Augmented Renal Clearance Implies a Need for Increased Amoxicillin-Clavulanic Acid Dosing in Critically Ill Children

There is little data available to guide amoxicillin-clavulanic acid dosing in critically ill children. The primary objective of this study was to investigate the pharmacokinetics of both compounds in this pediatric subpopulation. Patients admitted to the pediatric intensive care unit (ICU) in whom intravenous amoxicillin-clavulanic acid was indicated (25 to 35 mg/kg of body weight every 6 h) were enrolled. Population pharmacokinetic analysis was conducted, and the clinical outcome was documented. A total of 325 and 151 blood samples were collected from 50 patients (median age, 2.58 years; age range, 1 month to 15 years) treated with amoxicillin and clavulanic acid, respectively. A three-compartment model for amoxicillin and a two-compartment model for clavulanic acid best described the data, in which allometric weight scaling and maturation functions were added a priori to scale for size and age. In addition, plasma cystatin C and concomitant treatment with vasopressors were identified to have a significant influence on amoxicillin clearance. The typical population values of clearance for amoxicillin and clavulanic acid were 17.97 liters/h/70 kg and 12.20 liters/h/70 kg, respectively. In 32% of the treated patients, amoxicillin-clavulanic acid therapy was stopped prematurely due to clinical failure, and the patient was switched to broader-spectrum antibiotic treatment. Monte Carlo simulations demonstrated that four-hourly dosing of 25 mg/kg was required to achieve the therapeutic target for both amoxicillin and clavulanic acid. For patients with augmented renal function, a 1-h infusion was preferable to bolus dosing. Current published dosing regimens result in subtherapeutic concentrations in the early period of sepsis due to augmented renal clearance, which risks clinical failure in critically ill children, and therefore need to be updated. (This study has been registered at Clinicaltrials.gov as an observational study [{"type":"clinical-trial","attrs":{"text":"NCT02456974","term_id":"NCT02456974"}}NCT02456974].)     

Evolution of Hepatitis C Virus Quasispecies during Repeated Treatment with the NS3/4A Protease Inhibitor Telaprevir

In treating hepatitis B virus (HBV) and human immunodeficiency virus (HIV) infections, the rapid reselection of resistance-associated variants (RAVs) is well known in patients with repeated exposure to the same class of antiviral agents. For chronic hepatitis C patients who have experienced virologic failure with direct-acting antiviral drugs, the potential for the reselection of persistent RAVs is unknown. Nine patients who received 14 days of telaprevir monotherapy were retreated with telaprevir-based triple therapy 4.3 to 5.7 years later. In four patients with virologic failure with both telaprevir-containing regimens, population-based and deep sequencing (454 GS-FLX) of the NS3 protease gene were performed before and at treatment failure (median coverage, 4,651 reads). Using deep sequencing, with a threshold of 1.0% for variant calling, no isolates were found harboring RAVs at the baseline time points. While population-based sequencing uncovered similar resistance patterns (V36M plus R155K for subtype 1a and V36A for subtype 1b) in all four patients after the first and second telaprevir treatments, deep sequencing analysis revealed a median of 7 (range, 4 to 23) nucleotide substitutions on the NS3 backbone of the resistant strains, together with large phylogenetic differences between viral quasispecies, making the survival of resistant isolates highly unlikely. In contrast, in a comparison of the two baseline time points, the median number of nucleotide exchanges in the wild-type isolates was only 3 (range, 2 to 8), reflecting the natural evolution of the NS3 gene. In patients with repeated direct antiviral treatment, a continuous evolution of HCV quasispecies was observed, with no clear evidence of persistence and reselection but strong signs of independent de novo generation of resistance. Antiviral therapy for chronic viral infections, like HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV), faces several challenges. These viruses have evolved survival strategies and proliferate by escaping the host''s immune system. The development of direct-acting antiviral agents is an important achievement in fighting these infections. Viral variants conferring resistance to direct antiviral drugs lead to treatment failure. For HIV/HBV, it is well known that viral variants associated with treatment failure will be archived and reselected rapidly during retreatment with the same drug/class of drugs. We explored the mechanisms and rules of how resistant variants are selected and potentially reselected during repeated direct antiviral therapies in chronically HCV-infected patients. Interestingly, in contrast to HIV and HBV, we could not prove long-term persistence and reselection of resistant variants in HCV patients who failed protease inhibitor-based therapy. This may have important implications for the potential to reuse direct-acting antivirals in patients who failed the initial direct antiviral treatment. (The phase IIIb study described in this paper is registered at ClinicalTrials.gov under registration number {"type":"clinical-trial","attrs":{"text":"NCT01054573","term_id":"NCT01054573"}}NCT01054573.)     

Artemisinins,New Miconazole Potentiators Resulting in Increased Activity against Candida albicans Biofilms

Mucosal biofilm-related fungal infections are very common, and the incidence of recurrent oral and vulvovaginal candidiasis is significant. As resistance to azoles (the preferred treatment) is occurring, we aimed at identifying compounds that increase the activity of miconazole against Candida albicans biofilms. We screened 1,600 compounds of a drug-repositioning library in combination with a subinhibitory concentration of miconazole. Synergy between the best identified potentiators and miconazole was characterized by checkerboard analyses and fractional inhibitory concentration indices. Hexachlorophene, pyrvinium pamoate, and artesunate act synergistically with miconazole in affecting C. albicans biofilms. Synergy was most pronounced for artesunate and structural homologues thereof. No synergistic effect could be observed between artesunate and fluconazole, caspofungin, or amphotericin B. Our data reveal enhancement of the antibiofilm activity of miconazole by artesunate, pointing to potential combination therapy consisting of miconazole and artesunate to treat C. albicans biofilm-related infections.     

CT-guided transthoracic biopsy: histopathologic results and complication rates

PURPOSE

We aimed to investigate the effectiveness and complications of transthoracic CT-guided biopsy techniques.

METHODS

A total of 94 CT-guided percutaneous transthoracic biopsy procedures performed in 85 patients were retrospectively evaluated. Core biopsy technique was used in 87 procedures and transthoracic fine-needle aspiration biopsy was used in seven procedures.

RESULTS

Diagnostic results were achieved in 79 of 94 biopsy procedures. Pathology results were malignant in 54 patients, suspicious for malignancy in three patients, benign in five patients, and benign nonspecific in 17 patients. Specific diagnoses were obtained in 59 patients (62.8%) using core biopsy, but no specific diagnosis could be reached with transthoracic fine-needle aspiration biopsy. Complications included pneumothorax in 27 patients (28.7%) and parenchymal hemorrhage during and after the procedure in eight patients (8.5%).

CONCLUSIONS

CT-guided percutaneous transthoracic needle biopsy is a highly accurate procedure for histopathological diagnosis of thoracic masses. In addition, percutaneous transthoracic biopsy has an acceptably low complication rate and it reduces the need for more invasive surgical procedures.Since the beginning of the 21st century, lung cancer has been cited as one of the most common causes of death (1). World Health Organization declared lung cancer as the first leading cause of death in men and second in women, among all types of cancers (2).Percutaneous transthoracic biopsies are performed either using fine-needle aspiration biopsy (transthoracic fine-needle aspiration biopsy, TTFNAB) method or using the incisional or core biopsy method. Incisional biopsy and core biopsy are used to obtain a part of tissue from the lesion for histological diagnosis. On the other hand, TTFNAB is used to obtain aspiration material, which is used for cytological examination and lesion diagnosis (3, 4).Indications of transthoracic needle biopsy include solitary and multiple pulmonary nodules, mass lesions, persistent focal infiltration, consolidation, presence of cavities and abscesses, pleural lesions, and mediastinal and hilar mass diagnosis (3, 5).The aim of this study was to investigate the technique, suitability, and complications in CT-guided transthoracic biopsy of lung masses.     

乳腺恶性腺肌上皮瘤影像学诊断探讨并文献复习

目的:研究乳腺恶性腺肌上皮瘤(Malignant Adenomyoepithelioma,MAME)的影像学表现,探讨该病术前影像诊断的可能性及方法。材料与方法:将乳腺恶性腺肌上皮瘤的X线及超声表现与病理结果相对照,并复习近年来对该病影像学表现有较详细描述的文献,研究该病的影像学表现。结果:乳腺恶性腺肌上皮瘤X线表现常见为分叶状高密度肿块,轮廓清晰,边缘光滑或有毛刺,内密度可不均匀,周围无其他恶性征象。超声图像主要表现为实性结节或边界清楚以实性成分为主的包块,轮廓可呈分叶状,部分包块内见大量液性暗区,肿瘤血供丰富,对周围组织结构无明显浸润。结论:乳腺恶性腺肌上皮瘤X线及超声表现缺乏明确的特异性,形态学表现介于良恶性之间,内部密度或回声不均,结合患者病史较长,有短期内突然增大的病史时,要注意存在该病的可能,要进一步追查。