Caridad Pontes

Beta-lactam dosing in critically ill patients with septic shock and continuous renal replacement therapy

Although early and appropriate antibiotic therapy remains the most important intervention for successful treatment of septic shock, data guiding optimization of beta-lactam prescription in critically ill patients prescribed with continuous renal replacement therapy (CRRT) are still limited. Being small hydrophilic molecules, beta-lactams are likely to be cleared by CRRT to a significant extent. As a result, additional variability may be introduced to the per se variable antibiotic concentrations in critically ill patients. This article aims to describe the current clinical scenario for beta-lactam dosing in critically ill patients with septic shock and CRRT, to highlight the sources of variability among the different studies that reduce extrapolation to clinical practice, and to identify the opportunities for future research and improvement in this field. Three frequently prescribed beta-lactams (meropenem, piperacillin and ceftriaxone) were chosen for review. Our findings showed that present dosing recommendations are based on studies with drawbacks limiting their applicability in the clinical setting. In general, current antibiotic dosing regimens for CRRT follow a one-size-fits-all fashion despite emerging clinical data suggesting that drug clearance is partially dependent on CRRT modality and intensity. Moreover, some studies pool data from heterogeneous populations with CRRT that may exhibit different pharmacokinetics (for example, admission diagnoses different to septic shock, such as trauma), which also limit their extrapolation to critically ill patients with septic shock. Finally, there is still no consensus regarding the %T>MIC (percentage of dosing interval when concentration of the antibiotic is above the minimum inhibitory concentration of the pathogen) value that should be chosen as the pharmacodynamic target for antibiotic therapy in patients with septic shock and CRRT. For empirically optimized dosing, during the first day a loading dose is required to compensate the increased volume of distribution, regardless of impaired organ function. An additional loading dose may be required when CRRT is initiated due to steady-state equilibrium breakage driven by clearance variation. From day 2, dosing must be adjusted to CRRT settings and residual renal function. Therapeutic drug monitoring of beta-lactams may be regarded as a useful tool to daily individualize dosing and to ensure optimal antibiotic exposure.

Meropenem population pharmacokinetics in critically ill patients with septic shock and continuous renal replacement therapy: influence of residual diuresis on dose requirements.

ABSTRACT Meropenem dosing in critically ill patients with septic shock and continuous renal replacement therapy (CRRT) is complex, with the recommended maintenance doses being 500 mg to 1,000 mg every 8 h (q8h) to every 12 h. This multicenter study aimed to describe the pharmacokinetics (PKs) of meropenem in this population to identify the sources of PK variability and to evaluate different dosing regimens to develop recommendations based on clinical parameters. Thirty patients with septic shock and CRRT receiving meropenem were enrolled (153 plasma samples were tested). A population PK model was developed with data from 24 patients and subsequently validated with data from 6 patients using NONMEM software (v.7.3). The final model was characterized by CL = 3.68 + 0.22 · (residual diuresis/100) and V = 33.00 · (weight/73)2.07, where CL is total body clearance (in liters per hour), residual diuresis is the volume of residual diuresis (in milliliters per 24 h), and V is the apparent volume of distribution (in liters). CRRT intensity was not identified to be a CL modifier. Monte Carlo simulations showed that to maintain concentrations of the unbound fraction (fu) of drug above the MIC of the bacteria for 40% of dosing interval T (referred to as 40% of the ƒuT>MIC), a meropenem dose of 500 mg q8h as a bolus over 30 min would be sufficient regardless of the residual diuresis. If 100% of the ƒuT>MIC was chosen as the target, oligoanuric patients would require 500 mg q8h as a bolus over 30 min for the treatment of susceptible bacteria (MIC < 2 mg/liter), while patients with preserved diuresis would require the same dose given as an infusion over 3 h. If bacteria with MICs close to the resistance breakpoint (2 to 4 mg/liter) were to be treated with meropenem, a dose of 500 mg every 6 h would be necessary: a bolus over 30 min for oligoanuric patients and an infusion over 3 h for patients with preserved diuresis. Our results suggest that residual diuresis may be an easy and inexpensive tool to help with titration of the meropenem dose and infusion time in this challenging population.

Evaluation of responsive gene expression as a sensitive and specific biomarker in patients with ulcerative colitis

Background:Clinical trials in ulcerative colitis (UC) rely on certain parameters to evaluate responses that are highly subjective or of low sensitivity. Here, using a select group of genes, we tested the accuracy of gene expression analysis as a biomarker of clinical, endoscopic, and histologic improvements. Methods:Intestinal biopsies were obtained from UC patients included in two cohorts. Cohort 1 was used to select for genes whose expression was modulated in active (vs. inactive) UC. Cohort 2 included patients recruited in a phase II study receiving placebo, mesalazine, or dersalazine sodium for 4 weeks. The expression of 44 genes identified in Cohort 1 was assessed at weeks 0 and 4, and was then correlated with biomarkers, as well as with clinical, endoscopic, and histologic scores. Results:Significant changes in the expression of 31 of the 44 genes tested were detected in Cohort 2 at week 4. Gene expression (&Dgr;Ct) significantly correlated with the total Mayo score, C-reactive protein (CRP), and fecal calprotectin. The number of genes significantly regulated at week 4 was highly associated with histologic and endoscopic responses. Logistic regression analysis identified four separate genes (IFITM1, ITGB2, IL1R2, IL2RA) whose relative change was independently associated with endoscopic remission with high specificity and sensitivity. Conclusions:Change in the expression of a select set of genes can serve as an early biomarker, one with high specificity and sensitivity to clinical, endoscopic, and histologic responses. This could represent a new tool for identifying early response to treatment in mild to moderately active UC patients.

Recomendaciones metodológicas de las agencias reguladoras

Las autoridades sanitarias, mediante las agencias de medicamentos, determinan la idoneidad de los nuevos tratamientos para su uso en la poblacion general en terminos de beneficio y riesgo, y regulan su comercializacion y condiciones de utilizacion segun criterios estrictos de calidad, seguridad y eficacia. Para aplicar el principio de transparencia, las agencias hacen publicos los requisitos que despues se exigiran, en forma de documentos guia, facilmente disponibles en internet. Todas estas guias incorporan de uno u otro modo unas recomendaciones basicas: a) metodologia adecuada al objetivo y especificada en detalle a priori; b) trazabilidad; c) comprobacion de la adecuacion de los metodos usados; d) justificacion de cualquier desviacion del plan inicial, y e) demostracion de la robustez de los resultados en distintos escenarios. Las directrices reguladoras difieren de otras referencias metodologicas en un enfasis sobre los aspectos practicos del diseno y la conduccion de los estudios, los principios metodologicos aceptables y los sistemas de control de calidad de la investigacion. Si bien estas exigencias pueden no ser de aplicacion estricta a algunos tipos de investigacion, las guias estan facilmente disponibles y son una buena referencia a considerar para la autoria, revision y edicion de ensayos clinicos. El objetivo de este articulo es revisar algunas de estas directrices que pueden ser de especial utilidad.

Safety and activity of dersalazine sodium in patients with mild-to-moderate active colitis: double-blind randomized proof of concept study.

Background:Dersalazine sodium is an inhibitor of platelet activator factor with potential efficacy in patients with ulcerative colitis through an alternative mechanism of action. The study was a first proof of clinical safety and activity of dersalazine sodium in patients with ulcerative colitis. Methods:A double-blind study of randomized patients with ulcerative colitis (Mayo score ≥5 and ⩽10, including a sigmoidoscopy subscore ≥2) to dersalazine sodium 1200 mg/12 h, mesalazine 1200 mg/12 h, or placebo for 4 weeks. Mayo scores were calculated on week 2 (partial Mayo) and week 4 (full Mayo). All patients received open-label mesalazine for 4 additional weeks, and a final visit was done at week 8. Results:The study included 34 patients (13 dersalazine sodium, 10 mesalazine, and 11 placebo). Clinical remission was observed in 46.2% patients treated with dersalazine sodium versus 12.5% in mesalazine and 10% in placebo after 4 weeks of treatment. Colon biopsies showed significantly decreased expression of inflammatory genes in dersalazine sodium patients. Adverse events at least possibly related to treatment were observed in 23%, 12.5%, and 7.6% of patients receiving dersalazine sodium, mesalazine, and placebo, respectively; no serious adverse reactions were reported. Increased liver enzymes were reported in 2/13 patients receiving dersalazine sodium, with normal bilirubin levels; both returned to normal values on treatment interruption. Conclusions:Studies in wider populations are needed to confirm the clinical activity of dersalazine sodium. Weekly measurements of liver function tests may be necessary for early detection of adverse events.

Preoperative management of colorectal cancer–induced iron deficiency anemia in clinical practice: data from a large observational cohort

Preoperative anemia prevalence among colorectal cancer (CRC) patients is high and may adversely influence postoperative outcome. This study assesses the efficacy of a preoperative anemia managing protocol in CRC.

Analgesic Use and Risk for Acute Coronary Events in Patients With Osteoarthritis: A Population-based, Nested Case-control Study.

PURPOSE Recent controversies on the safety profiles of opioids and paracetamol (acetaminophen) have led to changes in clinical guidance on osteoarthritis (OA) management. We studied the existing association between the use of different OA drug therapies and the risk for acute coronary events. METHODS A cohort of patients with clinically diagnosed OA (according to ICD-10 codes) was identified in the SIDIAP database. Within the cohort, cases with incident acute coronary events (acute myocardial infarction or unstable angina) between 2008 and 2012 were identified using ICD-10 codes and data from hospital admission. Controls were matched 3:1 to acute coronary event-free patients matched by sex, age (±5 years), geographic area, and years since OA diagnosis (±2 years). Linked pharmacy dispensation data were used for assessing exposure to drug therapies. Multivariate conditional logistic regression models were fitted to estimate adjusted odds ratios of acute coronary events. FINDINGS Totals of 5663 cases and 16,989 controls were studied. Previous morbidity and cardiovascular risk were higher in cases than in controls, with no significant differences in type or number of joints with OA. Multivariate adjusted analyses showed increased risks (odds ratio; 95% CI) related to the use of diclofenac (1.16; 1.06-1.27), naproxen (1.25; 1.04-1.48), and opioid analgesics (1.13; 1.03-1.24). No significant associations were observed with cyclooxygenase-2 selective NSAIDs, topical NSAIDs, glucosamine, chondroitin sulfate, paracetamol, or metamizole. IMPLICATIONS In patients with clinically diagnosed OA, the use of nonselective NSAIDs or opioid analgesics is associated with an increased risk for acute coronary events. These risks should be considered when selecting treatments of OA in patients at high cardiovascular risk.

Safety and Activity of UR-1505 in Atopic Dermatitis: A Randomized, Double-blind Phase II Exploratory Trial

PURPOSE UR-1505 is a new small molecule with immune modulator properties intended for the topical treatment of inflammatory skin diseases that has shown anti-inflammatory effects in models of skin inflammation. We compared the activity of UR-1505 ointment against its vehicle in the treatment of atopic dermatitis. Secondary objectives included exploring dose response, safety, and local tolerability of UR-1505. METHODS Patients with AD lesions on 2 symmetrical topographic areas (arms, leg, or trunk) were included in this unicenter randomized, double-blind, within-patient, controlled Phase II exploratory trial and received simultaneously 2 different treatments (0.5%, 1%, or 2% UR-1505 and vehicle or 0.1% tacrolimus ointment) once daily during 28 days. The primary efficacy end point was the change from baseline in the Investigator Global Assessment score at Day 28. Secondary end points were percentage of area clearance, local Eczema Area Severity Index (local EASI), and local tolerability. A linear mixed model was used, fitting treatment, body side, and group (treatment at the contralateral side) as fixed factors and the patient as a random effect. FINDINGS Twenty-eight patients were randomized and 25 patients were included in the per protocol analysis, with 50 evaluable lesions (n = 13 for vehicle, n = 8 for UR-1505 0.5%, n = 9 for 1% UR-1505, n=8 for 2% UR-1505, and n=12 for tacrolimus). The mean Investigator Global Assessment score change from baseline at Day 28 was -1.7 for vehicle, -1.0, -1.2, and -1.5 for 0.5%, 1%, and 2% UR-1505, respectively, and -2.6% for tacrolimus (P = 0.002). No serious nor causal adverse reactions were reported in this study, but patients reported numerous local symptoms after product applications, especially itching, tingling, tightness, and heat/burning sensations at frequencies that were similar for vehicle, 1% UR-1505, and 2% UR-1505; more frequent with 0.5% UR-1505; and lowest for tacrolimus. IMPLICATIONS This study found that UR-1505 may not be a suitable option for the treatment of atopic dermatitis due to its lack of clinically relevant effect compared with its vehicle and 0.1% tacrolimus ointment.

Rare disease registries: potential applications towards impact on development of new drug treatments

BackgroundLow prevalence, lack of knowledge about the disease course, and phenotype heterogeneity hamper the development of drugs for rare diseases. Rare disease registries (RDRs) can be helpful by playing a role in understanding the course of the disease, and providing information necessary for clinical trial design, if designed and maintained properly. We describe the potential applications of a RDR and what type of information should be incorporated to support the design of clinical trials in the process of drug development, based on a broad inventory of registry experience. We evaluated two existing RDRs in more detail to check the completeness of these RDRs for trial design.ResultsBefore and during the application for regulatory approval a RDR can improve the efficiency and quality in clinical trial design by informing the sample size calculation and expected disease course. In exceptional circumstances information from RDRs has been used as historical controls for a one-armed clinical trial, and high quality RDRs may be used for registry-based randomized controlled trials. In the post marketing phase of (conditional) drug approval a disease-specific RDR is likely to provide more relevant information than a product-specific registry.ConclusionsA RDR can be very helpful to improve the efficiency and quality of clinical trial design in several ways. To enable the applicability and optimal use of a RDR longitudinal data collection is indispensable, and specific data collection, prepared for repeated measurement, is needed. The developed checklist can help to define the appropriate variables to include. Attention should be paid to the inclusion of patient-relevant outcome measures in the RDR from the start. More research and experience is needed on the possibilities and limitations of combining RDR information with clinical trial data to maximize the availability of relevant evidence for regulatory decisions in rare diseases.

Use of α 2 -Adrenergic Agonists to Improve Surgical Field Visibility in Endoscopy Sinus Surgery: A Systematic Review of Randomised Controlled Trials

PURPOSE We assessed the evidence for the use of α2-adrenergic agonists (A2AAs) in bleeding control and field quality in endoscopic sinus surgery. METHODS We systematically reviewed randomized clinical trials (RCTs) assessing A2AAs in endoscopic sinus surgery. Abstracts were reviewed by 2 investigators for eligibility, and selected articles were fully reviewed. Data on study design, population, A2AA drug and control groups, bleeding and surgical field quality outcomes, and adverse effects were extracted and synthesized. FINDINGS A total of 13 RCTs that included 896 individuals (7 double-blind trials, 5 single-blind trials, and 1 open-label trial) were selected that assessed the efficacy of clonidine (6 RCTs, 407 patients), dexmedetomidine (6 RCT, 423 patients), or both (1 RCT, 66 patients). Clonidine was compared with placebo (3 RCTs), midazolam (1 RCT), and remifentanil (2 RCTs). Dexmedetomidine was compared with esmolol (2 RCTs), remifentanil (2 RCTs), nitroglycerin and esmolol (1 RCT), and magnesium sulfate (1 RCT). Clonidine and dexmedetomidine were compared in 1 RCT. Clonidine reduced the proportion of individuals with an impaired surgical field by 23% vs placebo (number needed to treat = 4). Clonidine was better than midazolam and remifentanil in 2 trials, and dexmedetomidine was better than magnesium sulfate and esmolol in 2 trials but was not superior to esmolol, remifentanil, or nitroglycerin in 4 trials. Dexmedetomidine produced significantly better differences in bleeding outcomes versus clonidine. Adverse events were infrequent and mainly caused by hypotension or bradycardia. IMPLICATIONS RCTs consistently report that A2AAs reduce bleeding and improve surgical field quality during endoscopic sinus surgery. Adverse event reporting was often omitted in RCTs. Well-designed RCTs with appropriate sample sizes are desirable to identify the best A2AAs and confirm their potential effects on clinical outcomes.