Interaction of Avibactam with Class B Metallo-β-Lactamases

β-Lactamases are the most important mechanisms of resistance to the β-lactam antibacterials. There are two mechanistic classes of β-lactamases: the serine β-lactamases (SBLs) and the zinc-dependent metallo-β-lactamases (MBLs). Avibactam, the first clinically useful non-β-lactam β-lactamase inhibitor, is a broad-spectrum SBL inhibitor, which is used in combination with a cephalosporin antibiotic (ceftazidime). There are multiple reports on the interaction of avibactam with SBLs but few such studies with MBLs. We report biochemical and biophysical studies on the binding and reactivity of avibactam with representatives from all 3 MBL subfamilies (B1, B2, and B3). Avibactam has only limited or no activity versus MBL-mediated resistance in pathogens. Avibactam does not inhibit MBLs and binds only weakly to most of the MBLs tested; in some cases, avibactam undergoes slow hydrolysis of one of its urea N-CO bonds followed by loss of CO₂, in a process different from that observed with the SBLs studied. The results suggest that while the evolution of MBLs that more efficiently catalyze avibactam hydrolysis should be anticipated, pursuing the development of dual-action SBL and MBL inhibitors based on the diazabicyclooctane core of avibactam may be productive.     

Histopathologic quantification of viable tumor versus treatment effect in surgically resected recurrent glioblastoma

Journal of Neuro-Oncology - The prognostic impact of the histopathologic features of recurrent glioblastoma surgical specimens is unknown. We sought to determine whether key histopathologic...     

High cost of stage IV pressure ulcers

Background

The aim of this study was to calculate and analyze the cost of treatment for stage IV pressure ulcers.

Methods

A retrospective chart analysis of patients with stage IV pressure ulcers was conducted. Hospital records and treatment outcomes of these patients were followed up for a maximum of 29 months and analyzed. Costs directly related to the treatment of pressure ulcers and their associated complications were calculated.

Results

Nineteen patients with stage IV pressure ulcers (11 hospital-acquired and 8 community-acquired) were identified and their charts were reviewed. The average hospital treatment cost associated with stage IV pressure ulcers and related complications was $129,248 for hospital-acquired ulcers during 1 admission, and $124,327 for community-acquired ulcers over an average of 4 admissions.

Conclusions

The costs incurred from stage IV pressure ulcers are much greater than previously estimated. Halting the progression of early stage pressure ulcers has the potential to eradicate enormous pain and suffering, save thousands of lives, and reduce health care expenditures by millions of dollars.     

Oxidation-mediated DNA cross-linking contributes to the toxicity of 6-thioguanine in human cells

The thiopurines azathioprine and 6-mercaptopurine have been extensively prescribed as immunosuppressant and anticancer agents for several decades. A third member of the thiopurine family, 6-thioguanine (6-TG), has been used less widely. Although known to be partly dependent on DNA mismatch repair (MMR), the cytotoxicity of 6-TG remains incompletely understood. Here, we describe a novel MMR-independent pathway of 6-TG toxicity. Cell killing depended on two properties of 6-TG: its incorporation into DNA and its ability to act as a source of reactive oxygen species (ROS). ROS targeted DNA 6-TG to generate potentially lethal replication-arresting DNA lesions including interstrand cross-links. These triggered processing by the Fanconi anemia and homologous recombination DNA repair pathways. Allopurinol protected against 6-TG toxicity by acting as a ROS scavenger and preventing DNA damage. Together, our findings provide mechanistic evidence to support the proposed use of thiopurines to treat HR-defective tumors and for the coadministration of 6-TG and allopurinol as an immunomodulation strategy in inflammatory disorders. Cancer Res; 72(18); 4787-95. ?2012 AACR.     

A missense mutation in damage‐specific DNA binding protein 2 is a genetic risk factor for limbal squamous cell carcinoma in horses

Squamous cell carcinoma (SCC) is the most common cancer of the equine eye, frequently originating at the limbus, with the potential to invade the cornea, cause visual impairment, and result in loss of the eye. Several breeds of horses have a high occurrence of limbal SCC implicating a genetic basis for limbal SCC predisposition. Pedigree analysis in the Haflinger breed supports a simple recessive mode of inheritance and a genome‐wide association study (N = 23) identified a 1.5 Mb locus on ECA12 significantly associated with limbal SCC (P _corrected= 0.04). Sequencing the most physiologically relevant gene from this locus, damage specific DNA binding protein 2 (DDB2 ), identified a missense mutation (c.1013 C > T p.Thr338Met) that was strongly associated with limbal SCC (P = 3.41 × 10^?10). Genotyping 42 polymorphisms narrowed the ECA12 candidate interval to 483 kb but did not identify another variant that was more strongly associated. DDB2 binds to ultraviolet light damaged DNA and recruits other proteins to perform global genome nucleotide excision repair. Computational modeling predicts this mutation to be deleterious by altering conformation of the β loop involved in photolesion recognition. This DDB2 variant was also detected in two other closely related breeds with reported cases of ocular SCC, the Belgian and the Percheron, suggesting it may also be a SCC risk factor in these breeds. Furthermore, in humans xeroderma pigmentosum complementation group E, a disease characterized by sun sensitivity and increased risk of cutaneous SCC and melanomas, is explained by mutations in DDB2 . Cross‐species comparison remains to be further evaluated.     

Incisional negative pressure wound therapy after hemiarthroplasty for femoral neck fractures – reduction of wound complications

The aim of the study was to evaluate the use of incisional negative pressure wound therapy (iNPWT) in wound healing after femoral neck fracture (FNF) treated with hip hemiarthroplasty (HA) and its influence on postoperative seromas, wound secretion, as well as time and material consumption for dressing changes. The study is a prospective randomised evaluation of iNPWT in patients with large surgical wounds after FNF. Patients were randomised either to be treated by iNPWT (group A) or a standard wound dressing (group B). Follow‐up included ultrasound measurements of seroma volumes on postoperative days 5 and 10, duration of wound secretion, and time and material spent for wound dressing changes. For comparison of the means, we used the t‐test for independent samples, P > 0·05 was considered significant. There were 21 patients randomised in this study. Group A (11 patients, 81·6 ± 5·2 years of age) developed a seroma of 0·257 ± 0·75 cm³ after 5 days and had a secretion of 0·9 ± 1·0 days, and the total time for dressing changes was 14·8 ± 3·9 minutes, whereas group B (ten patients, 82·6 ± 8·6 years of age) developed a seroma of 3·995 ± 5·01 cm³ after 5 days and had a secretion of 4·3 ± 2·45 days, and the total time for dressing changes was 42·9 ± 11·0 minutes. All mentioned differences were significant. iNPWT has been used on many different types of traumatic and non‐traumatic wounds. This prospective, randomised study has demonstrated decreased development of postoperative seromas, reduction of total wound secretion days and reduction of needed time for dressing changes.