Subtherapeutic Levels Research Articles

A Pilot Study of Plasma Antipsychotic Drugs Concentrations of First Episode Patients with Psychosis From Epirus - Greece

Background: This contribution is a study on plasma antipsychotics concentrations of first episode outpatients with psychosis (FEPs), under antipsychotic treatment; it aims to attract attention to the importance of the drug-driven management of psychiatric patients for improving adherence and clinical efficacy. Methods: The plasma antipsychotic concentrations were determined retrospectively (after the completion of selection of all samples) and therefore, they were not used to monitor patients’ response to pharmacotherapy. A total of 120 plasma samples from 35 psychiatric patients were collected and tested for antipsychotics. The concentrations of eight antipsychotic drugs (amisulpride, aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone and paliperidone) and seven of their metabolites were determined. Results: Overall, 74% of the samples had therapeutic antipsychotic levels, 19% had subtherapeutic concentrations, while supra-therapeutic concentrations were measured for clozapine (7%). Therapeutic drug concentrations were recorded in 54% of plasma samples from patients being under olanzapine medication and in all patients under long-acting injectables. Sub-therapeutic levels were either attributed to non-adherence, or they reflected residual levels due to medication changes. Supra-therapeutic levels were recorded for clozapine and were not followed by adverse effects. Conclusion: This is the first study on antipsychotic plasma levels conducted in Greece. Our results show the importance of performing measurement of plasma antipsychotics levels, at appropriate time intervals, for improving adherence, clinical decision making and thus clinical efficacy. Especially for FEPs, such approach could contribute to early detection of treatment limitations and improve outcome.

Stratifying Therapeutic Enoxaparin Dose in Morbidly Obese Patients by BMI Class: A Retrospective Cohort Study.

Enoxaparin is a low-molecular weight heparin (LMWH) commonly used for treatment of venous thromboembolism and acute coronary syndromes. The recommended dose for these conditions is weight-based (1mg/kg) and doesn't require dose-capping. However, previous studies have shown that in those with a body mass index (BMI) > 40kg/m2, this dose results in supratherapeutic levels. This study investigated enoxaparin dosing in morbidly obese patients with a goal of identifying a dose with the greatest chance of producing favorable anti-factorXa (anti-Xa) levels. This retrospective cohort study by electronic chart review was used to record data of patients who received enoxaparin with anti-Xa level monitoring between 2012 and 2017. The primary outcome was the enoxaparin dose that results in a therapeutic anti-Xa level (0.5-1.0IU/mL) among three BMI groups. Secondary outcomes were bleeding and thromboembolic events. Two hundred forty-one patients were included in the study, and 132 achieved a therapeutic dose. For those with a BMI of 40-50kg/m2, the median therapeutic dose was 0.97mg/kg every 12h. In subjects with a BMI of 50-60kg/m2, the median therapeutic dose was 0.70mg/kg. Finally, the median therapeutic dose for subjects with a BMI over 60kg/m2 was 0.71mg/kg. In all three groups, 53-65% of patients had a supratherapeutic anti-Xa level while less than 10% had a subtherapeutic level. Relatively few patients (4.1%) experienced major bleeding and only one thromboembolic event was reported. Standard dosing of enoxaparin in morbidly obese patients will most likely lead to supratherapeutic anti-Xa levels and thus further investigation is warranted to better determine appropriate dosing.

Treatment Failures of Direct Oral Anticoagulants.

Use of direct oral anticoagulants (DOACs) has increased over the years, because they have become a safe and effective alternative to the Vitamin-K antagonists in various clinical scenarios. With their increased use, reports have emerged describing their failure. What are the patient characteristics and clinical settings in which DOAC treatment failure manifests? We searched published reports in Google Scholar, PubMed, MEDLINE, and Embase from the introduction of DOACs in any therapy until March 2019. Information on patient characteristics, comorbidities, primary anticoagulation indications, pharmacologic treatment, and outcomes were collected. Primary endpoints were new thrombus formation, failure of resolution of an existing thrombus, or discovery of subtherapeutic drug level. Other endpoints were time to treatment failure, manifestations of treatment failure, and new treatment after DOAC failure. Our search yielded 51 manuscripts, describing 79 patients who exhibited DOAC failure. The most common treatment failures were in patients with antiphospholipid syndrome (44.3%), atrial fibrillation (30.4%), and deep venous thrombosis (6.3%). There was a trend toward higher failure rate for rivaroxaban (65.8%) followed by dabigatran (27.8%), apixaban (7.6%), and then edoxaban (1.3%). Each agent had different median failure times. Most common manifestations of treatment failure were stroke/transient ischemic attack (20.3%), pulmonary embolism (19.0%), and deep venous thrombosis (19.0%). More than half of patients were transitioned to a Vitamin-K antagonist after DOAC failure (55.7%). Our analysis illustrates that DOACs may fail in the setting of Food and Drug Administration and non-Food and Drug Administration- approved indications. In clinical practice, it may be best to choose between available anticoagulant drugs on a case-by-case basis.

487P - Comparison of intratumoral docetaxel exposure in cancer patients between nanoparticle entrapped docetaxel (CPC634) and conventional docetaxel (Cd): The CriTax study

BackgroundIneffective chemotherapy may partly be caused by subtherapeutic intratumoral drug levels. Nanomedicines are developed to improve the therapeutic index, by increasing intratumoral drug exposure and preserving healthy tissue. CPC634 is a new nanoparticle entrapping docetaxel. Here, we hypothesized that CPC634 increases intratumoral docetaxel level and overall duration of exposure. MethodsIn this randomized cross-over study we assessed both plasma and intratumoral pharmacokinetics (PK) of docetaxel after intravenous administration of 75mg/m2 conventional docetaxel (Cd) and CPC634. We aimed to identify a 25% increase of intratumoral docetaxel exposure after CPC634 infusion compared to Cd. Adult patients were randomized to receive Cd in cycle 1 and CPC634 in cycle 2 or vice versa. Tumor biopsies were taken 24, 48, 72, 96, 168 or 336hours after infusion during both cycles. Total docetaxel concentration (TDC) was determined for both drugs and released docetaxel for CPC634 in tumor tissue and plasma. PK data were analyzed using mixed modeling. ResultsIn total, 21 evaluable patients were included. In plasma, the area under the curve (AUCinf) of released docetaxel was higher (+27%, 95% CI: 11-44%, P=0.001) while peak plasma concentration (Cmax) (-91%, 95% CI: -92:-89%, P<0.001) and clearance (-21%, 95% CI: -31;-10%, P=0.001) decreased during CPC634 administration versus Cd. Intratumoral TDC was 375% higher (95% CI: 187-686%, P<0.001) after CPC634 administration, while released docetaxel was comparable to Cd (+8%, 95% CI: -30-+69%, P=0.71). ConclusionsThe plasma PK profile of CPC634 is favorable compared to Cd since a lower Cmax, lower clearance and prolonged higher systemic exposure is seen. Higher intratumoral TDC levels were reached with CPC634, while released docetaxel levels were comparable to Cd. The almost 4-fold increased tumor accumulation for prolonged period of time of TDC supports the expectation that CPC634 will exhibit beneficial efficacy/safety balance. Additional studies assessing the intratumoral exposure to CPC634 (NCT0371243) and a phase II efficacy study of CPC634 in platinum resistant ovarian cancer patients (NCT03742713) are currently ongoing. Clinical trial identificationNetherlands Trial Registry NL6299 (NTR6474). Legal entity responsible for the studyProf. Dr. A.H.J. Mathijssen as principle investigator. FundingCristal Therapeutics. DisclosureC.J.F. Rijcken: Officer / Board of Directors: Cristal Therapeutics; Leadership role: Cristal Therapeutics; Shareholder / Stockholder / Stock options: Cristal Therapeutics; Full / Part-time employment: Cristal Therapeutics. R. Hanssen: Full / Part-time employment: Cristal Therapeutics. R.H.J. Mathijssen: Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Boehringer; Research grant / Funding (institution): Cristal Therapeutics; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pamgene; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi; Honoraria (institution): Servier; Honoraria (institution): Novartis; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Astellas. S.L. Koolen: Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Roche; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Cristal Therapeutics; Travel / Accommodation / Expenses: Ipsen. All other authors have declared no conflicts of interest.

The Epidemiologic Burden of Tacrolimus Variability among Kidney Transplant Recipients in the United States

Background: Within-patient tacrolimus level variability >30% has been shown to be a risk factor for de novo donor-specific antibody formation and death-censored graft failure among kidney transplant recipients. The burden of tacrolimus variability and the correlation between variability and subtherapeutic tacrolimus levels were examined in a large national data set. Methods: All tacrolimus levels drawn at LabCorp® facilities in the United States with a diagnosis code for kidney transplant between November 2011 and September 2017 were examined, excluding values that could represent new allografts. Tacrolimus variability was calculated if at least 3 levels were available. The percentage of subtherapeutic (<4.0 ng/dL) tacrolimus levels (%subT) was also calculated. Interdependence between %subT and tacrolimus variability was assessed with correlation analysis and linear regression. Results: There were 410,257 tacrolimus levels among 27,375 patients, who had 11 (interquartile range [IQR] 6–20) tacrolimus levels over a median follow-up of 26.5 (IQR 12.8–46.1) months. Median tacrolimus variability was 30.6%, and 51.6% of patients exceeded 30% variability. Median %subT was 11.1% (IQR 0–30.8%), and 34.3% of patients had no subtherapeutic levels. The correlation coefficient between tacrolimus variability and %subT was 0.253 (p< 0.001). In linear regression, tacrolimus variability increased 1.86% for each 10% increase in %subT (p < 0.001), but R-squared for this model was only 0.06. Conclusion: More than half of established kidney transplant patients from a large national sample exhibited levels of tacrolimus variability that have been associated with inferior transplant outcomes. Tacrolimus variability has a weak association with subtherapeutic levels, but represents a more complicated constellation of clinical factors.

Vancomycin-associated nephrotoxicity in non-critically ill patients admitted in a Brazilian public hospital: A prospective cohort study.

IntroductionVancomycin is widely used to treat infections caused by Gram positive bacteria, mostly methicillin-resistant strains. Despite its therapeutic effectiveness, vancomycin is a nephrotoxic drug that has been associated with the occurrence of acute kidney injury (AKI). In this study, we sought to evaluate the variability of serum trough concentrations of vancomycin and to determine the incidence and risk factors of vancomycin-associated nephrotoxicity (VAN) in non-critically ill patients.MethodsThis was a prospective cohort including Brazilian public hospital inpatients from April 2017 to June 2018. The participants received intravenous vancomycin therapy for at least 48 hours for any suspected or confirmed infection by Gram positive bacteria. Demographic, clinical and laboratory data were collected. Information on vancomycin therapy and concomitant use of other nephrotoxic drugs were also recorded. Patients were followed up until discontinuation of vancomycin treatment or death, whatever occurred first. The primary outcome was the occurrence of AKI. We performed a Poisson regression to determine risk factors for AKI.ResultsOverall, 98 participants were included in the study. Median age was 55.9 (interquartile range [IQR] 40.6–66.8) years and 58 (59.2%) were men. Most of them showed subtherapeutic (<10mg/L) or supratherapeutic (>20mg/L) trough levels of vancomycin; 42.9% and 15.3%, respectively. A total of 19 (19.4%) patients developed AKI. Poisson regression showed that male sex (odds ratio [OR] 2.90; confidence interval [CI] 95% 1.28–6.53; p = 0.011), concomitant use of piperacillin-tazobactam (OR 4.66; CI 95% 2.26–9.58; p <0.001) and vancomycin trough levels above 20mg/mL (OR 4.21; CI 95% 1.57–11.278; p = 0.004) were independently associated with AKI.ConclusionsOur study showed that usual doses of vancomycin did not reach recommended therapeutic serum trough levels of vancomycin in non-critically ill patients. Besides that, nephrotoxicity was common in this population, being associated with male sex, concomitant use of piperacillin-tazobactam and supra-therapeutic trough serum levels of vancomycin.

Invasive Fungal Infections in the Pediatric Intensive Care Unit.

Invasive Fungal Infections in the Pediatric Intensive Care Unit.

Differential Impact of Subtherapeutic Antibiotics and Ionophores on Intestinal Microbiota of Broilers.

Antimicrobial growth promoters (AGPs) are commonly used in the livestock industry at subtherapeutic levels to improve production efficiency, which is achieved mainly through modulation of the intestinal microbiota. However, how different classes of AGPs, particularly ionophores, regulate the gut microbiota remains unclear. In this study, male Cobb broiler chickens were supplemented for 14 days with or without one of five commonly used AGPs including three classical antibiotics (bacitracin methylene disalicylate, tylosin, and virginiamycin) and two ionophores (monensin and salinomycin) that differ in antimicrobial spectrum and mechanisms. Deep sequencing of the V3-V4 region of the bacterial 16S rRNA gene revealed that two ionophores drastically reduced a number of rare bacteria resulting in a significant decrease in richness and a concomitant increase in evenness of the cecal microbiota, whereas three antibiotics had no obvious impact. Although each AGP modulated the gut microbiota differently, the closer the antibacterial spectrum of AGPs, the more similarly the microbiota was regulated. Importantly, all AGPs had a strong tendency to enrich butyrate- and lactic acid-producing bacteria, while reducing bile salt hydrolase-producing bacteria, suggestive of enhanced metabolism and utilization of dietary carbohydrates and lipids and improved energy harvest, which may collectively be responsible for the growth-promoting effect of AGPs.

Characterizing the soil microbiome and quantifying antibiotic resistance gene dynamics in agricultural soil following swine CAFO manure application.

As agriculture industrializes, concentrated animal feeding operations (CAFOs) are becoming more common. Feces from CAFOs is often used as fertilizer on fields. However, little is known about the effects manure has on the soil microbiome, which is an important aspect of soil health and fertility. In addition, due to the subtherapeutic levels of antibiotics necessary to keep the animals healthy, CAFO manure has elevated levels of antibiotic resistant bacteria. Using 16s rRNA high-throughput sequencing and qPCR, this study sought to determine the impact of swine CAFO manure application on both the soil microbiome and abundance of select antibiotic resistance genes (ARGs) and mobile element genes (erm(B), erm(C), sul1, str(B), intI1, IncW repA) in agricultural soil over the fall and spring seasons. We found the manure community to be distinct from the soil community, with a majority of bacteria belonging to Bacteroidetes and Firmicutes. The soil samples had more diverse communities dominated by Acidobacteria, Actinobacteria, Proteobacteria, Verrucomicrobia, and unclassified bacteria. We observed significant differences in the soil microbiome between all time points, except between the spring samples. However, by tracking manure associated taxa, we found the addition of the manure microbiome to be a minor driver of the shift. Of the measured genes, manure application only significantly increased the abundance of erm(B) and erm(C) which remained elevated in the spring. These results suggest bacteria in the manure do not survive well in soil and that ARG dynamics in soil following manure application vary by resistance gene.

Impact of IgG Monitoring and IVIG Supplementation on the Frequency of Febrile Illnesses in Pediatric Acute Lymphoblastic Leukemia Patients Undergoing Maintenance Chemotherapy.

Monitoring serum immunoglobulin G (IgG) levels in pediatric oncology patients and treating subtherapeutic levels with intravenous immunoglobulin (IVIG) may prevent infections; however, evidence is limited. This retrospective study assessed pediatric acute lymphoblastic leukemia patients diagnosed 2006 to 2011 to evaluate if monitoring/supplementing IgG would reduce febrile illnesses during maintenance chemotherapy. A subject was categorized as "ever IgG monitored" if they had ≥1 IgG levels checked and their risk days were stratified into not IgG monitored days and IgG monitored days. IgG monitored days were further stratified into IgG monitored with IVIG supplementation, monitored with no IVIG supplementation (IgG level >500 mg/dL) and monitored with no IVIG supplementation days (IgG level <500 mg/dL). Generalized linear mixed effects poisson models were used to compare events (febrile episode, positive blood culture, and febrile upper respiratory infection rates among these groups. In 136 patients, the febrile episode rate was higher in the ever IgG monitored cohort than the never monitored cohort (5.26 vs. 3.78 episodes/1000 d). Among monitored patients, IVIG monitoring and supplementation did not significantly impact the febrile episode, febrile upper respiratory infection, or the positive blood culture rates. These data suggest that monitoring/supplementing low IgG is not indicated for infection prophylaxis in acute lymphoblastic leukemia patients during maintenance chemotherapy.

Nutrition Related Stress Factors Reduce the Transfer of Extended-Spectrum Beta-Lactamase Resistance Genes between an Escherichia coli Donor and a Salmonella Typhimurium Recipient In Vitro.

The transfer of extended spectrum β-lactamase (ESBL)-genes occurs frequently between different bacteria species. The aim of this study was to investigate the impact of nutrition related stress factors on this transfer. Thus, an Escherichia coli donor and a Salmonella Typhimurium recipient were co-incubated for 4 h in media containing different levels of the stress factors’ pH, osmolality, copper, zinc and acetic, propionic, lactic, and n-butyric acid, as well as subtherapeutic levels of cefotaxime, sulfamethoxazole/trimethoprim, and nitrofurantoin. Conjugation frequencies were calculated as transconjugants per donor, recipient, and total bacterial count. A correction factor for the stress impact on bacterial growth was used. Acetic, lactic, and n-butyric, acid, as well as pH, showed no significant impact. In contrast, increasing concentrations of propionate, zinc, copper, and nitrofurantoin, as well as increased osmolality reduced conjugation frequencies. Sulfamethoxazole/trimethoprim and cefotaxime showed increased transconjugants per donor, which decreased after correction for stress. This study showed, for the model mating pair, that conjugation frequencies decreased under different physiological stress conditions, and, thus, the hypothesis that stress factors may enhance conjugation should be viewed with caution. Furthermore, for studies on in vitro gene transfer, it is vital to consider the impact of studied stressors on bacterial growth.

Diagnosis and management of children with Blue Rubber Bleb Nevus Syndrome: A multi-center case series

BackgroundBlue Rubber Bleb Nevus Syndrome (BRBNS) is a rare, severe, sporadically occurring disorder characterized by multiple venous malformations. AimsTo present and analyze a case series of pediatric patients with BRBNS and to describe diagnostic approaches and management options applied. Patients and methodsMulticenter, retrospective study, evaluating the diagnosis and management of children with BRBNS. ResultsEighteen patients diagnosed with BRBNS were included. Cutaneous venous malformations were observed in 78% and gastrointestinal venous malformations in 89%. Lesions were also found in other organs including muscles, joints, central nervous system, eyes, parotid gland, spine, kidneys and lungs. Gastrointestinal lesions were more common in the small intestine than in stomach or colon. The management varied significantly among centers. Endoscopic therapy and surgical therapy alone failed to prevent recurrence of lesions. In younger children and in patients with musculoskeletal or other organ involvement, sirolimus was used with 100% success rate in our series (5 patients treated) although poor compliance with subtherapeutic sirolimus trough levels led to recurrence in a minority. ConclusionsConsidering the multi-organ involvement in BRBNS, diagnosis and management requires a multidisciplinary approach. The treatment includes conservative, medical, endoscopic and surgical options. Prospective multicenter studies are needed to identify the optimal management of this rare condition.

The Evolving Clinical Presentation of Acute Rejection in Facial Transplantation.

Acute rejection is one of the most frequent complications in facial transplantation, with potentially severe consequences for the recipient if overlooked. Clinical signs, such as erythema or edema, are helpful to diagnose acute rejection in the early follow-up stage; however, it is not well known whether these clinical signs remain reliable markers of acute rejection beyond the second posttransplant year. To determine the diagnostic value of clinical signs of acute rejection after facial transplantation over time. A retrospective, single-center cohort study was conducted of patients who underwent facial transplantation at Brigham and Women's Hospital between April 2009 and October 2014, with up to an 8-year follow-up. Medical records were reviewed until September 30, 2017. The medical records from 104 encounters with 7 patients who underwent partial or full facial transplantation were analyzed for symptoms of rejection, immunosuppressive therapy, and histopathologic findings. The occurrence of 5 clinical signs of acute rejection were evaluated: erythema, edema, exanthema, suture line erythema, and mucosal lesions. Odds ratios (ORs) were calculated to determine the statistically significant association of these signs with the histopathologic diagnosis of rejection. In addition, tacrolimus blood levels, as a surrogate marker of immunosuppressive therapy, were evaluated. Of the 7 patients included in the study, 5 were men. The mean follow-up was 66 months (range, 35-101). Of 104 clinical encounters, 46 encounters (44.2%) represented rejection episodes and 58 encounters (55.8%) represented no-rejection episodes. Beyond 2 years posttransplantation, only erythema (OR, 6.53; 95% CI, 1.84-20.11; P = .004) and exanthema (OR, ∞; 95% CI, 2.2-∞; P = .004) were demonstrated to be reliable clinical signs of acute rejection in facial transplantation. There was also a statistically significant association of subtherapeutic tacrolimus levels with late rejection episodes (OR, 3.79; 95% CI, 1.25-12.88; P = .03). In addition, the occurrence of subclinical rejection was more frequent during later follow-up times (7 [24.1%] late rejections vs 1 [5.9%] early rejection). Five of 8 subclinical rejections (62.5%) were associated with subtherapeutic tacrolimus levels. Clinical signs of acute rejection in facial transplantation appear to be of limited diagnostic value, particularly after the second postoperative year. Until alternative biomarkers for rejection are identified, protocol skin biopsies will remain necessary for guiding assessments of allograft rejection. 3.

Delivery of Rapamycin Using In Situ Forming Implants Promotes Immunoregulation and Vascularized Composite Allograft Survival

Vascularized composite allotransplantation (VCA), such as hand and face transplantation, is emerging as a potential solution in patients that suffered severe injuries. However, adverse effects of chronic high-dose immunosuppression regimens strongly limit the access to these procedures. In this study, we developed an in situ forming implant (ISFI) loaded with rapamycin to promote VCA acceptance. We hypothesized that the sustained delivery of low-dose rapamycin in proximity to the graft may promote graft survival and induce an immunoregulatory microenvironment, boosting the expansion of T regulatory cells (Treg). In vitro and in vivo analysis of rapamycin-loaded ISFI (Rapa-ISFI) showed sustained drug release with subtherapeutic systemic levels and persistent tissue levels. A single injection of Rapa-ISFI in the groin on the same side as a transplanted limb significantly prolonged VCA survival. Moreover, treatment with Rapa-ISFI increased the levels of multilineage mixed chimerism and the frequency of Treg both in the circulation and VCA-skin. Our study shows that Rapa-ISFI therapy represents a promising approach for minimizing immunosuppression, decreasing toxicity and increasing patient compliance. Importantly, the use of such a delivery system may favor the reprogramming of allogeneic responses towards a regulatory function in VCA and, potentially, in other transplants and inflammatory conditions.

Vancomycin Use in a Paediatric Intensive Care Unit of a Tertiary Care Hospital.

Vancomycin is one of the commonly used anti-microbial drugs in intensive care units (ICUs). Guidelines recommend maintaining therapeutic trough levels of vancomycin (10-20mg/L). The success of achieving the recommended therapeutic concentration of vancomycin is influenced by several factors, and this is even more complex in children, particularly those admitted in the ICU. Hence, we carried out the present study inchildren admitted in the ICU who were administered vancomycin. We carried out a chart review of children admitted in the paediatric ICU unit of a tertiary care hospital over a period of 3years. Information on their demographic factors, diagnoses, duration of hospital stay, vancomycin treatment (dose, frequency and time of administration) and concomitant drugs, and vancomycin trough levels were retrieved. Descriptive statistics were used for representing the demographic factors, and multivariable logistic regression analyses were carried out to assess the determining factors. One-hundred and two children were identified, of whom 13 had renal dysfunction. Two-hundred and fifty-two vancomycin trough levels were available, of which only 25% were observed in the recommended range (10-20mg/L) amongst patients without any renal dysfunction and 22% amongst patients with renal dysfunction. Vancomycin was administered intravenously at an average [standard deviation (SD)] dose (mg/dose) of 13 (3.9) mostly either thrice or four times daily. Even in patients receiving vancomycin as a definitive therapy, only 40.9% achieved the recommended trough levels. Lower trough levels were associated with an increased risk of mortality. Nearly 4% of the levels were above 20mg/L (toxic range). Seven children were suspected to have acute kidney injury (AKI) during the course of therapy where the cumulative vancomycin dose and mortality rate was higher. Only one serum vancomycin level during augmented renal clearance was observed in the recommended range. All the patients received at least one concomitant drug that either had nephrotoxic potential or predominant renal elimination, and use of a greater number of such drugs was associated with an increased risk of AKI. The current vancomycin dosing strategy is ineffective in achieving therapeutic trough levels in children admitted to the ICU. Sub-therapeutic vancomycin trough levels significantly increase the risk of mortality.

Frequency of the CYP2C19*17 polymorphism in a Chilean population and its effect on voriconazole plasma concentration in immunocompromised children

Invasive fungal infections (IFIs) are the most frequent cause of morbidity and mortality in immunocompromised children. Voriconazole is the first-line antifungal choice in the treatment of IFIs like aspergillosis. Voriconazole pharmacokinetics vary widely among patients and voriconazole is metabolized mainly in the liver by the CYP2C19 enzyme, which is highly polymorphic. The CYP2C19*17 allele is characterized by the presence of four single nucleotide polymorphisms expressing an ultra-rapid enzyme phenotype with an accelerated voriconazole metabolism, is associated with low (sub-therapeutic) plasma levels in patients treated with the standard dose. Considering that in our center a high percentage of children have sub-therapeutic levels of voriconazole when treated with standard doses, we sought to determine the frequency of the CYP2C19*17 polymorphism (rs12248560) in a Chilean population and determine the association between voriconazole concentrations and the rs12248560 variant in immunocompromised children. First, we evaluated the frequency of the rs12248560 variant in a group of 232 healthy Chilean children, and we found that 180 children (77.6%) were non-carriers of the rs12248560 variant, 49 children (21.1%) were heterozygous carriers for rs12248560 variant and only 3 children (1.3%) were homozygous carriers for rs12248560 variant, obtaining an allelic frequency of 12% for variant in a Chilean population. To determine the association between voriconazole concentrations and the rs12248560 variant, we analyzed voriconazole plasma concentrations in a second group of 33 children treated with voriconazole. In these patients, carriers of the rs12248560 variant presented significantly lower voriconazole plasma concentrations than non-carriers (p = 0,011). In this study, we show the presence of the rs12248560 variant in a Chilean population and its accelerating effect on the pharmacokinetics of voriconazole in pediatric patients. From these data, it would be advisable to consider the variant of the patient prior to calculating the dosage of voriconazole.

The relationship between zidovudine, lamivudine and nevirapine plasma drug levels and antiretroviral treatment outcomes in Nigeria children living with HIV

Plasma concentrations of antiretrovirals are significant and important determinants of treatment failure and toxicity. The relationship between antiretroviral pharmacokinetic exposures and immunovirological outcomes has not been extensively studied in our setting. The aim of this study was to investigate the relationship between antiretroviral plasma concentrations and virological and immunological treatment outcomes in children living with human immunodeficiency virus (HIV) A retrospective collection of demographic, clinical , laboratory data and a prospective determination of plasma drug concentrations in 120 children aged 2-14 years after two years of receiving fixed dose zidovudine, lamivudine and nevirapine tablets using a simple, rapid, sensitive and validated method of high performance liquid chromatography with UV detection for simultaneous quantification of zidovudine, lamivudine and nevirapine in human plasma. All analyses were performed using graph pad prism version 5.0. A perfect agreement (p 100 cells/mm3). At 2 years zidovudine, lamivudine and nevirapine therapeutic levels, zidovudine supra therapeutic levels ,and nevirapine subtherapeutic levels were respectively significantly associated with immunologic success (CD4%>15 %). Low nevirapine levels can be used to identify those that require adherence counseling. Despite good virological and immunological outcomes, plasma concentrations of zidovudine, lamivudine and nevirapine were not significantly associated with virological and immunological outcomes (Absolute CD4 counts) but was significantly associated with immunological outcomes (CD4%). Plasma drug levels may be good surrogates of adherence but not of treatment outcomes. Monitoring CD4% remains important to optimize paediatric HIV treatment.Keywords: Antiretroviral treatment, children, therapeutic drug monitoring, treatment outcomes, immune-virological outcomes, plasma concentrations, zidovudine, lamivudine and nevirapine

Psychological processing of a kidney transplantation, perceived quality of life, and immunosuppressant medication adherence.

Introduction: Though psychosocial well-being and quality of life generally improve after transplantation, a relevant proportion of patients suffers from psychosocial problems. Further analysis of the psychological coping after kidney transplantation is needed to identify patients at risk. The aim of this study was to examine the psychological response after kidney transplantation and its associations with health-related quality of life and immunosuppressant medication adherence.Materials and methods: The coping process after kidney transplantation was investigated with the Transplant Effects Questionnaire (TxEQ; subscales: worry, guilt, disclosure, adherence, responsibility) in 267 adult kidney transplant recipients ≥12 months post-transplantation. Furthermore, perceived health-related quality of life, self-reported immunosuppressant medication adherence, and sub-therapeutic immunosuppressant trough levels as biological markers of adherence were assessed.Results: Patients showed moderate scores concerning the subscales “worry”, “guilt”, and “responsibility” as well as high scores concerning “disclosure”. Except for “adherence”, all TxEQ subscales were associated with mental, but not with physical health-related quality of life and self-reported adherence. Sub-therapeutic immunosuppressant trough levels were significantly associated only with the TxEQ subscale “worry”.Conclusions: The present results suggest a conditional structure in which mental health-related quality of life is negatively associated with worries, guilt, and responsibility and positively with disclosure. Adherence seems to be a complex behavior, which is not necessarily directly associated with the psychological processing of organ transplantations. As mental health-related quality of life is related to this psychological processing, the TxEQ could be used as a screening tool for problematic psychological processing after kidney transplantation.

Course and Outcome of Children with Convulsive Status Epilepticus Admitted to a Pediatric Intensive Care Unit.

IntroductionThe objective of this study was to describe the course and the outcomes of children with convulsive status epilepticus and to evaluate the differences between two groups of children with new-onset seizures and known seizure disorders.MethodsThis is a retrospective, single-center study. Children with convulsive status epilepticus admitted to our tertiary care pediatric intensive care unit were included in the study. Medical records were reviewed to obtain the demographic- and seizure-related variables.ResultsAmong 139 children with status epilepticus, 69.7% (n = 99) had a known seizure disorder. Focal seizures were present in 23.9% of children, and 34.6% required intubation; there was an overall mortality rate of 1.2%. The children with new-onset seizures were younger and received electroencephalography (EEG) and neuroimaging more often compared to children with known seizure disorders (p < 0.05). However, an abnormal EEG was more common among children with known seizure disorders (p < 0.001).ConclusionsSub-therapeutic anti-epileptic drugs levels were common among children with known seizure disorders presenting with status epilepticus. Gender, race, insurance status, type of seizures, intubation requirement, lengths of stay, and mortality were not significantly different between the two groups.

Evaluation of vancomycin target trough attainment with published dosing regimens in the neonatal intensive care unit population.

Study aims to evaluate whether vancomycin dosing from published dosing algorithms correlate with the attainment of target troughs of 10 to 20 mg/L. NICU patients who received minimum three doses of vancomycin and had a trough level met inclusion criteria. Dosing information was retrospectively evaluated to determine which published dosing regimen was followed. Dosing algorithms used were matched to NeoFax/Harriet Lane, renal-function directed dosing, and weight-directed dosing, in which the latter two can be found in Pediatric and Neonatal Lexi-Drugs. Primary outcome was percentage of troughs within therapeutic (10 to 20 mg/L) and subtherapeutic (less than 10 mg/L) levels. Of 97 troughs evaluated, NeoFax/Harriet Lane accounted for 86.6%, renal-function directed accounted for 5.1%, and weight-directed dosing accounted for 18.5% of dosing algorithms. NeoFax/Harriet Lane, renal-function directed, and weight-directed dosing attained therapeutic levels between 10 to 20 mg/L at a rate of 60.7%, 60%, and 50% of the time, respectively. With respect to initiation of therapy, a higher dose of 15 mg/kg versus 10 mg/kg attained therapeutic levels (p < 0.001; OR 11.22; 95% CI, 3.96 to 31.81), while a serum creatinine value below 0.5 mg/dL attained subtherapeutic levels (p = 0.028; OR 0.068; 95% CI, 0.006 to 0.74). NeoFax, Harriet Lane, and renal-directed dosing from Pediatric and Neonatal Lexi-Drugs achieved target troughs within the 10 to 20 mg/L range more often than weight-directed dosing from Pediatric and Neonatal Lexi-Drugs. Initiating therapy at a higher dose and patient serum creatinine value above 0.5 mg/dL were factors significantly associated with a 10 to 20 mg/L range.