Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors

Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-beta-lactamases (MBLs). Here we report the discovery and optimization of potent broad-spectrum MBL inhibitors. A high-throughput screen for NDM-1 inhibitors identified indole-2-carboxylates (InCs) as potential beta-lactamase stable beta-lactam mimics. Subsequent structure-activity relationship studies revealed InCs as a new class of potent MBL inhibitor, active against all MBL classes of major clinical relevance. Crystallographic studies revealed a binding mode of the InCs to MBLs that, in some regards, mimics that predicted for intact carbapenems, including with respect to maintenance of the Zn(II)-bound hydroxyl, and in other regards mimics binding observed in MBL-carbapenem product complexes. InCs restore carbapenem activity against multiple drug-resistant Gram-negative bacteria and have a low frequency of resistance. InCs also have a good in vivo safety profile, and when combined with meropenem show a strong in vivo efficacy in peritonitis and thigh mouse infection models.Peer reviewe

Clinical characteristics and outcome in 223 diabetic patients with deep foot infections

Clinical characteristics and outcome in 223 consecutive diabetic patients with deep foot infections are reported. Patients were treated by a multidisciplinary diabetic foot-care team at the University Hospital, Lund, Sweden, and were prospectively followed until healing or death. About 50% of patients lacked clinical signs of infection, such as a body temperature > 37.8°C, a sedimentation rate > 70 mm/hour, and white blood cell count (WBC) > 10 x 109/liter. Eighty-six percent had surgery before healing or death. Thirty-nine percent healed without amputation; 34% healed after a minor and 8% after a major amputation. Sixteen percent were unhealed at death, and 3% were unhealed at the end of the observation period. Of those unhealed at death or follow-up, 4 patients had had a major and 11 a minor amputation. After correction for age and sex, duration of diabetes 45 mmHg, and an ankle pressure > 80 mm Hg, absence of exposed bone and a white blood cell count < 12 x 109/liter were all related to healing without amputation in a logistic regression analysis. We conclude that although only 1 in 10 had a major amputation, nearly all diabetic patients with a deep foot infection needed surgery and more than one third had a minor amputation before healing or death in spite of a well- functioning diabetic foot-care team responsible for all included patients

Sustained reduction in major amputations in diabetic patients - 628 amputations in 461 patients in a defined population over a 20-year period

Background and purpose With an ageing population and an increasing incidence of diabetes, reduction of the number of diabetes-related amputations becomes increasingly difficult to achieve and maintain. There is controversy in this respect regarding the degree of success. We started a multidisciplinary treatment program for diabetic foot ulcers in 1982, and have now assessed incidence rates of amputations from 1982 through 2001. Methods In a defined population, gradually increasing from 199,000 to 234,000, all diabetes-related amputations of the lower extremity from toe to hip were recorded from January 1, 1982 to December 31, 2001, using several sources of information. Results The incidence of major amputations decreased by 0.57 from 16 (11-22) to 6.8 (6.1-7.5) per 100,000 inhabitants between the first and last 4-year period. The most substantial decrease was seen in patients aged 80 years and older. The fraction of amputations with a final level at or below the ankle (n = 240) increased from 0.23 in the first 4-year period to 0.31, 0.49, 0.47, and 0.49 in the following 4-year periods. The overall fraction of re-amputation was 0.34 in the first 4-year period and 0.27, 0.21, 0.32, and 0.21 in the following 4-year periods. The fraction of amputations in diabetic patients that were channeled through the footcare team prior to amputation increased from 0.51 in the first 4-year period to 0.83, 0.86, 0.90, and 0.90 in the following 4-year periods. Interpretation Our findings indicate that a substantial decrease in the incidence of major lower extremity amputations in diabetic patients has been achieved and maintained

Contamination of pasteurised milk by Bacillus cereus in the filling machine

The contamination of pasteurized milk by Bacillus cereus during the ®lling process was studied in two dairy plants. Samples of pasteurized milk were taken at four different sites along the production line. The samples were stored at 7 °C for 7 d, or at 10 °C for 5 d, before plate counting and random selection of B. cereus isolates. Isolates of B. cereus were typed by the polymerase chain reaction (PCR)-based method randomly ampli®ed polymorphic DNA (RAPD). Samples taken at three different sites between the pasteurizer and the ®lling machine were all holding similar low concentrations of B. cereus, while an increase of the B. cereus count was seen in the consumer packages. More B. cereus of different RAPD types was growing in the consumer packages than in samples taken just before the ®lling machine. Several RAPD types found in the consumer packages were not detected in the samples taken just before the ®lling machine

Amputation-Free Survival in Patients With Diabetes Mellitus and Peripheral Arterial Disease With Heel Ulcer : Open Versus Endovascular Surgery

BACKGROUND:: Heel ulcers in patients with diabetes mellitus (DM) and peripheral arterial disease (PAD) are hard to heal. The aim of the present study was to evaluate the difference in amputation-free survival (AFS) between open and endovascular revascularization in patients with DM, PAD, and heel ulcers.METHODS:: Retrospective comparative study of results of open versus endovascular surgery in patients with DM, PAD, and heel ulcer presented at the multidisciplinary diabetes foot clinic between 1983 and 2013.RESULTS:: Patients with heel ulcers were treated with endovascular intervention (n = 97) and open vascular surgery (n = 30). Kaplan-Meier analysis showed that the AFS was higher in patients undergoing open vascular surgery compared to the endovascular group ( P = .009). Multivariate analysis showed that open vascular surgery versus endovascular therapy (hazard ratio 2.1, 95% confidence interval 1.1-3.9; P = .025) was an independent factor associated with higher AFS. The proportion of patients undergoing endovascular therapy in the former (1983-2000) time period was 47% compared to 89% in the latter (2001-2013) time period ( P < .001).CONCLUSION:: The AFS was higher after open than endovascular surgery among patients with DM and PAD with heel ulcer. These results suggest that open vascular surgery should be offered more often as opposed to current practice