Antiinfective therapy with a small molecule inhibitor of Staphylococcus aureus sortase

Methicillin-resistant Staphylococcus aureus (MRSA) is the most frequent cause of hospital-acquired infection, which manifests as surgical site infections, bacteremia, and sepsis. Due to drug-resistance, prophylaxis of MRSA infection with antibiotics frequently fails or incites nosocomial diseases such as Clostridium difficile infection. Sortase A is a transpeptidase that anchors surface proteins in the envelope of S. aureus, and sortase mutants are unable to cause bacteremia or sepsis in mice. Here we used virtual screening and optimization of inhibitor structure to identify 3-(4-pyridinyl)-6-(2-sodiumsulfonatephenyl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole and related compounds, which block sortase activity in vitro and in vivo. Sortase inhibitors do not affect in vitro staphylococcal growth yet protect mice against lethal S. aureus bacteremia. Thus, sortase inhibitors may be useful as antiinfective therapy to prevent hospital-acquired S. aureus infection in high-risk patients without the side effects of antibiotics.The gram-positive bacterium Staphylococcus aureus colonizes the human skin and nares yet also causes invasive diseases such as skin and soft tissue infections, osteomyelitis, pneumonia, bacteremia, sepsis, and endocarditis (1). Methicillin-resistant S. aureus (MRSA) acquired resistance against many different drugs, including β-lactam, cephalosporin, fluoroquinolone, aminoglycoside, tetracycline, macrolide, trimethoprim-sulfamethoxazole, and vancomycin antibiotics (2). In the United States, MRSA isolates are responsible for >50% of S. aureus infections in hospitals and long-term care facilities (3). Individuals at high risk of MRSA infection include very-low-birth-weight neonates, elderly, and patients with indwelling catheters, endotracheal intubation, medical implantation of foreign bodies (prosthetic joints, implants and heart valves), trauma, surgical procedures, diabetes, dialysis, and immunosuppressive or cancer therapy (4). Antibiotic prophylaxis is designed to mitigate the risk of S. aureus infection, especially in surgical patients; however, this frequently fails due to drug resistance (5). Importantly, antibiotic therapy suppresses human microbiota and promotes Clostridium difficile infection, which is also associated with increased morbidity and mortality (6, 7). Several trials for vaccines and immune therapeutics were designed to prevent MRSA infection in hospital settings; these efforts have thus far failed to meet their study end points (4).Surface proteins of S. aureus are secreted as precursors with C-terminal sorting signals that are cleaved by sortase A (SrtA) between the threonine (T) and the glycine (G) residues of their LPXTG motif (8, 9). The active site cysteine residue of sortase forms an acyl enzyme intermediate that is relieved by the nucleophilic attack of the amino group (pentaglycine crossbridge) in peptidoglycan synthesis precursors (10). Surface proteins attached to peptidoglycan precursors are subsequently incorporated into the cell wall envelope and displayed on the staphylococcal surface (9). Genome sequencing revealed that all S. aureus isolates encode 17–21 surface proteins with LPXTG sorting signals, which fulfill diverse functions during the infectious process (11). SrtA mutants cannot assemble surface proteins into their envelope and are unable to form abscess lesions in organ tissues or cause lethal bacteremia when inoculated into the bloodstream of mice (12, 13). In contrast, mutations that abrogate the expression of secreted virulence factors may cause attenuation but do not abrogate the ability of S. aureus to cause infectious diseases (12).We reasoned that small molecule inhibitors blocking SrtA may be useful as antiinfectives to prevent S. aureus infection without affecting the growth of other bacteria. If so, such compounds could be used to reduce the incidence of MRSA infections without the side effects of antibiotics.     

Differences in Methylmercury and Inorganic Mercury Biomagnification in a Tropical Marine Food Web

Methylmercury (MeHg), inorganic mercury (Hg_inorg) and their biomagnification factors (BMF) were evaluated along a non-degraded Brazilian bay food web. Highly significant differences (p < 0.0001) were found between MeHg and Hg_inorg concentrations among all organisms (microplankton, shrimp, fish and dolphin). MeHg increased with increasing trophic position while Hg_inorg did not present the same pattern. BMF values for MeHg were higher than 1 for all trophic interactions from source to consumer, indicating that MeHg was transferred more efficiently and biomagnified over the entire web. Only one BMF exceeding one was observed for Hg_inorg (27) between microplankton and their consumer, planktivorous fish. BMF values for Hg_inorg were significantly different than those found for MeHg (20) at the base of the food web.     

Endoscopic transluminal necrosectomy in necrotising pancreatitis: a systematic review

Objective

We performed a systematic review to assess the outcome of endoscopic transluminal necrosectomy in necrotising pancreatitis with additional focus on indication, disease severity, and methodological quality of studies.

Design

We searched the literature published between January 2005 and June 2013. Cohorts, including patients with (infected) necrotising pancreatitis, undergoing endoscopic necrosectomy were included. Indication, disease severity, and methodological quality were described. The main outcomes were mortality, major complications, number of endoscopic sessions, and definitive successful treatment with endoscopic necrosectomy alone.

Results

After screening 581 papers, 14 studies, including 455 patients, fulfilled the eligibility criteria. All included studies were retrospective analyses except for one randomized, controlled trial. Overall methodological quality was moderate to low (mean 5, range 2–9). Less than 50 % of studies reported on pre-procedural severity of disease: mean APACHE-II score before intervention was 8; organ failure was present in 23 % of patients; and infected necrosis in 57 % of patients. On average, four (range 1–23) endoscopic interventions were performed per patient. With endoscopic necrosectomy alone, definitive successful treatment was achieved in 81 % of patients. Mortality was 6 % (28/460 patients) and complications occurred in 36 % of patients. Bleeding was the most common complication.

Conclusions

Endoscopic transluminal necrosectomy is an effective treatment for the majority of patients with necrotising pancreatitis with acceptable mortality and complication rates. It should be noted that methodological quality of the available studies is limited and that the combined patient population of endoscopically treated patients is only moderately ill.     

Superior vena cava graft infection in thoracic surgery: a retrospective study of the French EPITHOR database

 Open in a separate windowOBJECTIVESTo report our experience on the management of superior vena cava graft infection.METHODSBetween 2001 and 2018, patients with superior vena cava synthetic graft or patch reconstruction after resection of intrathoracic tumours or benign disease were selected retrospectively from the French EPITHOR database and participating thoracic centres. Our study population includes patients with superior vena cava graft infection, defined according to the MAGIC consensus. Superior vena cava synthetic grafts in an empyema or mediastinitis were considered as infected.RESULTSOf 111 eligible patients, superior vena cava graft infection occurred in 12 (11.9%) patients with a polytetrafluoroethylene graft secondary to contiguous contamination. Management consisted of either conservative treatment with chest tube drainage and antibiotics (n = 3) or a surgical graft-sparing strategy (n = 9). Recurrence of infection appears in 6 patients. Graft removal was performed in 2 patients among the 5 reoperated patients. The operative mortality rate was 25%.CONCLUSIONSSuperior vena cava graft infection may develop as a surgical site infection secondary to early mediastinitis or empyema. Graft removal is not always mandatory but should be considered in late or recurrent graft infection or in infections caused by aggressive microorganisms (virulent or multidrug resistant bacteria or fungi).     

Therapeutische Interventionen bei peri- und postmenopausalen Beschwerden

Die S3-Leitlinie „Peri- und Postmenopause – Diagnostik und Therapie“ beinhaltet Handlungsanweisungen und Empfehlungen für die Hormonersatztherapie (HRT) zur Behandlung klimakterischer Beschwerden, die von etwa 50 % der perimenopausalen Frauen und bei 30–80 % der postmenopausalen Frauen angegeben werden. Eine HRT mit Östrogenen (ET) oder Östrogenen und Gestagenen (EPT) wird als symptomatische Therapie zur Behandlung von klimakterischen Beschwerden mit klinisch relevanter Beeinträchtigung der Lebensqualität eingesetzt. Alternativ können auch Isoflavone, Cimicifuga-Präparate, Serotonin- bzw. Serotonin-Noradrenalin-Wiederaufnahmehemmer, Clonidin, Gabapentin oder kognitive Verhaltenstherapie angewendet werden. Im vorliegenden Artikel werden Effektivität und Sicherheit sowie Nebenwirkungen und systemische Wirkungen dieser unterschiedlichen Therapieformen entsprechend den Vorgaben der S3-Leitlinie „Peri- und Postmenopause – Diagnostik und Therapie“ dargestellt.     

S3-Leitlinie Peri- und Postmenopause – Diagnostik und Interventionen

Die Gynäkologie -     

Hormonersatztherapie und vaskuläres Risiko

Gynäkologische Endokrinologie - Auch die neue Version der AWMF-S3-Leitlinie „Peri- und Postmenopause – Diagnostik und Interventionen“ der Deutschen Gesellschaft für...