 12 h and subsequently at 500 mg every 8 h on day 3. On day 11, the platelet count decreased to 51 × 10⁹/L, vancomycin was switched to 500 mg every 12 h, and platelet transfusion was given. On day 17, the platelet count dropped to 27 × 10⁹/L, and platelet transfusion was administered again. On day 23, vancomycin was adjusted to 500 mg every 8 h as the trough concentration dropped to the minimum effective concentration. On day 33, the platelet count declined to approximately 40 × 10⁹/L. After platelet transfusion, the platelet count rebounded to 90 × 10⁹/L on day 35 but dropped again to 42 × 10⁹/L on day 43. Based on the time-to-platelet count curve and Naranjo’s Adverse Drug Reaction Probability Scale score, VIT was suspected. After vancomycin discontinuation and platelet transfusion, the platelet count gradually normalized. CONCLUSIONThe diagnosis of VIT can be achieved through the time-to-platelet count curve and Naranjo’s Adverse Drug Reaction Probability Scale score. The platelet count cannot be normalized simply by platelet transfusion alone, and vancomycin discontinuation is essential.     

Does contemporary vancomycin dosing achieve therapeutic targets in a heterogeneous clinical cohort of critically ill patients? Data from the multinational DALI study

Introduction

The objective of this study was to describe the pharmacokinetics of vancomycin in ICU patients and to examine whether contemporary antibiotic dosing results in concentrations that have been associated with favourable response.

Methods

The Defining Antibiotic Levels in Intensive Care (DALI) study was a prospective, multicentre pharmacokinetic point-prevalence study. Antibiotic dosing was as per the treating clinician either by intermittent bolus or continuous infusion. Target trough concentration was defined as ≥15 mg/L and target pharmacodynamic index was defined as an area under the concentration-time curve over a 24-hour period divided by the minimum inhibitory concentration of the suspected bacteria (AUC_0–24/MIC ratio) >400 (assuming MIC ≤1 mg/L).

Results

Data of 42 patients from 26 ICUs were eligible for analysis. A total of 24 patients received vancomycin by continuous infusion (57%). Daily dosage of vancomycin was 27 mg/kg (interquartile range (IQR) 18 to 32), and not different between patients receiving intermittent or continuous infusion. Trough concentrations were highly variable (median 27, IQR 8 to 23 mg/L). Target trough concentrations were achieved in 57% of patients, but more frequently in patients receiving continuous infusion (71% versus 39%; P = 0.038). Also the target AUC_0–24/MIC ratio was reached more frequently in patients receiving continuous infusion (88% versus 50%; P = 0.008). Multivariable logistic regression analysis with adjustment by the propensity score could not confirm continuous infusion as an independent predictor of an AUC_0–24/MIC >400 (odds ratio (OR) 1.65, 95% confidence interval (CI) 0.2 to 12.0) or a C_min ≥15 mg/L (OR 1.8, 95% CI 0.4 to 8.5).

Conclusions

This study demonstrated large interindividual variability in vancomycin pharmacokinetic and pharmacodynamic target attainment in ICU patients. These data suggests that a re-evaluation of current vancomycin dosing recommendations in critically ill patients is needed to more rapidly and consistently achieve sufficient vancomycin exposure.     

Vancomycin removal during a plasma exchange transfusion.

OBJECTIVE: To report a case of clinically significant removal of vancomycin during a plasma exchange transfusion in a patient with sickle-cell anemia. CASE SUMMARY: A 46-year-old African American woman with sickle-cell disease was admitted on three separate occasions and treated with vancomycin. Vancomycin serum drug concentrations were obtained on all three admissions. During one of the admissions, a plasma exchange transfusion was performed the same day vancomycin concentrations were obtained. The vancomycin serum drug concentrations were considerably lower than predicted, resulting in potentially subtherapeutic vancomycin concentrations. Bayesian pharmacokinetic forecasting was used in interpreting the vancomycin concentrations. DISCUSSION: Searches from MEDLINE (1966-September 2000) and Drugs and Pharmacology (1990-September 2000) were performed to obtain pertinent published literature. CONCLUSIONS: Plasma exchange transfusions may result in clinically significant removal of vancomycin from the plasma. The potential exists of underdosing vancomycin in patients who are receiving frequent plasma exchange transfusions. Further research may be warranted to determine whether these patients may be candidates for more frequent and vigilant monitoring of vancomycin concentrations.     

Aminoglycosides in Critically Ill Septic Patients With Acute Kidney Injury Receiving Continuous Renal Replacement Therapy: A Multicenter,Observational Study

PurposeData on aminoglycoside stewardship in critically ill septic patients with acute kidney injury (AKI) needing continuous renal replacement therapy (CRRT) are scarce. The objectives of the study were to determine, during CRRT, the time window with low likelihood for safe reinjection and the proportion of inappropriate reinjection.MethodsA post hoc observational analysis of a multicenter randomized trial comparing the risk of hemodialysis catheter infection with ethanol lock vs placebo in critically ill patients with AKI was conducted. Eligible patients were adults in intensive care units from 6 French hospitals. Any patient with AKI needing CRRT and receiving an antimicrobial therapy for a septic episode occurring before (≤24 hours) or during CRRT was included. The aminoglycoside orders were left to the physicians’ discretion, but high dose once daily was the schedule of aminoglycoside administration.FindingsA total of 145 septic episodes treated by aminoglycosides were analyzed in patients receiving CRRT. A mean (SD) of 1.6 (0.8) amikacin and 1.8 (1.2) gentamicin administrations per patient were observed. During CRRT, C_max was 17.3 mg/L (interquartile range, 13.2-22.5 mg/L) for gentamicin and 50 mg/L (interquartile range, 43.7-76.6 mg/L) for amikacin. The plasma drug concentration at 24 hours (C_H24) was 2.3 mg/L (interquartile range, 1.6-3.2 mg/L) for gentamicin and 9.3 (interquartile range, 6.6-12.0 mg/L) for amikacin. Sixty-five C_min dosages remained above the reinjection threshold. Inappropriate reinjection was observed in 11 of 65 episodes (17%). Inappropriate reinjection (defined by, at the reinjection time, C_min dosages above the threshold; ie, C_min >2 mg/L for gentamicin and >5 mg/L for amikacin) was observed in 17% of analyzed episodes. Most patients did not need reinjection until approximately ≥30 hours after their initial administration.ImplicationsDuring CRRT, as indicated by the C_H24 value, which was higher than the recommended threshold, the interval to obtain a C_min low enough to allow for redosing aminoglycosides is significantly longer than 24 hours. This interval is not always respected and leads to an of inappropriate reinjection rate of 17%. ClinicalTrials.gov identifier: ISRCTNCT00875069.     

Factors Impacting Unbound Vancomycin Concentrations in Different Patient Populations

The unbound drug hypothesis states that only unbound drug concentrations are active and available for clearance, and highly variable results regarding unbound vancomycin fractions have been reported in the literature. We have determined the unbound vancomycin fractions in four different patient groups by a liquid chromatography tandem mass spectrometry (LC-MS/MS) method and identified factors that modulate vancomycin binding. We have further developed and validated a prediction model to estimate unbound vancomycin concentrations. Vancomycin (unbound and total) concentrations were measured in 90 patients in four different hospital wards (hematology [n = 33 samples], intensive care unit [ICU] [n = 51], orthopedics [n = 44], and pediatrics [age range, 6 months to 14 years; n = 18]) by a validated LC-MS/MS method. Multiple linear mixed model analysis was performed to identify patient variables that were predictive of unbound vancomycin fractions and concentrations. The variables included in the model were patient age, ward, number of coadministered drugs with high protein binding, kidney function (estimated glomerular filtration rate [determined by Chronic Kidney Disease Epidemiology Collaboration formula]), alpha-1-acid glycoprotein, albumin, total bilirubin, IgA, IgM, urea, and total vancomycin concentrations. In the pediatric cohort, the median unbound vancomycin fraction was 81.3% (range, 61.9 to 95.9%), which was significantly higher (P < 0.01) than the unbound fraction found in the three adult patient cohorts (hematology, 60.6% [48.7 to 90.6%]; ICU, 61.7% [47.0 to 87.6%]; orthopedics, 56.4% [45.9 to 78.0%]). The strongest significant predictor of the unbound vancomycin concentration was the total drug concentration, completed by albumin in the pediatric cohort and albumin and IgA in the adult cohorts. Validation of our model was performed with data from 13 adult patients. A mean difference of 0.3 mg/liter (95% confidence interval [CI], −1.3 to 0.7 mg/liter; R² = 0.99 [95% CI, 0.95 to 0.99]) between measured and calculated unbound vancomycin concentrations demonstrated that the predictive performance of our model was favorable. Unbound vancomycin fractions vary significantly between pediatric and adult patients. We developed a formula to estimate the unbound fraction derived from total vancomycin, albumin, and IgA concentrations in adult patients.     

Interpreting γ-hydroxybutyrate concentrations for clinical and forensic purposes

Introduction: γ-Hydroxybutyric acid is an endogenous substance, a therapeutic agent, and a recreational drug of abuse. This psychoactive substance acts as a depressant of the central nervous system and is commonly encountered in clinical and forensic practice, including impaired drivers, poisoned patients, and drug-related intoxication deaths.

Objective: The aim of this review is to assist clinical and forensic practitioners with the interpretation of γ-hydroxybutyric acid concentrations in blood, urine, and alternative biological specimens from living and deceased persons.

Methods: The information sources used to prepare this review were PubMed, Scopus, and Web-of-Science. These databases were searched using keywords γ-hydroxybutyrate (GHB), blood, urine, alternative specimens, non-conventional biological matrices, saliva, oral fluid, sweat, hair, vitreous humor (VH), brain, cerebrospinal fluid (CSF), dried blood spots (DBS), breast milk, and various combinations thereof. The resulting 4228 references were screened to exclude duplicates, which left 1980 articles for further consideration. These publications were carefully evaluated by taking into account the main aims of the review and 143 scientific papers were considered relevant.

Analytical methods: The analytical methods used to determine γ-hydroxybutyric acid in blood and other biological specimens make use of gas- or liquid-chromatography coupled to mass spectrometry. These hyphenated techniques are accurate, precise, and specific for their intended purposes and the lower limit of quantitation in blood and other specimens is 0.5?mg/L or less.

Human pharmacokinetics: GHB is rapidly absorbed from the gut and distributes into the total body water compartment. Only a small fraction of the dose (1–2%) is excreted unchanged in the urine. The plasma elimination half-life of γ-hydroxybutyric acid is short, being only about 0.5–0.9?h, which requires timely sampling of blood and other biological specimens for clinical and forensic analysis.

Endogenous concentrations of GHB in blood: GHB is both an endogenous metabolite and a drug of abuse, which complicates interpretation of the laboratory results of analysis. Moreover, the concentrations of GHB in blood and other specimens tend to increase after sampling, especially in autopsy cases. This requires the use of practical “cut-off” concentrations to avoid reporting false positive results. These cut-offs are different for different biological specimen types.

Concentrations of GHB in clinical and forensic practice: As a recreational drug GHB is predominantly used by young males (94%) with a mean age of 27.1 years. The mean (median) and range of concentrations in blood from apprehended drivers was 90?mg/L (82?mg/L) and 8–600?mg/L, respectively. The concentration distributions in blood taken from living and deceased persons overlapped, although the mean (median) and range of concentrations were higher in intoxication deaths; 640?mg/L (280?mg/L) and 30–9200?mg/L, respectively.

Analysis of GHB in alternative specimens: All biological fluids and tissue containing water are suitable for the analysis of GHB. Examples of alternative specimens discussed in this review are CSF, saliva, hair strands, breast milk, DBS, VH, and brain tissue.

Conclusions: Body fluids for the analysis of GHB must be obtained as quickly as possible after a poisoned patient is admitted to hospital or after a person is arrested for a drug-related crime to enhance chances of detecting the drug. The sampling of urine lengthens the window of detection by 3–4?h compared with blood samples, but with longer delays between last intake of GHB and obtaining specimens, hair strands, and/or nails might be the only option. In postmortem toxicology, the concentrations of drugs tend to be more stable in bladder urine, VH, and CSF compared with blood, because these sampling sites are protected from the spread of bacteria from the gut. Accordingly, the relationship between blood and urine concentrations of GHB furnishes useful information when drug intoxication deaths are investigated.     

万古霉素血药浓度监测的临床应用

目的：通过监测万古霉素血药浓度,分析血药浓度与疗效、药物不良反应的关系,指导万古霉素在耐甲氧西林葡萄球菌（M RS ）等革兰阳性球菌感染中的合理用药。方法在有指征应用万古霉素的M RS等革兰阳性球菌感染患者中进行该药药物浓度监测。留取血样时间为万古霉素给药至少4个剂量后,在给药前30 min内采血送检谷浓度,给药结束后30 min至1 h内采血送检峰浓度,采用荧光偏振免疫法测定万古霉素血药浓度,同时收集临床资料,进行统计分析。结果25例患者万古霉素血药谷浓度为3．22-50．79 mg／L ,谷浓度＜5 mg／L者3例,5-＜10 mg／L者11例,10-15 mg／L者3例,＞15 mg／L者8例;峰浓度为13．57-60．47 mg／L ,峰浓度＜25 mg／L者14例,25-40 mg／L者7例,＞40 mg／L者4例。感染患者临床好转率为80．0％（20／25）;细菌清除率为87．5％（21／24）。13例患者根据血药浓度监测结果调整用药剂量,其治疗好转率为92．3％（12／13）。4例患者出现肾功能损害。结论万古霉素血药浓度个体差异较大,通过监测血药浓度制定的万古霉素个体化给药方案用于治疗M RS等革兰阳性球菌感染可提高治愈率,减少药物不良反应。     

Use of intravenous immunoglobulin for the treatment of severe Clostridium difficile colitis

Background:Clostridium difficile is a gram-positive, anaerobic, spore-forming, rod-shaped bacterium responsible for most of the hospital-acquired diarrhea in developed countries. The organism received its name because it was difficult to isolate and grow in culture. Infections in the elderly have been associated with significant morbidity and mortality as well as prolonged hospitalization.Case summary:A 72-year-old white male presented with a 5-day history of abdominal pain, nausea, and severe diarrhea but no fever or chills. He had had recent chemotherapy for Merkel cell carcinoma of the right ear. Medical history included hypothyroidism for 10 years and non-Hodgkin's lymphoma in remission for 4 years after a stem cell transplant. The patient was receiving oral vancomycin, levofloxacin, thyroxine, and esomeprazole. He had severe infection secondary to chemotherapy for Merkel cell carcinoma; in addition, he had failed to respond to metronidazole and vancomycin treatment, with the resulting development of colon dilatation and hypoalbuminemia. Colonoscopy showed severe ulceration with inflammation suggestive of severe persistent colitis. At that point, the patient was given 1 dose of IV immunoglobulin (IVIG) 400 mg/kg; vancomycin treatment was continued. Two days after IVIG therapy, the patient's diarrhea improved, with complete resolution after 6 days; bowel dilatation resolved completely after 7 days; and oral intake improved after 2 days. The patient continued on a tapering dose of vancomycin for 6 weeks. He was discharged home and had no recurrence despite antibiotic use for pseudomonas and staphylococcus bacteremia.Conclusions:Severe C difficile colitis has been reported more frequently in the literature recently, especially in elderly patients. Tissue culture assay is the best diagnostic test to detect the cytotoxin; enzyme immunoassay is the test used in most hospitals, but it has a sensitivity of only −75%. Treatment options remain limited to eradicate this serious infection. Antibiotic therapy, infection control measures, and early diagnosis are essential components of successful outcome for this disease. This patient's infection resolved with the addition of IVIG with no recurrence, suggesting the possible benefit of this treatment in certain patients with severe colitis who do not respond to standard therapy.     

Intraperitoneal vancomycin concentrations during peritoneal dialysis-associated peritonitis: correlation with serum levels

♦ Background: For the treatment of peritoneal dialysis–associated peritonitis (PDP), it has been suggested that serum concentrations of vancomycin be kept above 12 mg/L – 15 mg/L. However, studies correlating vancomycin concentrations in serum and peritoneal dialysate effluent (PDE) during active infection are sparse. We undertook the present study to investigate this issue and to determine whether achieving the recommended serum level of vancomycin results in therapeutic levels intraperitoneally.♦ Methods: We studied patients treated with intraperitoneal (IP) vancomycin for non-gram-negative PDP. We gave a single dose (approximately 30 mg/kg) at presentation, and we subsequently measured vancomycin levels in PDE on day 5; we wanted to determine if efflux of vancomycin from serum to PDE during a 4-hour dwell was consistent and resulted in therapeutic levels.♦ Results: Of the 48 episodes of PDP studied, serum vancomycin concentrations exceeding 12 mg/L were achieved in 98% of patients, but in 11 patients (23%), a PDE vancomycin level below 4 mg/L—the minimal inhibitory concentration (MIC) of many gram-positive organisms—was observed at the end of a 4-hour dwell on day 5. The correlation between the concentrations of vancomycin in serum and PDE (from efflux of antibiotic over 4 hours) was statistically significant, but poor (R² = 0.18).♦ Conclusions: Our data support the International Society for Peritoneal Dialysis statement that adequate serum vancomycin concentrations can be achieved with intermittent dosing (single dose every 5 days), but cannot guarantee therapeutic PDE levels in the treatment of PDP. Intermittent dosing of vancomycin may not consistently result in PDE concentrations markedly greater than MIC of many important pathogens. Although the clinical significance of this finding remains to be determined, it may be preferable to give smaller but more frequent doses of PDE vancomycin (continuous dosing) for adults with PDP (as is currently recommended for children).     

Development and validation of an ultra-high performance liquid chromatography – high resolution mass spectrometry method for the quantification of total and free teicoplanin in human plasma

ObjectivesThe antibiotic teicoplanin, used for the treatment of infections caused by Gram-positive bacteria, is highly bound to plasma proteins (percentage protein binding, %PB, around 90%) and therapeutic plasma levels of total teicoplanin are 10–100 mg/L. Because of the low free concentrations (i.e. <1–10 mg/L), current immunoassays are not able to quantify free teicoplanin concentrations, although they might be more relevant in therapeutic drug monitoring than total concentrations.Design and methodsIn this study, an ultra-high performance liquid chromatography – high resolution mass spectrometry (UHPLC-HRMS) method for the quantification of total and free teicoplanin in K₂EDTA plasma samples was developed and validated. Furthermore, %PB obtained by ultrafiltration was compared with that obtained by equilibrium dialysis using spiked samples from healthy subjects. Analytes were separated using a phenylhexyl column, gradient mobile phase analysis was used, total run time was 4.5 min and teicoplanin was detected by orbitrap MS.ResultsThe precision and accuracy were below 15% and within ±15%, respectively and teicoplanin was found to be stable for at least 14 days in plasma at 4 °C. The %PB of teicoplanin in spiked plasma from healthy subjects as obtained by ultrafiltration (94.1 ± 1.3%) was in good agreement with that obtained by equilibrium dialysis (93.6 ± 0.4%), whereas mean %PB of teicoplanin in samples from infected patients who received the antibiotic was 87.7 ± 4.2% (range: 79.6–95.4%).ConclusionA novel highly sensitive UHPLC-HRMS method was developed and validated for the quantification of total and free teicoplanin in human K₂EDTA plasma samples. Amongst others, this method is suitable for therapeutic drug monitoring.     

Vancomycin population pharmacokinetics during extracorporeal membrane oxygenation therapy: a matched cohort study

Introduction

The aim of this study was to describe the population pharmacokinetics of vancomycin in critically ill patients treated with and without extracorporeal membrane oxygenation (ECMO).

Methods

We retrospectively reviewed data from critically ill patients treated with ECMO and matched controls who received a continuous infusion of vancomycin (35 mg/kg loading dose over 4 hours followed by a daily infusion adapted to creatinine clearance, CrCl)). The pharmacokinetics of vancomycin were described using non-linear mixed effects modeling.

Results

We compared 11 patients treated with ECMO with 11 well-matched controls. Drug dosing was similar between groups. The median interquartile range (IQR) vancomycin concentrations in ECMO and non-ECMO patients were 51 (28 to 71) versus 45 (37 to 71) mg/L at 4 hours; 23 (16 to 38) versus 29 (21 to 35) mg/L at 12 hours; 20 (12 to 36) versus 23 (17–28) mg/L at 24 hours (ANOVA, P =0.53). Median (ranges) volume of distribution (Vd) was 99.3 (49.1 to 212.3) and 92.3 (22.4 to 149.4) L in ECMO and non-ECMO patients, respectively, and clearance 2.4 (1.7 to 4.9) versus 2.3 (1.8 to 3.6) L/h (not significant). Insufficient drug concentrations (that is drug levels <20 mg/dL) were more common in the ECMO group. The pharmacokinetic model (non-linear mixed effects modeling) was prospectively validated in five additional ECMO-treated patients over a 6-month period. Linear regression analysis comparing the observed concentrations and those predicted using the model showed good correlation (r² of 0.67; P <0.001).

Conclusions

Vancomycin concentrations were similar between ECMO and non-ECMO patients in the early phase of therapy. ECMO treatment was not associated with significant changes in Vd and drug clearance compared with the control patients.