The Role of Fluoroquinolones in the Treatment of Tuberculosis in 2019

The inability to use powerful antituberculosis drugs in an increasing number of patients seems to be the biggest threat towards global tuberculosis (TB) elimination. Simplified, shorter and preferably less toxic drug regimens are being investigated for pulmonary TB to counteract emergence of drug resistance. Intensified regimens with high-dose anti-TB drugs during the first weeks of treatment are being investigated for TB meningitis to increase the survival rate among these patients. Moxifloxacin, gatifloxacin and levofloxacin are seen as core agents in case of resistance or intolerance against first-line anti-TB drugs. However, based on their pharmacokinetics (PK) and pharmacodynamics (PD), these drugs are also promising for TB meningitis and might perhaps have the potential to shorten pulmonary TB treatment if dosing could be optimized. We prepared a comprehensive summary of clinical trials investigating the outcome of TB regimens based on moxifloxacin, gatifloxacin and levofloxacin in recent years. In the majority of clinical trials, treatment success was not in favour of these drugs compared to standard regimens. By discussing these results, we propose that incorporation of extended PK/PD analysis into the armamentarium of drug-development tools is needed to clarify the role of moxifloxacin, gatifloxacin and levofloxacin for TB, using the right dose. In addition, to prevent failure of treatment or emergence of drug-resistance, PK and PD variability advocates for concentration-guided dosing in patients at risk for too low a drug-exposure

Fluorescence-Guided Visualization of Soft-Tissue Sarcomas by Targeting Vascular Endothelial Growth Factor A:A Phase 1 Single-Center Clinical Trial

Resection of soft-tissue sarcoma (STS) is accompanied by a high rate of tumor-positive surgical margins (14%-34%), which potentially lead to decreased disease-free survival. Vascular endothelial growth factor A is overexpressed in malignant tumors, including STS, and can be targeted with bevacizumab-800CW during fluorescence-guided surgery for real-time tumor detection. In this phase 1 clinical trial, we determined the feasibility, safety, and optimal dose of bevacizumab-800CW for fluorescence-guided surgery in STS for in vivo and ex vivo tumor detection. Methods: Patients with a histopathologic diagnosis of STS were included. In the dose-escalation phase, patients received bevacizumab-800CW intravenously 3 d before surgery (10, 25, and 50 mg; n = 8). In the subsequent dose-expansion phase, 7 additional patients received bevacizumab800CW at the optimal dose. Fluorescence images were obtained in vivo and ex vivo during all stages of standard care. The optimal dose was determined by calculating in vivo and ex vivo tumor-to-background ratios (TBR) and correlating these results with histopathology. Results: Fifteen patients with STS completed this study. All tumors could be visualized during in vivo and ex vivo imaging. The optimal bevacizumab-800CW dose proved to be 10 mg, with a median in vivo TBR of 2.0 (+/- 0.58) and a median ex vivo TBR of 2.67 (+/- 1.6). All 7 tumor-positive margins could be observed in real time after surgical resection. Conclusion: GS using 10 mg of bevacizumab-800CW is feasible and safe for intraoperative imaging of STS, potentially allowing tumor detection and margin assessment during surgery. An additional follow-up phase 2 study is needed to confirm the diagnostic accuracy

Completion pancreatectomy or a pancreas-preserving procedure during relaparotomy for pancreatic fistula after pancreatoduodenectomy:a multicentre cohort study and meta-analysis

Background: Despite the fact that primary percutaneous catheter drainage has become standard practice, some patients with pancreatic fistula after pancreatoduodenectomy ultimately undergo a relaparotomy. The aim of this study was to compare completion pancreatectomy with a pancreas-preserving procedure in patients undergoing relaparotomy for pancreatic fistula after pancreatoduodenectomy.Methods: This retrospective cohort study of nine institutions included patients who underwent relaparotomy for pancreatic fistula after pancreatoduodenectomy from 2005-2018. Furthermore, a systematic review and meta-analysis were performed according to the PRISMA guidelines.Results: From 4877 patients undergoing pancreatoduodenectomy, 786 (16 per cent) developed a pancreatic fistula grade B/C and 162 (3 per cent) underwent a relaparotomy for pancreatic fistula. Of these patients, 36 (22 per cent) underwent a completion pancreatectomy and 126 (78 per cent) a pancreas-preserving procedure. Mortality was higher after completion pancreatectomy (20 (56 per cent) versus 40 patients (32 per cent); P=0.009), which remained after adjusting for sex, age, BMI, ASA score, previous reintervention, and organ failure in the 24h before relaparotomy (adjusted odds ratio 2.55, 95 per cent c.i. 1.07 to 6.08). The proportion of additional reinterventions was not different between groups (23 (64 per cent) versus 84 patients (67 per cent); P=0.756). The meta-analysis including 33 studies evaluating 745 patients, confirmed the association between completion pancreatectomy and mortality (Mantel-Haenszel random-effects model: odds ratio 1.99, 95 per cent c.i. 1.03 to 3.84).Conclusion: Based on the current data, a pancreas-preserving procedure seems preferable to completion pancreatectomy in patients in whom a relaparotomy is deemed necessary for pancreatic fistula after pancreatoduodenectomy.Surgical oncolog

Somatostatin analogues for the prevention of pancreatic fistula after open pancreatoduodenectomy:A nationwide analysis

BACKGROUND: Somatostatin analogues (SA) are currently used to prevent postoperative pancreatic fistula (POPF) development. However, its use is controversial. This study investigated the effect of different SA protocols on the incidence of POPF after pancreatoduodenectomy in a nationwide population. METHODS: All patients undergoing elective open pancreatoduodenectomy were included from the Dutch Pancreatic Cancer Audit (2014-2017). Patients were divided into six groups: no SA, octreotide, lanreotide, pasireotide, octreotide only in high-risk (HR) patients and lanreotide only in HR patients. Primary endpoint was POPF grade B/C. The updated alternative Fistula Risk Score was used to compare POPF rates across various risk scenarios. RESULTS: 1992 patients were included. Overall POPF rate was 13.1%. Lanreotide (10.0%), octreotide-HR (9.4%) and no protocol (12.7%) POPF rates were lower compared to the other protocols (varying from 15.1 to 19.1%, p = 0.001) in crude analysis. Sub-analysis in patients with HR of POPF showed a significantly lower rate of POPF when treated with lanreotide (10.0%) compared to no protocol, octreotide and pasireotide protocol (21.6-26.9%, p = 0.006). Octreotide-HR and lanreotide-HR protocol POPF rates were comparable to lanreotide protocol, however not significantly different from the other protocols. Multivariable regression analysis demonstrated lanreotide protocol to be positively associated with a low odds-ratio (OR) for POPF (OR 0.387, 95% CI 0.180-0.834, p = 0.015). In-hospital mortality rates were not affected. CONCLUSION: Use of lanreotide in all patients undergoing pancreatoduodenectomy has a potential protective effect on POPF development. Protocols for HR patients only might be favorable too. However, future studies are warranted to confirm these findings

Pancreatic resection in the pediatric, adolescent and young adult population:nationwide analysis on complications

Background: The aim of this study was to determine pancreatic surgery specific short- and long-term complications of pediatric, adolescent and young adult (PAYA) patients who underwent pancreatic resection, as compared to a comparator cohort of adults. Methods: A nationwide retrospective cohort study was performed in PAYA patients who underwent pancreatic resection between 2007 and 2016. PAYA was defined as all patients <40 years at time of surgery. Pancreatic surgery-specific complications were assessed according to international definitions and textbook outcome was determined. Results: A total of 230 patients were included in the PAYA cohort (112 distal pancreatectomies, 99 pancreatoduodenectomies), and 2526 patients in the comparator cohort. For pancreatoduodenectomy, severe morbidity (29.3% vs. 28.6%; P = 0.881), in-hospital mortality (1% vs. 4%; P = 0.179) and textbook outcome (62% vs. 58%; P = 0.572) were comparable between the PAYA and the comparator cohort. These outcomes were also similar for distal pancreatectomy. After pancreatoduodenectomy, new-onset diabetes mellitus (8% vs. 16%) and exocrine pancreatic insufficiency (27% vs. 73%) were lower in the PAYA cohort when compared to adult literature. Conclusion: Pancreatic surgery-specific complications were comparable with patients ≥40 years. Development of endocrine and exocrine insufficiency in PAYA patients who underwent pancreatoduodenectomy, however, was substantially lower compared to adult literature

Controlled Radical Polymerization of Vinyl Acetate Mediated by a Bis(imino)pyridine Vanadium Complex

Source type: Prin

Secretory protein beta-lactoglobulin in cattle stable dust may contribute to the allergy-protective farm effect

15 Pág.Growing up on a cattle farm and consuming raw cow's milk protects against asthma and allergies. We expect a cattle-specific protein as active component in this farm effect.This study was supported by the Austrian Science Fund FWF (SFB F4606-B28 and MCCA W1248-B30 to EJJ), in part by Biomedical International R+D GmbH, Vienna, Austria, and by Bencard Allergie GmbH, Munich, Germany.Peer reviewe

Pharmacokinetic drug interactions of antimicrobial drugs:a systematic review on oxazolidinones, rifamycines, macrolides, fluoroquinolones, and Beta-lactams

Like any other drug, antimicrobial drugs are prone to pharmacokinetic drug interactions. These drug interactions are a major concern in clinical practice as they may have an effect on efficacy and toxicity. This article provides an overview of all published pharmacokinetic studies on drug interactions of the commonly prescribed antimicrobial drugs oxazolidinones, rifamycines, macrolides, fluoroquinolones, and beta-lactams, focusing on systematic research. We describe drug-food and drug-drug interaction studies in humans, affecting antimicrobial drugs as well as concomitantly administered drugs. Since knowledge about mechanisms is of paramount importance for adequate management of drug interactions, the most plausible underlying mechanism of the drug interaction is provided when available. This overview can be used in daily practice to support the management of pharmacokinetic drug interactions of antimicrobial drugs

Het effekt van strooizout op de bodem en bermvegetatie mede in relatie tot het voorkomen van “kust”-halofyten langs binnenlands wegennet

In deze literatuurstudie is gekeken naar wat de indirecte en directe gevolgen zijn van het gebruik van strooizout op de aanwezige bermvegetatie. Begin jaren zestig werd het strooizout in Nederland geïntroduceerd ter bestrijding van gladheid voor de winterse verkeersveiligheid. In de beginperiode werd voornamelijk gebruik gemaakt van gedenatureerd keukenzout (NaCl). Tegenwoordig schakelt men steeds meer over op het gebruik van mengsels van keukenzout met calcium- of magnesiumchloride. De laatste twee stoffen vergroten de werking van het strooizout en hebben een positief effect op dé fysische en chemische eigenschappen van de bodem. Van het strooizout (NaC1) blijkt met name het natrium-ion een grote invloed uit te oefenen op de fysische en chemische eigenschappen van de bodem. Het chloor-ion heeft weinig invloed op de bodem zelf maar blijkt wel van belang te zijn voor het vormen van "chloor-metaal complexen". Hierdoor geraken de anders sterk geadsorbeerde zware metalen in de bodem in oplossing. Door een toename van Na4- en Cl-ionen (overmaat) in de bodemoplossing verandert de minerale huishouding voor de planten. Het verhoogde zoutgehalte in de bodem veroorzaakt via een aantal fysiologische processen een sterfte onder de zoutgevoelige soorten (glycofyten). Met name het chloor-ion speelt hierbij een belangrijke rol. De door afsterving ontstane open plekken kunnen dan worden opgevuld door meer zouttolerante en resistente soorten of oecotypen. Het verhoogde zoutgehalte in de bermbodem langs binnenlandse wegen blijkt tot een nieuw fenomeen te hebben geleid en wel die van de invasie van "kust"-halofyten (planten uit zoute milieus). Vanaf 1972 zijn in verschillende landen vondsten van kustplanten langs met zout bestrooide wegen gedaan. De bermhalofyten blijken met name in een strook van enkele decimeters breed direct naast de wegverharding te groeien. Die hier door de mens via het moderne transportwezen onopzettelijk naar toe zijn gebracht. Van de bermhalofyten blijken met name Puccinellia distans (L), Parl. en Cochlearia danica L. succesvolle soorten te zijn.

Grondwaterstroming en grondwatersamenstelling van de diepe ondergrond van het gebied Roden/Norg in relatie met de geologische gesteldheid

Met twee bestaande computerprogramma's is voor het herinrichtingsgebied Roden/Norg in noordwest Drenthe, onderzocht hoe de diepe grondwatersamenstelling en -stroming in relatie staan met de geologische ondergrond. De verwerkte gegevens zijn bestaande gegevens, afkomstig van de Rijks Geologische Dienst, DGV.-TNO., Provinciale Waterstaat en het RIVM. Eerst wordt er een inleiding gegeven op de geologie en hydrologie van het gebied, wat gekenmerkt wordt door het voorkomen van potklei. De potklei is hier een grillige afzetting met een varierende dikte van enkele decimeters tot Ca. 50 m bij Roden. De gegevens zijn ingevoerd via de editor EDIN van de CYBER of via de digitaliseertafel. Met het statistische pakket SPSS en het grafische pakket SURFACEII, zijn de gegevens verwerkt. Het diepe grondwater stroomt in noordwestelijke richting vanaf het Drents Plateau. Het watervoerende pakket wordt gevormd door de Formaties van Urk, Enschede, Peelo en de Mengzone. De voorkomende potklei, is bij voldoende dikte, waterondoorlatend en heeft op de waterstroming een sturend effekt. Geconcludeerd kan worden, dat door de potklei het diepe grondwater onder druk naar boven wordt geperst en langs de randen naar boven welt. Op plaatsen waar de potklei dun is, kan het water door de potklei heen en in ondiepere lagen terecht komen. Het diepe grondwater kan onderscheiden worden aan de hand van Stiffdiagranimen. Het diepe grondwater is van het calciumbicarbonaat type, door langere verblijftijd in de ondergrond. In de bovenlaag wordt overwegend het infiltratietype gevonden.