Analysis of AcrB in Klebsiella pneumoniae reveals natural variants promoting enhanced multidrug resistance

Infections caused by Klebsiella pneumoniae are often difficult to manage due to the high frequency of multidrug resistance, often conferred by efflux pumps. In this study, we analyzed sequence variations of the major RND family multidrug efflux pump AcrB from 387 assembled K. pneumoniae genomes. We confirm that AcrB is a highly-conserved efflux pump in K. pneumoniae, and identified several variants that were prevalent in clinical isolates. Molecular dynamics analyses on two of these variants (L118M and S966A) suggested conformational changes that may correlate with increased drug efflux capabilities. The L118M change resulted in enhanced protein rigidity while the flexibility of drug binding pockets was stable or increased, and the interactions between the proximal pockets and water molecules were stronger. For S966A, the significantly enlarged proximal pocket suggested higher drug accommodation ability. Consistent with these predictions, the L118M and S966A variants conferred a slightly increased ability to grow in the presence of tetracycline and to survive cefoxitin exposure when overexpressed. In summary, our results suggest that the emergence of enhanced-function AcrB variants may be a potential risk for increased antibiotic resistance in clinical K. pneumoniae isolates.     

Clinical implications of additional posterior fractures in combined anterior-posterior pelvic ring fractures in elderly patients

ObjectivesHistorically, pelvic ring fractures (PRF) are considered to occur predominantly in the anterior ring and therfore to be mechanically stable. Combined anterior and posterior (A + P) PRF are expected to be less mechanically stable and therefore to be associated with higher levels of pain and reduced mobility compared to isolated anterior fractures. The current study investigates the clinical relevance of combined A + P PRF in elderly patients.MethodsA prospective multicentre cohort study was conducted in patients >70 years of age with anterior PRF after low-energy trauma diagnosed on conventional radiographs. All patients underwent an additional CT-scan. Patients were divided into two groups; isolated anterior or combined A + P fractures. Patients were treated conservatively with adequate analgesia for at least one week. If patients could not be mobilised after conservative treatment, surgical fixation was performed. Numerical Rating Scale (NRS) pain scores, dependence on walking aids and Activities of Daily Living scores (ADL) were measured at 2–4 weeks, and 3, 6 and 12 months after fracture.Results102 patients (age 81.1 ± 7.6 years) were included. Isolated anterior fractures were diagnosed in 25 (24.5%) and A + P fractures in 77 (75.5%) patients. Baseline characteristics did not differ between the two groups. Most patients were successfully treated conservatively and 5 (4.9%) underwent percutaneous trans-iliac, trans-sacral screw fixation after failure of conservative treatment. At 2–4 weeks post trauma, patients with A + P fractures had similar median pain scores (3 (range 0–8) vs. 5 (0–10), p = 0.19) and ADL scores (85 (25–100) vs. 78.6 (5–100), p = 0.67), but were more dependent on walking aids (92.8% vs. 72.2%; p = 0.02) compared to patients with isolated anterior fractures. There were no significant differences at 3 months. At one year follow-up the median NRS pain and ADL scores for both fracture groups were 0 and 100, respectively. Mortality was 10.8%, and additional loss to follow-up was 17.6%.ConclusionsThe vast majority of elderly patients with PRF have combined A + P fractures. The clinical implications of additional posterior pelvic ring fractures in elderly patients appears to be limited.     

Confounded association between proton pump inhibitor use and risk of biliary tract cancer: Result from three cohorts

Recent epidemiological studies suggested that proton pump inhibitor (PPI) use was associated with an increased risk of biliary tract cancer (BTC), however, confounders were not adequately controlled. Our study aimed to evaluate PPI use and subsequent risk of BTC and its subtypes in three well-established cohorts. We conducted a pooled analysis of the subjects free of cancers in UK Biobank (n = 463 643), Nurses' Health Study (NHS, n = 80 235) and NHS II (n = 95 869). Propensity score weighted Cox models were used to estimate marginal HRs of PPIs use on BTC risk, accounting for potential confounders. We documented 284 BTC cases in UK Biobank (median follow-up: 7.6 years), and 91 cases in NHS and NHS II cohorts (median follow-up: 15.8 years). In UK biobank, PPI users had a 96% higher risk of BTC compared to nonusers in crude model (HR 1.96, 95% CI 1.44-2.66), but the effect was attenuated to null after adjusting for potential confounders (HR 0.95, 95% CI 0.60-1.49). PPI use was not associated with risk of BTC in the pooled analysis of three cohorts (HR 0.93, 95% CI 0.60-1.43). We also observed no associations between PPI use with risk of intrahepatic (HR 1.00, 95% CI 0.49-2.04), extrahepatic bile duct (HR 1.09, 95% CI 0.52-2.27) and gallbladder cancers (HR 0.66, 95% CI 0.26-1.66) in UK Biobank. In summary, regular use of PPIs was not associated with the risk of BTC and its subtypes.     

Evaluation of a novel flow-controlled syringe infusion pump for precise and continuous drug delivery at low flow rates: a laboratory study

Syringe infusion pumps are used for the administration of short-acting drugs in anaesthesia and critical care medicine, but are prone to flow irregularities at low flow rates. A flow-controlled syringe infusion pump using an integrated flow sensor for feedback control represents a new approach to overcoming these limitations. This study compares the performance of a prototype flow-controlled syringe pump both at start-up, and during vertical displacement manoeuvres, with that of a standard infusion syringe pump. The novel pump almost completely eliminated delays at start-up and flow irregularities during hydrostatic pressure changes. Related fluctuations in plasma drug concentration were minimised and the known disadvantages of standard syringe infusion pumps currently used in clinical practice were reduced. Besides providing fast start-up to steady-state flow and precise continuous drug delivery at low flow rates during hydrostatic pressure changes, the new pump offers the potential for the development of target-controlled infusion algorithms for short-acting cardiovascular and other drugs.