Efficacies of Ceftazidime-Avibactam and Ceftazidime against Pseudomonas aeruginosa in a Murine Lung Infection Model

This study aimed to determine the efficacy of human-simulated plasma exposures of 2 g ceftazidime plus 0.5 g avibactam every 8 h administered as a 2-h infusion or a ceftazidime regimen that produced a specific epithelial lining fluid (ELF) percentage of the dosing interval in which serum free drug concentrations remain above the MIC (fT>MIC) against 28 Pseudomonas aeruginosa isolates within a neutropenic murine pneumonia model and to assess the impact of host infection on pulmonary pharmacokinetics. The fT>MIC was calculated as the mean and upper end of the 95% confidence limit. Against the 28 P. aeruginosa strains used, the ceftazidime-avibactam MICs were 4 to 64 μg/ml, and those of ceftazidime were 8 to >128 μg/ml. The change in log₁₀ CFU after 24 h of treatment was analyzed relative to that of 0-h controls. Pharmacokinetic studies in serum and ELF were conducted using ceftazidime-avibactam in infected and uninfected mice. Humanized ceftazidime-avibactam doses resulted in significant exposures in the lung, producing reductions of >1 log₁₀ CFU against P. aeruginosa with ceftazidime-avibactam MICs of ≤32 μg/ml (ELF upper 95% confidence limit for fT>MIC [ELF fT>MIC] of ≥19%), except for one isolate with a ceftazidime-avibactam MIC of 16 μg/ml. No efficacy was observed against the isolate with a ceftazidime-avibactam MIC of 64 μg/ml (ELF fT>MIC of 0%). Bacterial reductions were observed with ceftazidime against isolates with ceftazidime MICs of 32 μg/ml (ELF fT>MIC of ≥12%), variable efficacy at ceftazidime MICs of 64 μg/ml (ELF fT>MIC of ≥0%), and no activity at a ceftazidime MIC of 128 μg/ml, where the ELF fT>MIC was 0%. ELF fT>MICs were similar between infected and uninfected mice. Ceftazidime-avibactam was effective against P. aeruginosa, with MICs of up to 32 μg/ml with an ELF fT>MIC of ≥19%. The data suggest the potential utility of ceftazidime-avibactam for treatment of lung infections caused by P. aeruginosa.     

Paleocene latitude of the Kohistan–Ladakh arc indicates multistage India–Eurasia collision

We report paleomagnetic data showing that an intraoceanic Trans-Tethyan subduction zone existed south of the Eurasian continent and north of the Indian subcontinent until at least Paleocene time. This system was active between 66 and 62 Ma at a paleolatitude of 8.1 ± 5.6 °N, placing it 600–2,300 km south of the contemporaneous Eurasian margin. The first ophiolite obductions onto the northern Indian margin also occurred at this time, demonstrating that collision was a multistage process involving at least two subduction systems. Collisional events began with collision of India and the Trans-Tethyan subduction zone in Late Cretaceous to Early Paleocene time, followed by the collision of India (plus Trans-Tethyan ophiolites) with Eurasia in mid-Eocene time. These data constrain the total postcollisional convergence across the India–Eurasia convergent zone to 1,350–2,150 km and limit the north–south extent of northwestern Greater India to <900 km. These results have broad implications for how collisional processes may affect plate reconfigurations, global climate, and biodiversity.

Classically, the India–Eurasia collision has been considered to be a single-stage event that occurred at 50–55 million years ago (Ma) (1, 2). However, plate reconstructions show thousands of kilometers of separation between India and Eurasia at the inferred time of collision (3, 4). Accordingly, the northern extent of Greater India was thought to have protruded up to 2,000 km relative to present-day India (5, 6) (Fig. 1). Others have suggested that the India–Eurasia collision was a multistage process that involved an east–west trending Trans-Tethyan subduction zone (TTSZ) situated south of the Eurasian margin (7–9) (Fig. 1). Jagoutz et al. (9) concluded that collision between India and the TTSZ occurred at 50–55 Ma, and the final continental collision occurred between the TTSZ and Eurasia at 40 Ma (9, 10). This model reconciles the amount of convergence between India and Eurasia with the observed shortening across the India–Eurasia collision system with the addition of the Kshiroda oceanic plate. Additionally, the presence of two subduction systems can explain the rapid India–Eurasia convergence rates (up to 16 mm a⁻¹) that existed between 135 and 50 Ma (9), as well as variations in global climate in the Cenozoic (11).Open in a separate windowFig. 1.The first panel is an overview map of tectonic structure of the Karakoram–Himalaya–Tibet orogenic system. Blue represents India, red represents Eurasia, and the Kohistan–Ladakh arc (KLA) is shown in gray. The different shades of blue highlight the deformed margin of the Indian plate that has been uplifted to form the Himalayan belt, and the zones of darker red within the Eurasian plate highlight the Eurasian continental arc batholith. Thick black lines denote the suture zones which separate Indian and Eurasian terranes. The tectonic summary panels illustrate the two conflicting collision models and their differing predictions of the location of the Kohistan–Ladakh arc. India is shown in blue, Eurasia is shown in red, and the other nearby continents are shown in gray. Active plate boundaries are shown with black lines, and recently extinct boundaries are shown with gray lines. Subduction zones are shown with triangular tick marks.While the existence of the TTSZ in the Cretaceous is not disputed, the two conflicting collision models make distinct predictions about its paleolatitude in Late Cretaceous to Paleocene time; these can be tested using paleomagnetism. In the single-stage collision model, the TTSZ amalgamated with the Eurasian margin prior to ∼80 Ma (12) at a latitude of ≥20 °N (13, 14). In contrast, in the multistage model, the TTSZ remained near the equator at ≤10 °N, significantly south of Eurasia, until collision with India (9) (Fig. 1).No undisputed paleomagnetic constraints on the location of the TTSZ are available in the central Himalaya (15–17). Westerweel et al. (18) showed that the Burma Terrane, in the eastern Himalaya, was part of the TTSZ and was located near the equator at ∼95 Ma, but they do not constrain the location of the TTSZ in the time period between 50 and 80 Ma, which is required to test the two collision hypotheses. In the western Himalaya, India and Eurasia are separated by the Bela, Khost, and Muslimbagh ophiolites and the 60,000 km² intraoceanic Kohistan Ladakh arc (19, 20) (Fig. 1). These were obducted onto India in the Late Cretaceous to Early Paleocene (19), prior to the closure of the Eocene to Oligocene Katawaz sedimentary basin (20) (Fig. 1). The Kohistan–Ladakh arc contacts the Eurasian Karakoram terrane in the north along the Shyok suture and the Indian plate in the south along the Indus suture (21) (Fig. 1). Previous paleomagnetic studies suggest that the Kohistan–Ladakh arc formed as part of the TTSZ near the equator in the early Cretaceous but provide no information on its location after 80 Ma (22–25). While pioneering, these studies lack robust age constraints, do not appropriately average paleosecular variation of the geodynamo, and do not demonstrate that the measured magnetizations have not been reset during a subsequent metamorphic episode.     

Effects of dietary polyunsaturated and saturated fats on lipoproteins in the baboon

The effects of 2 different dietary fats (40% of calories from corn oil or coconut oil), in the presence of high-dietary cholesterol (1.7 mg/kcal), on the lipoprotein profiles of baboons (Papio cynocephalus sp) were studied by analytic ultracentrifugation, gradient gel electrophoresis (GGE), and heparin-manganese chloride precipitation. Relative to the corn oil (polyunsaturated fat) diet, the coconut oil (saturated fat) diet significantly increased total serum cholesterol by 43% (P less than 0.001) by increasing non-precipitable cholesterol (HDL-C) 58% (P less than 0.001) and precipitable cholesterol (VLDL + LDL-C) 35% (P less than 0.001). Analytic ultracentrifugal observations indicated that the increase in HDL-C was due to considerable increases in both HDL-I (baboon HDL of size 100-125 A and hydrated density 1.063-1.120 g/ml) and F1.20 degrees 9-28 lipoproteins (material of size 125-220 A and hydrated density 1.03-1.08 g/ml, and containing HDL apolipoproteins and apo E). Concentrations of other HDL subpopulations were unaffected by the dietary saturated rat. The increase in VLDL + LDL-C was due to increased LDL (S degree F 5-12 lipoproteins) and, to some extent, F1.20 degrees 9-28 lipoproteins because the larger, faster floating subspecies of the F1.20 degrees 9-28 lipoproteins were precipitable by heparin-manganese. In contrast, saturated fat (relative to polyunsaturated fat) induced lower concentrations of IDL (SF degree 12-20) and VLDL (SF degree 20-100). Lipoprotein size distributions by GGE indicated 5 HDL subpopulations and 2 or more LDL subpopulations in the sera of most baboons. The type of dietary fat did not affect the particle size range of each of the the HDL or LDL subpopulations. The results indicate that dietary fat markedly modulates the distribution of cholesterol between apo A-I-containing (HDL and F1.20 degrees 9-28) and apo B-containing (IDL and VLDL) lipoproteins without altering the presence of subpopulations based on particle size.     

Arterial-wave reflections are increased in heart failure patients with a left-ventricular assist device

BACKGROUND: Chronic heart failure (HF) is associated with increased central arterial pulse-wave reflections, which may contribute to increased myocardial oxygen demand. Although the treatment of HF via left-ventricular assist device (LVAD) placement has recently become widespread, the effects of LVAD therapy on central arterial pulse-wave reflections are unknown. METHODS: Central aortic pulse-wave analysis was performed on patients with end-stage HF awaiting cardiac transplantation and on healthy age-matched controls using the SphygmoCor (Akor Medical, Sydney, Australia) system. Arterial pulse-wave data were compared between patients receiving LVAD support versus those receiving intravenous inotropic drugs and healthy control patients. RESULTS: Five patients on LVAD support were compared with 10 patients on inotropic drugs and 10 healthy control patients. Aortic augmented pressure and the aortic augmentation index (AI(a)) were higher in LVAD patients compared with inotrope and control patients, despite similar brachial and aortic blood pressures between groups. The AI(a) was significantly higher in LVAD patients than in patients on inotropic drugs (28.2% +/- 10% v 7.9% +/- 9%, P < or = .01). Additionally, there was a significantly higher aortic systolic tension time index, an index of left-ventricular myocardial oxygen demand, in the LVAD group compared with the inotrope group (2655 +/- 298 mm Hg/sec/min v 1748 +/- 303 mm Hg/sec/min, P < .01). CONCLUSIONS: Central arterial pressure-wave reflection is increased in end-stage HF patients on LVAD support compared with those on inotropic drugs, leading to an increase in aortic augmented pressure, AI(a), and systolic tension time index. The AI(a) is also higher in LVAD patients than in healthy controls. This increased central arterial-wave reflection places an additional hemodynamic load on the LVAD device and may have relevance to the medical management of patients after LVAD placement and to the longevity of the LVAD device itself.     

Weight Change and Glycemic Control After Diagnosis of Type 2 Diabetes

BACKGROUND  Limited community-based data describe weight change after diabetes diagnosis. OBJECTIVE  To evaluate weight change patterns and associations in the 1st year after diabetes mellitus type 2 diagnosis. DESIGN  Retrospective cohort study. PARTICIPANTS  Patients aged 21–75 with diabetes mellitus type 2 diagnosed between 1 January 1997 and 31 December 2004, identified from electronic medical records in Kaiser Permanente Northwest, a health maintenance organization. Eligible patients met weight measurement criteria (a baseline and three additional weight measurements) and did not have a condition associated with unintentional weight change (n = 4,135). MEASUREMENTS  We estimated 12-month patient weight trajectories using growth curve analyses, grouped similar trajectories using cluster analysis, and compared characteristics among groups. RESULTS  The four weight trajectory groups were “higher stable weight” (n = 757; 18.3%), “lower stable weight” (n = 2,236; 54.1%), “weight gain” (n = 664; 16.0%), and “weight loss” (n = 478; 11.6%). After adjustments, members of the weight-loss group were more likely than those in the weight-gain group to be older, female, take fewer medications, have had nutritionist visits, and have a lower mean HbA_1c. Those in the weight-loss group were less likely to be in a race group at higher risk for obesity, have depression or dyslipidemia, or have taken >30 days of a sulfonylurea alone or with metformin. CONCLUSIONS  A small-but-substantial group of patients had a mean weight trajectory that included a clinically significant weight loss. Weight-loss trajectories were strongly associated with better glycemic control when compared to weight gain. Patients with certain characteristics may need more support for weight loss. This study was supported by grant no. R21 DK073546–02 (Weight in Secondary Prevention) from the National Institute of Diabetes and Digestive and Kidney Diseases     

Bilateral versus unilateral botulinum toxin injections for chronic anal fissure: a randomised trial

Background

Botulinum toxin injected into the internal anal sphincter is used in the treatment of chronic anal fissure but there is no standardised technique for its administration. This randomised single centre trial compares bilateral (either side of fissure) to unilateral injection.

Methods

Participants were randomised to receive bilateral (50?+?50 units) or unilateral (100 units) Dysport^® injections into the internal anal sphincter in an outpatient setting. Injection-related pain assessed by visual analogue scale was the primary outcome measure. Secondary outcomes were healing rate, fissure pain, incontinence, and global health scores.

Results

Between October 2008 and April 2012, 100 patients with chronic anal fissure were randomised to receive bilateral or unilateral injections. Injection-related pain was comparable in both groups. There was no difference in healing rate. Initially, there was greater improvement in fissure pain in the bilateral group but at 1 year the unilateral group showed greater improvement. Cleveland Clinic Incontinence score was lower in the unilateral group in the early post-treatment period and global health assessment (EuroQol EQ-VAS) was higher in the unilateral group at 1 year.

Conclusions

Injection-related pain was similar in bilateral and unilateral injection groups. Unilateral injection was as effective as bilateral injections in healing and improving fissure pain without any deterioration in continence.

     

Enterococcal infections in surgical patients: the mystery continues.

The frequency of isolation of enterococci from surgical patients has increased significantly during the past decade, although the role of these organisms as pathogens in mixed infections remains a mystery. Bacteremia and other infections in which enterococci are the only pathogens frequently result in high morbidity and mortality among patients unless specific antimicrobial therapy is initiated promptly. Debate continues concerning the necessity for treatment with such agents when this organism is isolated as a component of a polymicrobial infecting flora. Our recent data indicate that enterococci are rarely isolated in postoperative infections after penetrating abdominal trauma if no gastrointestinal perforation has occurred. However, they were found in 56% of postoperative infections of patients with gastrointestinal perforation. In contrast, enterococci were isolated in only 9% of cultures of specimens from patients with secondary suppurative peritonitis. The occurrence of superinfection after therapy with a cephalosporin appears to be an important factor in this finding. Future studies are necessary to evaluate the efficacy of antibiotic treatment of enterococcal infections and to assess the need for prophylaxis against enterococci.