Subtherapeutic Serum Concentrations Research Articles

An evaluation of the empirical vancomycin dosing guide in pediatric cardiology

BackgroundHigher doses of vancomycin are currently prescribed due to the emergence of bacterial tolerance and resistance. This study aimed to evaluate the efficacy and safety of the currently adopted vancomycin dosing guide in pediatric cardiology.MethodsThis was a single-center prospective cohort study with pediatric cardiac patients, younger than 14 years, from June 2020 to March 2021. The patients received intravenous vancomycin (40 mg/kg/day divided every 6–8 h) according to the department’s vancomycin medication administration guide (MAG) for at least three days.ResultsIn total, 88 cardiac patients were included, with a median age of 0.82 years (IQR: 0.25–2.9), and 51 (58%) received cardiopulmonary bypass surgery (CPB). The majority (71.6%, n = 61) achieved a serum vancomycin level within the therapeutic range (7–20 mg/L). Infants, young children, and children exposed to CPB surgery had an increased incidence of subtherapeutic vancomycin levels, [7 (29.2%); P = 0.033], [13 (54.2%); P = 0.01], and [21 (87.5%); P = 0.009] respectively. After the treatment, 8 (10%) patients had an elevated Serum creatinine (SCr) and 2 (2.5%) developed acute kidney injury (AKI). However, no significant difference was found between the patients developing AKI or an elevated SCr and the group who did not, in terms of clinical, therapeutic, and demographic characteristics, except for the decreased incidence of SCr elevation in patients receiving an ACE inhibitor, [4 (36.4%); P = 0.036].ConclusionOur institution followed MAG recommendations; however, subtherapeutic serum concentrations were evident in infants, young children, and CPB patients. Strategies to prevent AKI should be investigated, as the possible causes have not been identified in this study.

Isoniazid urine spectrophotometry for prediction of serum pharmacokinetics in adults with TB.

Isoniazid (INH) is an important drug in many TB regimens, and unfavorable treatment outcomes can be caused by suboptimal pharmacokinetics. Dose adjustment can be personalized by measuring peak serum concentrations; however, the process involves cold-chain preservation and laboratory techniques such as liquid chromatography (LC)/mass spectrometry (MS), which are unavailable in many high-burden settings. Urine spectrophotometry could provide a low-cost alternative with simple sampling and quantification methods. We enrolled 56 adult patients on treatment for active TB. Serum was collected at 0, 1, 2, 4, 6, and 8 h for measurement of INH concentrations using validated LC-MS/MS methods. Urine was collected at 0-4, 4-8, and 8-24 h intervals, with INH concentrations measured using colorimetric methods. The median peak serum concentration and total serum exposure over 24 h were 4.8 mg/L and 16.4 mg*hour/L, respectively. Area under the receiver operator characteristic curves for urine values predicting a subtherapeutic serum concentration (peak <3.0 mg/L) were as follows: 0-4 h interval (AUC 0.85, 95% CI 0.7-0.96), 0-8 h interval (AUC 0.85, 95% CI 0.71-0.96), and 0-24 h urine collection interval (AUC 0.84, 95% CI 0.68-0.96). Urine spectrophotometry may improve feasibility of personalized dosing in high TB burden regions but requires further study of target attainment following dose adjustment based on a urine threshold.

Oral step-down with β-lactams for uncomplicated Enterobacterales bacteraemia

The preferred definitive treatments for invasive Enterobacterales infections, parenteral antibiotics, oral fluoroquinolones, and oral trimethoprim-sulfamethoxazole, are increasingly limited leading to interest in additional options [1–3]. Oral beta-lactams are a conceptionally attractive option because of their high tolerability and activity against Enterobacterales that do not meaningfully express ampC beta-lactamases, but views on their role are mixed due to concerns for subtherapeutic serum concentrations [1].

1822. Clinical Outcomes Associated with Oral Beta-Lactam Therapy versus Oral Fluoroquinolones/TMP-SMX for Uncomplicated Gram-Negative Bacteremia

Abstract Background Agents commonly used as oral step-down therapy in Enterobacterales bacteremia include fluoroquinolones and TMP-SMX. The use of these oral agents have been associated with adverse events. Oral β-lactams are not recommended to treat Enterobacterales bacteremia because of concerns for sub-therapeutic serum concentrations. Given the limited data on clinical effectiveness of oral β-lactams and increased limitations with fluoroquinolones and TMP-SMX, oral β-lactams may be an alternative option. The purpose of this study is to evaluate the clinical effectiveness in patients transitioned to oral β-lactams versus fluoroquinolones or TMP-SMX for the step-down treatment of uncomplicated Enterobacterales bacteremia. Methods A multi-center, retrospective, propensity-score matched, observational cohort study was conducted from July 1, 2017 to December 31, 2020, at 11 Memorial Hermann Health System hospitals among 690 patients with uncomplicated Enterobacterales bacteremia. Patients were included if they received &amp;gt; 1 day of intravenous antibiotic therapy followed by definitive oral step-down therapy with a β-lactam, fluoroquinolone, or TMP-SMX. The primary outcome was treatment failure within 30 days of starting oral antibiotics, defined as at least one of the following: recurrent bacteremia, transition to IV antibiotics, new-onset sepsis, 30-day readmission, or 30-day all-cause mortality. Results After the patients were propensity score matched 1:1, a total of 199 patients with uncomplicated Enterobacterales bacteremia were included in each group. Treatment failure occurred in 8 patients (4%) who received β-lactams and 10 patients (5%) who received fluoroquinolones or TMP-SMX (OR, 0.79 [95% CI, 0.306-2.04] p-value 0.629). Median length of hospital stay was 5 days for both groups (p-value 0.911), and median duration of oral antibiotics was 10 days in the fluoroquinolone or TMP-SMX group and 11 days in the β-lactam group (p-value 0.377). Conclusion Based on the results of this study, no significant difference in treatment failure was seen in patients who were transitioned to β-lactams versus fluoroquinolones or TMP-SMX as oral step-down therapy for uncomplicated Enterobacterales bacteremia. Oral β-lactams appear to be a safe and effective option. Disclosures All Authors: No reported disclosures.

Use of Fluoroquinolones or Sulfamethoxazole-Trimethoprim Compared to Β-Lactams for Oral Step-Down Therapy in Hospitalized Patients With Uncomplicated Enterobacterales Bacteremia.

Antibiotic therapy for uncomplicated Enterobacterales bacteremia from a urinary source has traditionally consisted of fluoroquinolones (FQs) and sulfamethoxazole-trimethoprim (SXT). However, adverse events associated with FQs and emerging antimicrobial resistance have led to alternative agents, specifically oral Β-lactams (OBLs), being utilized despite concern of subtherapeutic serum concentrations related to their low relative bioavailability. To compare efficacy of antibiotic therapies with bioavailability differences in patients with uncomplicated bacteremia from a urinary source. This was a retrospective study comparing clinical efficacy in hospitalized adult patients receiving OBL or FQ/SXT. Patients were required to receive at least 48 hours of appropriate intravenous antibiotic therapy and at least one dose of oral therapy. The primary outcome was all-cause hospital readmission within 30 days of discharge. Secondary outcomes included readmission with recurrent infectious etiology and readmission due to Clostridioides difficile infection. Of 210 eligible patients, 91 received FQ/SXT and 119 received OBL. There was no difference between the groups in all-cause hospital readmission (FQ/SXT: 16.5%; OBL: 14.3%) (P = 0.660 [95% confidence interval, CI = -0.076, 0.120]) or readmission with recurrent bacteremia (FQ/SXT: 0%; OBL: 3.4%) (P = 0.135). There was a significant difference in repeat hospital admission with recurrent urinary tract infection (UTI) (FQ/SXT: 0%, OBL: 5.0%) (P = 0.037). OBLs appear to be non-inferior to FQ/SXT in the rate of all-cause hospital readmission within 30 days. However, OBLs may be associated with increased readmissions with recurrent UTI.

Implementation of a Pharmacist-Driven Vancomycin and Aminoglycoside Dosing Service in a Pediatric Hospital.

Pharmacy-driven antibiotic dosing services have been shown to improve clinical outcomes in adult patients. This study evaluated the effect of a pharmacist-driven antimicrobial dosing service on the percentage of therapeutic serum concentrations achieved following initial vancomycin or aminoglycoside dosing regimens. A secondary objective was to determine the effect of the dosing service on nephrotoxicity in pediatric patients. This single-center, retrospective study used data obtained from an electronic medical record to evaluate the utility of a pharmacist-driven vancomycin or aminoglycoside dosing protocol. Assessments of target, subtherapeutic, and supratherapeutic serum concentrations were evaluated. The occurrence of changes in serum creatinine and presentation of acute kidney injury (AKI) were also determined. The incidence (n [%]) of a therapeutic initial serum concentration was not statistically significant between pre-protocol and post-protocol groups (21 [46.7%] vs 22 [48.9%], respectively; p = 0.834). The incidence of initial supratherapeutic concentrations (19 [42.2%] vs 7 [15.6%]; p = 0.005) and the average number of supratherapeutic concentrations per antibiotic course (0.76 vs 0.26; p = 0.01) were higher in the pre-protocol group compared with the post-protocol group. The incidence of AKI was significantly lower in the post-protocol group (2.2% vs 13.3%; p = 0.049). Implementation of a pharmacist-driven dosing service did not affect the likelihood of achieving an initial therapeutic concentration. However, it did reduce the likelihood of both supratherapeutic concentrations and AKI. Additional studies in pediatric patients are needed to affirm the use of pharmacist dosing services.

Are Antibiotics Appropriately Dosed in Critically Ill Patients with Augmented Renal Clearance? A Narrative Review

Aims Augmented renal clearance (ARC), which is commonly defined as increased renal clearance above 130 ml/min/1.73 m2, is a common phenomenon among critically ill patients. The increased elimination rate of drugs through the kidneys in patients with ARC can increase the risk of treatment failure due to the exposure to subtherapeutic serum concentrations of medications and affect the optimal management of infections, length of hospital stay, and outcomes. The main goal of this review article is to summarize the recommendations for appropriate dosing of antibiotics in patients with ARC. Methods This article is a narrative review of the articles that evaluated different dosing regimens of antibiotics in patients with ARC. The keywords “Augmented Renal Clearance,” “Critically ill patients,” “Drug dosing,” “Serum concentration,” “Beta-lactams,” “Meropenem,” “Imipenem,” “Glycopeptide,” “Vancomycin,” “Teicoplanin,” “Linezolid,” “Colistin,” “Aminoglycosides,” “Amikacin,” “Gentamycin,” “Fluoroquinolones,” “Ciprofloxacin,” and “Levofloxacin” were searched in Scopus, Medline, PubMed, and Google Scholar databases, and pediatric, nonhuman, and non-English studies were excluded. Results PK properties of antibiotics including lipophilicity or hydrophilicity, protein binding, the volume of distribution, and elimination rate that affect drug concentration should be considered along with PD parameters for drug dosing in critically ill patients with ARC. Conclusion This review recommends a dosing protocol for some antibiotics to help the appropriate dosing of antibiotics in ARC and decrease the risk of subtherapeutic exposure that may be observed while receiving conventional dosing regimens in critically ill patients with ARC.

Homogeneous Immunoassay Using a Tri-Part Split-Luciferase for Rapid Quantification of Anti-TNF Therapeutic Antibodies.

Anti-TNF therapeutics bind and sequester tumor necrosis factor (TNF) to prevent downstream signaling and are clinically important in the treatment of several autoimmune diseases. Effective treatment with these drugs requires frequent therapeutic drug monitoring (TDM). Current analytical methods, including reporter gene assay (RGA), enzyme-linked immunosorbent assay (ELISA), and mobility shift assay (MSA), can be technically rigorous, slow, and expensive. These qualities prevent the implementation of point-of-care testing and ultimately limit the frequency and utility of monitoring. An assay simple enough to be performed in the clinic would enable increased TDM frequency, more accurate dosing, and improved patient outcomes. Toward this end, we developed a homogeneous immunoassay based on a tri-part split-luciferase system for "add-and-read" detection of anti-TNF therapeutics. In our platform, two small fragments of the split-luciferase, called β9 and β10, are each fused to a different interacting protein. The binding of each of these proteins to anti-TNF antibodies forces the split-luciferase components into proximity where they reform the active luciferase. We identified the fusion proteins, β9-protein A (β9-A) and β10-TNF, as promising binding pairs. We systematically adjusted assay conditions to optimize the signal/background (S/B) ratio, limit of detection (LOD), and percent recovery. The assay has a large dynamic range (0.5-32 μg/mL) and is sensitive enough to monitor both subtherapeutic and supratherapeutic serum concentrations of anti-TNF antibodies, as demonstrated in clinical samples.

Augmented renal clearance: a retrospective, cohort study of urinary creatinine clearance in critically ill patients in the United Kingdom.

ObjectiveAugmented renal clearance (ARC) is associated with sub-therapeutic antibiotic, anti-epileptic, and anticoagulant serum concentrations leading to adverse patient outcomes. We aimed to describe the prevalence and associated risk factors for ARC development in a large, single-centre cohort in the United Kingdom.MethodsWe conducted a retrospective observational study of critically unwell patients admitted to intensive care between 2014 and 2016. Urinary creatinine clearance was used to determine the ARC prevalence during the first 7 days of admission. Repeated measures logistic regression was used to determine risk factors for ARC development.ResultsThe ARC prevalence was 47.0% (95% confidence interval [95%CI]: 44.3%–49.7%). Age, sex, Acute Physiology and Chronic Health Evaluation (APACHE) II score, and sepsis diagnosis were significantly associated with ARC. ARC was more prevalent in younger vs. older (odds ratio [OR] 0.95 [95%CI: 0.94–0.96]), male vs. female (OR 0.32 [95%CI: 0.26–0.40]) patients with lower vs. higher APACHE II scores (OR 0.94 [95%CI: 0.92–0.96]).ConclusionsThis patient group probably remains unknown to many clinicians because measuring urinary creatinine clearance is not usually indicated in this group. Clinicians should be aware of the ARC risk in this group and consider measurement of urinary creatinine clearance.

Therapeutic Drug Monitoring in Patients with Suboptimal Response to Adalimumab for Hidradenitis Suppurativa: A Retrospective Case Series.

Adalimumab, a tumor necrosis factor-α inhibitor, is a biologic used for the treatment of moderate-to-severe hidradenitis suppurativa (HS). It is wellknown that patients may experience loss of efficacy from its use in other conditions, and it is suggested that developing a strategy for therapeutic drug monitoring (TDM) may help secure optimal clinical outcomes. We sought to determine serum adalimumab concentrations and anti-adalimumab antibody (AAA) status in patients with moderate-to-severe HS. A retrospective case series of 38 patients with suboptimal response to adalimumab 40mg weekly was conducted at a community dermatology clinic. Adalimumab serum trough levels, AAA status, and inflammatory biomarkers were collected. Blood was drawn on identification of suboptimal response (after a minimum of 12weeks) and was collected once prior to receiving the next scheduled dose. Kruskal-Wallis and Chi-squared tests were used for data analysis. A total of 38 patients had a median adalimumab trough concentration of 8.76 (interquartile range [IQR] 1.3-12.5) µg/mL. The median duration of adalimumab therapy of all patients was 21 (IQR 12-24) months. AAAs were detected in nine patients (24%), and all had subtherapeutic serum concentrations (< 6 µg/mL). Patients who were AAA+ had a significantly lower median adalimumab concentration than those who were AAA- (0.02µg/mL [range 0.02-0.81] vs. 10.14 [range 0.76-48.00]; p = 0.0006). Patients with AAAs had significantly lower serum adalimumab levels. The current study suggests that TDM may identify underlying reasons for suboptimal response and detect patients who may benefit from dose optimization strategies.

Oral β-Lactam Antibiotics vs Fluoroquinolones or Trimethoprim-Sulfamethoxazole for Definitive Treatment of Enterobacterales Bacteremia From a Urine Source

Oral β-lactam antibiotics are traditionally not recommended to treat Enterobacterales bacteremia because of concerns over subtherapeutic serum concentrations, but there is a lack of outcomes data, specifically after initial treatment with parenteral antibiotics. Given the limited data and increasing limitations of fluoroquinolones or trimethoprim-sulfamethoxazole (TMP-SMX), oral β-lactam antibiotics may be a valuable additional treatment option. To compare definitive therapy with oral β-lactam antibiotics vs fluoroquinolones or TMP-SMX for Enterobacterales bacteremia from a suspected urine source. A retrospective cohort study was conducted from January 1, 2007, to September 30, 2015, at 114 Veterans Affairs hospitals among 4089 adults with Escherichia coli, Klebsiella spp, or Proteus spp bacteremia and matching urine culture results. Additional inclusion criteria were receipt of active parenteral antibiotic(s) followed by conversion to an oral antibiotic. Exclusion criteria were previous Enterobacterales bacteremia, urologic abscess, or chronic prostatitis. Data were analyzed from April 15, 2019, to July 26, 2020. Conversion of therapy to an oral β-lactam antibiotic vs fluoroquinolones or TMP-SMX after 1 to 5 days of parenteral antibiotics. The main outcome was a composite of either 30-day all-cause mortality or 30-day recurrent bacteremia. Propensity-based overlap weights were used to adjust for differences between groups. Log binomial regression models were used to estimate adjusted relative risks (aRRs) and adjusted risk differences (aRDs). Of the 4089 eligible patients (3731 men [91.2%]; median age, 71 years [interquartile range, 63-81 years]), 955 received an oral β-lactam antibiotic, and 3134 received fluoroquinolones or TMP-SMX. The primary outcome occurred for 42 patients (4.4%) who received β-lactam antibiotics and 94 patients (3.0%) who received fluoroquinolones or TMP-SMX (aRD, 0.99% [95% CI, -0.42% to 2.40%]; aRR, 1.31 [95% CI, 0.87-1.95]). Mortality rates were 3.0% (n = 29) for patients receiving β-lactam antibiotics vs 2.6% (n = 82) for those receiving fluoroquinolones or TMP-SMX (aRD, 0.06% [95% CI, -1.13% to 1.26%]; aRR, 1.02 [95% CI, 0.67-1.56]). Recurrent bacteremia rates were 1.5% (n = 14) among those receiving β-lactam antibiotics vs 0.4% (n = 12) among those receiving fluoroquinolones or TMP-SMX (aRD, 1.03% [95% CI, 0.24%-1.82%]; aRR, 3.43 [95% CI, 0.42-27.90]). In this cohort study of adults with E coli, Klebsiella spp, or Proteus spp bacteremia from a suspected urine source, the relative risk of recurrent bacteremia was not significantly higher with β-lactam antibiotics compared with fluoroquinolones or TMP-SMX, and the absolute risk and risk difference were small (ie, <3%). No significant difference in mortality was observed. Oral β-lactam antibiotics may be a reasonable step-down treatment option, primarily when alternative options are limited by resistance or adverse effects. Further study is needed because statistical power was limited owing to a low number of recurrent bacteremia events.

Risk factors for sub\u2013therapeutic serum concentrations of magnesium sulfate in severe preeclampsia of Chinese patients

BackgroundMagnesium sulfate (MgSO4) is the standard drug for eclampsia prophylaxis and treatment. In China, the effective therapeutic serum magnesium level is 1.8–3.0 mmol/L. There is little information on how to achieve and maintain effective therapeutic concentrations. This study aimed to investigate risk factors for sub-therapeutic serum concentrations of MgSO4 in patients with severe preeclampsia.MethodsPatients with severe preeclampsia who received MgSO4 intravenous infusion were retrospectively reviewed. The maternal demographic characteristics, regimens for the administration of MgSO4, and lab test results of patients were collected. Multivariate logistic regression analysis and receiver operating characteristic (ROC) curve analysis were conducted for the risk factors influencing the serum magnesium concentration.ResultsA total of 93 patients with severe preeclampsia were included in the study. 52 (55.91%) patients did not attain therapeutic serum magnesium levels. A multivariate logistic regression analysis identified creatinine clearance (Ccr), whether the loading dose was given, and measurement time of serum magnesium concentration (referring to the time from start of MgSO4 infusion to blood draw for serum sampling) as independent risk factors for sub-therapeutic serum magnesium concentration (P < 0.05). ROC curve analysis indicated that the continuous variable Ccr had a significant predictive value for the serum magnesium concentration, which resulted in a cutoff point of 133 mL/min; while measurement time had limited predictive value, with cutoff point of 2.375 h.ConclusionsCcr, whether the loading dose was given, and measurement time were independent risk factors for sub-therapeutic serum magnesium concentration. A loading dose of MgSO4 everytime before the maintenance dose, as well as the duration of MgSO4 maintenance dose of more than 2.375 h are recommended for all the patients with severe PE. Routine evaluation of serum magnesium levels is a recommended practice for women with severe PE and whose Ccr is ≥133 mL/min.

Identification of a novel polymorphism associated with reduced clozapine concentration in schizophrenia patients\u2014a genome-wide association study adjusting for smoking habits

Clozapine (CLZ) is the superior antipsychotic drug for treatment of schizophrenia, but exhibits an extensive interpatient pharmacokinetic variability. Here, we conducted a genome-wide association study (GWAS) of CLZ serum concentration adjusting for known smoking habits, which is a major nongenetic factor reducing CLZ levels. The study included 484 patients with 10,283 steady-state serum concentrations of CLZ and N-desmethylclozapine, prescribed dosing, co-medications and known smoking habits (n = 422; 9284 serum samples) from a therapeutic drug monitoring (TDM) service. The GWAS analyses were performed with and without smoking habits as covariate, where possible hits were assessed in relation to the target CLZ concentration range applied in the TDM service (300–2500 nmol/L). The smoking-independent analysis of N-desmethylclozapine serum concentration and the CLZ-to-N-desmethylclozapine ratio replicated the previously identified locus on chromosome 4. After adjusting for smoking habits in patients confirmed as ‘smokers’ (61%) or ‘nonsmokers’ (39%), a novel variant (rs28379954; minor T>C allele frequency 4.1%; 7.6% CT carriers in the population) within the gene encoding the nuclear factor 1 B-type (NFIB) was significantly associated with reduced CLZ serum concentration (p = 1.68 × 10−8, beta = −0.376; explained variance 7.63%). There was no significant association between rs28379954 and N-desmethylclozapine concentration in the GWAS analysis (p = 5.63 × 10−5). The fraction of CLZ TDM samples below 300 nmol/L was significantly higher in carriers vs. noncarriers of the rs28379954 minor C allele [12.0% (95% CI: 9.4–14.7) vs. 6.2% (95% CI: 5.7–6.8), p < 0.001]. We identified a novel variant in the NFIB gene associated with reduced CLZ levels and increased risk of subtherapeutic serum concentrations. This warrants testing of clinical relevance of screening for this gene variant, and also experimental studies to investigate the biological mechanisms of NFIB involvement in CLZ pharmacokinetics.

&lt;p&gt;Serum Concentration of Vancomycin Is a Diagnostic Predictor of Nephrotoxic Acute Kidney Injury in Septic Patients in Clinical and Surgical Wards&lt;/p&gt;

Introduction and AimThere have been few studies to evaluate the monitoring of plasmatic concentrations of vancomycin in septic patients and their association with acute kidney injury (AKI) and death. This study aimed to evaluate the prevalence of adequate, subtherapeutic, and toxic serum concentrations of vancomycin in hospitalized septic patients and to associate the adequacy of therapeutic monitoring with clinical outcomes.MethodologyThis was a cohort-unicentric study that evaluated septic patients aged >18 years using vancomycin admitted to clinical and surgical wards of a Brazilian university center from August 2016 to July 2017 in a daily and uninterrupted way. We excluded patients with AKI prior to the introduction of vancomycin or with AKI development <48 hours after use, patients with AKI of other etiologies, stage V chronic kidney disease, and pregnant women.ResultsWe evaluated 225 patients, and 135 were included. Evaluation of serum concentration of vancomycin was realized in 94.1%, and of those, 59.3% presented toxic concentrations. The prevalence of AKI was 27.4% and happened on average on the ninth day of vancomycin usage. Between the fourth and sixth days, vancomycin serum concentration of >21.5 mg/L was a predictor of AKI, with area under the curve of 0.803 (95% CI 0.62–0.98, p=0.005), preceding the diagnosis of AKI by at least 3 days. Of these patients, 20.7% died, and serum concentrations of vancomycin between the fourth and sixth days were identified as risk factors associated with negative outcomes.ConclusionSerum concentration of vancomycin is an excellent predictor of AKI in patients admitted to wards, preceding the diagnosis of AKI by at least 72 hours. Toxic concentrations of vancomycin are associated with AKI, and AKI was a risk factor for death. Also, serum concentration of vancomycin >21.5 mg/L was the only variable associated with death in the Cox model.

Use of Body Surface Area for Dosing of Vancomycin.

Vancomycin weight-based dosing regimens often fail to achieve therapeutic trough serum concentration in children ≤12 years of age and rigorous studies evaluating efficacy and safety of body surface area (BSA)-based dosing regimens have not been performed. We compared vancomycin trough serum concentrations in pediatric patients receiving a weight- or BSA-based dosing regimen. This was a single-center, retrospective study evaluating pediatric patients, ages 1 to 12 years, who received vancomycin from September 2012 to October 2015. Patients received a minimum of 3 consecutive doses at the same scheduled interval within a dosing regimen prior to a measured vancomycin serum trough concentration. The primary outcome was percentage of initial vancomycin trough concentrations ≥10 mg/L. The secondary outcomes were percentage of supratherapeutic, therapeutic, and subtherapeutic vancomycin serum concentration for all patients, including a subset of overweight and obese patients, and number of nephrotoxic occurrences. BSA-based dosing regimens resulted in 50% of the initial vancomycin trough concentrations ≥ 10 mg/L compared with 17% for the weight-based dosing regimens (p < 0.0001). No statistically significant differences were noted between the 2 dosing regimens for supratherapeutic, therapeutic, or subtherapeutic trough concentrations for all patients, and for the subset of overweight and obese patients. Nephrotoxic occurrences were noted in 7% of the weight-based dosing regimens compared with none in the BSA-based dosing regimens. A BSA-based vancomycin dosing regimen resulted in significantly more initial vancomycin trough concentrations ≥10 mg/L and trended towards higher initial vancomycin trough concentrations without observable nephrotoxicity.

Valproate Interaction With Carbapenems: Review and Recommendations.

Introduction: Valproic acid is a commonly used antiepileptic drug. Combining valproate derivatives with carbapenem antibiotics is associated with a potential drug interaction that decreases serum concentration of valproate and may expose the patient to uncontrolled seizure risk from valproate subtherapeutic concentration. Raising awareness of this drug interaction among health care providers including emergency department physicians, neurologists, and pharmacists is highly needed. The aim of this article was to review the current literature about the potential drug interaction resulting from combining valproate derivatives with carbapenem antibiotics and to establish therapeutic recommendations regarding their use together. Methods: A review of the literature was conducted using Medline (through PubMed), Ovid, Embase, Cochrane library using the following keywords: valproate, valproic acid, carbapenem, ertapenem, doripenem, meropenem, imipenem, and valproate drug interaction. In addition, a manual search through major journals for articles referenced in PubMed was performed. Related publications from January 1998 till November 2018 were included in the initial search. Relevant publications were reviewed, and data regarding patients, type of carbapenem used, valproic acid dosing and level, interaction severity, and clinical outcome were summarized. Results and Discussion: Few clinical trials and multiple case reports have shown that carbapenem antibiotics including meropenem, ertapenem, imipenem, and doripenem can decrease the serum concentration of valproate derivatives leading to a subtherapeutic serum concentration and seizures in some patients. Valproic acid serum concentration may be significantly decreased with addition of a carbapenem antibiotic but generally return toward normal shortly after discontinuation of the carbapenem antibiotic. Conclusions: Generally, the concurrent use of carbapenem antibiotics with valproate derivatives should be avoided due to the potential of drug-drug interaction that results in subtherapeutic valproate serum concentration. Other antimicrobial agents should be considered as alternatives to carbapenems but if a concurrent carbapenem is necessary, using an additional antiepileptic agent is recommended. Therapeutic drug monitoring of valproate serum concentrations is warranted when a carbapenem-valproic acid combination therapy is unavoidable.

Neutropenia is independently associated with sub-therapeutic serum concentration of vancomycin

BackgroundWe aimed to identify the impact of the presence of neutropenia on serum vancomycin concentration (SVC). MethodsA retrospective study was conducted from January 2005 to December 2015. The study population was comprised of adult patients who were performed serum concentration of vancomycin. Patients with renal failure or using non-conventional dosages of vancomycin were excluded. ResultsA total of 1307 adult patients were included in this study, of whom 163 (12.4%) were neutropenic. Patients with neutropenia presented significantly lower SVCs than non-neutropenic patients (P<0.0001). Multiple linear regressions showed significant association between neutropenia and trough SVC (beta coefficients, −2.351; P=0.004). Multiple logistic regression analysis also revealed a significant association between sub-therapeutic vancomycin concentrations (trough SVC values<10mg/l) and neutropenia (odds ratio, 1.75, P=0.029) ConclusionsThe presence of neutropenia is significantly associated with low SVC, even after adjusting for other variables. Therefore, neutropenic patients had a higher risk of sub-therapeutic SVC compared with non-neutropenic patients. We recommended that vancomycin therapy should be monitored with TDM-guided optimization of dosage and intervals, especially in neutropenic patients.

Adequacy of a hospital-wide standard dose of 7 mg/kg bodyweight gentamicin sufficient to achieve an adequate prophylactic maximum serum concentration (Cmax) in burn patients undergoing surgical burn wound treatment

IntroductionPharmacokinetics of drugs can be significantly altered in burn patients. The aim of our study was to validate if the current hospital-wide standard dosage of 7mg/kg total bodyweight gentamicin is sufficient to achieve an adequate prophylactic Cmax (Cmax≥20mg/L). Materials and methodsA prospective observational cohort pharmacokinetic study was conducted in burn patients undergoing surgical burn wound treatment. Results36/40 (90%) burn patients undergoing surgical burn wound treatment at Rotterdam Burn Centre (Maasstad Hospital), the Netherlands, achieved adequate prophylactic serum concentrations (Cmax≥20mg/L) after a single prophylactic intravenous dose of 7mg/kg total bodyweight gentamicin. Total Body Surface Area (TBSA) burned and total bodyweight were statistically significantly correlated with the Cmax, with correlation coefficients of −0.316, 0.443 and p values of 0.047, 0.004, respectively. Other covariates (age, time after injury, serum creatinine, dose, gender, intensive care admittance) were not statistically significantly correlated. Occurrence of postoperative infection was limited (n=1), no statistically significant difference was observed between patients with a therapeutic and patients with a subtherapeutic serum concentration. ConclusionThe current hospital-wide standard dosage of 7mg/kg total bodyweight is sufficient to achieve an adequate prophylactic Cmax in burn patients undergoing surgical burn wound treatment.

Utility of voriconazole therapeutic drug monitoring: a meta-analysis.

Voriconazole therapeutic drug monitoring (TDM) is increasingly used in clinical practice. However, the utility of voriconazole TDM to guide therapy remains uncertain and controversial. We conducted a meta-analysis of studies assessing the relationship between voriconazole serum concentration and clinical outcomes of success and toxicity. We searched bibliographic databases for studies on voriconazole serum concentrations and clinical outcomes. We compared success outcomes between patients with therapeutic and subtherapeutic voriconazole serum concentrations, and toxicity outcomes between patients with and without supratherapeutic serum concentrations. Twenty-four studies were analysed. Pooled analysis for efficacy endpoint demonstrated that patients with therapeutic voriconazole serum concentrations (1.0-2.2 mg/L) were more likely to have successful outcomes compared with those with subtherapeutic voriconazole serum concentrations (OR 2.30; 95% CI 1.39-3.81). A therapeutic threshold of 1.0 mg/L was most predictive of successful outcome (OR 1.94; 95% CI 1.04-3.62). Patients with therapeutic concentrations did not have better survival rates. Pooled analysis for toxicity endpoint demonstrated that patients with supratherapeutic voriconazole serum concentrations (4.0-6.0 mg/L) were at increased risk of toxicity (OR 4.17; 95% CI 2.08-8.36). A supratherapeutic threshold of 6.0 mg/L was most predictive of toxicity (OR 4.60; 95% CI 1.49-14.16). Patients with therapeutic voriconazole serum concentrations were twice as likely to achieve successful outcomes. The likelihood of toxicity associated with supratherapeutic voriconazole serum concentrations was 4-fold that of therapeutic concentrations. Our findings suggest that the use of voriconazole TDM to aim for serum concentrations between 1.0 and 6.0 mg/L during therapy may be warranted to optimize clinical success and minimize toxicity.

A Prospective Study to Assess Vancomycin Serum Concentrations inPediatric Patients with Current Dosing Guidelines.

Concerns about increasing bacterial resistance to vancomycin, have caused the adult treatment guidelines to recommend higher trough concentrations based on the type and location of infectious disease. Although these recommendations are not specific to children, the values can be extrapolated. This prospective study was designed to evaluate efficacy of current vancomycin dosing recommendations to achieve therapeutic trough serum concentration in pediatric patients. Laboratory data, vancomycin dosing and subsequent serum concentrations of children in a community teaching pediatrics hospital were collected and analyzed. Trough serum levels were determined at steady state and compared with Infectious Disease Society of America (IDSA) 2011 guidelines for the treatment of Methicillin-Resistant Staphylococcus Aureus (MRSA) infections. In a prospective observational, cross-sectional study in a university medical center in Tehran, Iran, 50 patients, who received vancomycin for more than 4 doses, were recruited and their trough vancomycin level was determined. The mean age and creatinine clearance of patients were 5.47 ± 4.24 and 87.5 ± 31.25, respectively. Eleven (22%) patients received vancomycin at 40 mg/kg/day (low dose) and 39 (78%) at 60 mg/kg/day (high dose). Considering trough goals of 10-14 and 15-20 mg/L in low and high dose groups, serum levels in 91% (73% sub- therapeutics) and 85% (69% sub-therapeutics) of patients were not in recommended therapeutic range, respectively. This study has shown that current recommended vancomycin dosing regimens in pediatric patients (40-60 mg/kg/day), resulted in sub-therapeutic serum concentrations in our study population.