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Objectives Infections due to carbapenem-resistant Enterobacterales are considered urgent public health threats and often treated with a β-lactam/β-lactamase inhibitor combination. However, clinical treatment failure and resistance emergence have been attributed to inadequate dosing. We used a novel framework to provide insights of optimal dosing exposure of ceftazidime/avibactam. Methods Seven clinical isolates of Klebsiella pneumoniae producing different KPC variants were examined. Ceftazidime susceptibility (MIC) was determined by broth dilution using escalating concentrations of avibactam. The observed MICs were characterized as response to avibactam concentrations using an inhibitory sigmoid Emax model. Using the best-fit parameter values, %fT>MICi was estimated for various dosing regimens of ceftazidime/avibactam. A hollow-fibre infection model (HFIM) was subsequently used to ascertain the effectiveness of selected regimens over 120 h. The drug exposure threshold associated with bacterial suppression was identified by recursive partitioning. Results In all scenarios, ceftazidime MIC reductions were well characterized with increasing avibactam concentrations. In HFIM, bacterial regrowth over time correlated with emergence of resistance. Overall, suppression of bacterial regrowth was associated with %fT>MICi ≥ 76.1% (100% versus 18.2%; P Conclusions An optimal drug exposure to suppress KPC-producing bacteria was identified. The novel framework is informative and may be used to guide optimal dosing of other β-lactam/β-lactamase inhibitor combinations. Further in vivo investigations are warranted.

Acinetobacter baumannii (AB) has become multidrug-resistant (MDR) in recent years, and, currently, there are limited effective treatment options. Nutrient metals (e.g. iron) are essential to the metabolic functions of AB. This study examined the impact of iron chelation on the growth of AB in vitro and in vivo. Susceptible and MDR-AB bloodstream isolates (n = 9) were recovered from different patients between 2011 and 2018. Clonal diversity was ascertained by Fourier-transform infrared spectroscopy. In vitro bacterial densities were measured over 20 h to determine growth profiles. Variable amounts of a chelating agent [deferiprone (DFP)] were added to create a concentration gradient. Galleria mellonella larvae were inoculated with an isolate, with and without DFP. Quantitative culture was used to ascertain the bacterial burden of aggregate larvae immediately and 4 h post-infection. Increasing concentrations of DFP caused a transient and concentration-dependent hindrance to in vitro growth, compared to the no-treatment group. In vivo bacterial burden immediately post-infection in both groups was comparable. After 4 h, the burden was much higher in the control group comparatively (8.7 and 6.7 log CFU g−1). These results support that micro-nutrient limitation has the potential of being a novel approach for treating high-risk infections due to MDR-AB.

Model-based analysis of longitudinal optical density measurements from a bacterial suspension exposed to antibiotics has been proposed as a potentially efficient and effective method for extracting useful information to improve the individualized design of treatments for bacterial infections. To that end, the authors developed in previous work a mathematical modeling framework that can use such measurements for design of effective dosing regimens.Here we further explore ways to extract information from longitudinal optical density measurements to predict bactericidal efficacy of clinically relevant antibiotic exposures.Longitudinal optical density measurements were collected in an automated instrument where Acinetobacter baumannii, ATCC BAA747, was exposed to ceftazidime concentrations of 1, 4, 16, 64, and 256 mg/L and to ceftazidime/amikacin concentrations of 1/0.5, 4/2, 16/8, 64/32, and 256/128 (mg/L)/(mg/L) over 20 h. Calibrated conversion of measurements produced total (both live and dead) bacterial cell concentration data (CFU/mL equivalent) over time. Model-based data analysis predicted the bactericidal efficacy of ceftazidime and of ceftazidime/amikacin (at ratio 2:1) for periodic injection every 8 h and subsequent exponential decline with half-life of 2.5 h. Predictions were experimentally tested in an in vitro hollow-fiber infection model, using peak concentrations of 60 and 150 mg/L for injected ceftazidime and of 40/20 (mg/L)/(mg/L) for injected ceftazidime/amikacin.Model-based analysis predicted low (62%) confidence in clinically relevant suppression of the bacterial population by periodic injections of ceftazidime alone, even at high peak concentrations. Conversely, analysis predicted high (95%) confidence in bacterial suppression by periodic injections of ceftazidime/amikacin combinations at a wide range of peak concentrations ratioed at 2:1. Both predictions were experimentally confirmed in an in vitro hollow fiber infection model, where ceftazidime was periodically injected at peak concentrations 60 and 150 mg/L (with predicted suppression confidence 38% and 59%, respectively) and a combination of ceftazidime/amikacin was periodically injected at peak concentrations 40/20 (mg/L)/(mg/L) (with predicted suppression confidence 98%).The paper highlights the potential of clinicians using the proposed mathematical framework to determine the utility of different antibiotics to suppress a patient-specific isolate. Additional studies will be needed to consolidate and expand the utility of the proposed method.

Acinetobacter baumannii is a pathogenic bacterium commonly associated with multidrug resistance. In this issue of Antimicrobial Agents and Chemotherapy , a challenging case of ventilator-associated pneumonia is presented in which bacteriophage therapy was used as a last resort treatment in combination with systemic antibiotics. The data are promising, and several key areas are highlighted for future research.

Hypertension is a major cardiovascular disease risk factor and contributor to premature death globally. Family-based investigations confirmed a significant heritable component of blood pressure (BP), whereas genome-wide association studies revealed >1000 common and rare genetic variants associated with BP and/or hypertension. The kidney is not only an organ of key relevance to BP regulation and the development of hypertension, but it also acts as the tissue mediator of genetic predisposition to hypertension. The identity of kidney genes, pathways, and related mechanisms underlying the genetic associations with BP has started to emerge through integration of genomics with kidney transcriptomics, epigenomics, and other omics as well as through applications of causal inference, such as Mendelian randomization. Single-cell methods further enabled mapping of BP-associated kidney genes to cell types, and in conjunction with other omics, started to illuminate the biological mechanisms underpinning associations of BP-associated genetic variants and kidney genes. Polygenic risk scores derived from genome-wide association studies and refined on kidney omics hold the promise of enhanced diagnostic prediction, whereas kidney omics-informed drug discovery is likely to contribute new therapeutic opportunities for hypertension and hypertension-mediated kidney damage.

Aims Obesity and kidney diseases are common complex disorders with an increasing clinical and economic impact on healthcare around the globe. Our objective was to examine if modifiable anthropometric obesity indices show putatively causal association with kidney health and disease and highlight biological mechanisms of potential relevance to the association between obesity and the kidney. Methods and results We performed observational, one-sample, two-sample Mendelian randomization (MR) and multivariable MR studies in ∼300 000 participants of white-British ancestry from UK Biobank and participants of predominantly European ancestry from genome-wide association studies. The MR analyses revealed that increasing values of genetically predicted body mass index and waist circumference were causally associated with biochemical indices of renal function, kidney health index (a composite renal outcome derived from blood biochemistry, urine analysis, and International Classification of Disease-based kidney disease diagnoses), and both acute and chronic kidney diseases of different aetiologies including hypertensive renal disease and diabetic nephropathy. Approximately 13–16% and 21–26% of the potentially causal effect of obesity indices on kidney health were mediated by blood pressure and type 2 diabetes, respectively. A total of 61 pathways mapping primarily onto transcriptional/translational regulation, innate and adaptive immunity, and extracellular matrix and metabolism were associated with obesity measures in gene set enrichment analysis in up to 467 kidney transcriptomes. Conclusions Our data show that a putatively causal association of obesity with renal health is largely independent of blood pressure and type 2 diabetes and uncover the signatures of obesity on the transcriptome of human kidney.

Antimicrobial resistance has been steadily increasing in prevalence, and combination therapy is commonly used to treat infections due to multidrug resistant bacteria. Under certain circumstances, combination therapy of three or more drugs may be necessary, which makes it necessary to simulate the pharmacokinetic profiles of more than two drugs concurrently in vitro. Recently, a general theoretical framework was developed to simulate three drugs with distinctly different half-lives. The objective of the study was to experimentally validate the theoretical model. Clinically relevant exposures of meropenem, ceftazidime, and ceftriaxone were simulated concurrently in a hollow-fiber infection model, with the corresponding half-lives of 1, 2.5, and 8 h, respectively. Serial samples were obtained over 24 h and drug concentrations were assayed using validated LC-MS/MS methods. A one-compartment model with zero-order input was used to characterize the observed concentration-time profiles. The experimentally observed half-lives corresponding to exponential decline of all three drugs were in good agreement with the respective values anticipated at the experiment design stage. These results were reproducible when the experiment was repeated on a different day. The validated benchtop setup can be used as a more flexible preclinical tool to explore the effectiveness of various drug combinations against multidrug resistant bacteria.

Combination therapy for treatment of multi-drug resistant bacterial infections is becoming increasingly common. In vitro testing of drug combinations under realistic pharmacokinetic conditions is needed before a corresponding combination is eventually put into clinical use. The current standard for in vitro simulation of the pharmacokinetics of two drugs with distinct elimination half-lives cannot be extended for combinations of three or more agents, posing a growing need. To address that need we develop a general method to design an in vitro model for simultaneous simulation of the kinetics of an arbitrary number of N drugs with different half-lives. The method developed entails two possible configurations: (a) An in-series configuration, which generalizes the standard two-drug design for N drugs and offers additional flexibility even for two drugs, and (b) an in-parallel configuration, which is new, and offers yet additional flexibility over the in-series configuration. Corresponding design equations for sizing and operation of each configuration are rigorously developed for immediate use by experimenters. These equations were used for experimental verification using a combination of three antibiotics with distinctly different half-lives (meropenem, ceftazidime, and levofloxacin). While experimental verification involved antibiotics, the method is applicable to any anti-infective or anti-cancer drugs with distinct elimination pharmacokinetics. With increasing importance of in vitro simulation of the kinetics of an arbitrary number of drugs in combination, the methods developed here are an important new tool for the design of such in vitro models.

Objectives: The aim of this study was to correlate the results of a modified susceptibility testing method with outcomes of ceftazidime/avibactam (CAZ/AVI) therapy. Methods: Two bloodstream K. pneumoniae isolates (CAZ/AVI-susceptible) from an abdominal source were recovered from two unrelated patients. Both patients were treated with CAZ/AVI but had discordant outcomes: KP118 (eradication within 24 h) and KP286 (persistent bacteraemia for over 30 days). Carbapenemase production in the two isolates was confirmed by Carba NP test. The CAZ minimum inhibitory concentration (MIC) was determined with escalating AVI concentrations (0–16 mg/L). The concentration–response was characterised by the sigmoid inhibitory maximum effect model. The best-fit parameter values were used to predict %T > MICi associated with CAZ/AVI exposures expected in peritoneal fluid after standard dosing (2.5 g every 8 h). These CAZ/AVI exposures were simulated in a hollow-fibre infection model (HFIM), and the bacterial responses were correlated with observed clinical outcomes. Results: The AVI-dependent reduction in CAZ MIC was well characterised in both bacterial isolates (r2 ≥ 0.98). In the HFIM, sustained suppression of KP118 (T > MICi = 100%) was observed over 5 days, but not with KP286 (T > MICi

Introduction In a regional centre for plastic surgery, it had been noted that operations were being delayed due to lack of pre-operative investigations. A pre-operative investigation checklist was developed between anaesthetic and surgical staff for semi-elective plastic trauma surgery patients, based on NICE guidelines. The checklist recommends which blood, radiology and cardiopulmonary tests would be appropriate based upon age, ASA grade and co-morbidity. Method A complete cycle audit was used to evaluate the checklist. All patients having GA/block for plastic surgery trauma in a 2-week window were included. Data was collected retrospectively via electronic operative records, anaesthetic assessments, and clinical notes. A minimum of 15 patients was collected per cycle. A single page pre-operative checklist was created for pre-operative investigations were introduced after the first cycle. Results The first audit cycle had 16 patients, ASA1 (5), ASA 2(6) ASA 3 (5). 75% had appropriate pre-op investigations. In the second cycle 22 patients, ASA 1 (8), ASA 2 (9), ASA 3 (3), ASA 4 (1). 100% of patients had appropriate pre-operative investigations. Conclusions There was increased awareness of pre-operative investigations in medical and nursing staff after the introduction of the checklist. It has helped streamline the delivery of semi-elective trauma surgery in our unit.

Background Carbapenemases confer resistance against a broad range of beta-lactams with a prevalence of 40-60% among CRE (carbapenem-resistant Enterobacteriaceae). CAZ-AVI is commonly used to treat infections due to CPE (carbapenemase-producing Enterobacteriaceae), typically guided by susceptibility testing with a single AVI concentration. This methodology does not take into consideration varying AVI concentration observed in vivo, and may not reliably predict positive clinical outcomes. Our objective was to investigate a novel susceptibility testing method to guide CAZ-AVI therapy. Methods Two bloodstream K. pneumoniae isolates (CAZ/AVI susceptible) from an abdominal source were recovered from 2 unrelated patients. Both patients were treated with CAZ/AVI, but had discordant outcomes: KP118 (eradication within 24h) and KP286 (persistent bacteremia for over 30 days). Carbapenemase production in the 2 isolates was confirmed via Carba NP test, and CAZ susceptibility was determined in a clinically relevant range of AVI concentration (0 - 16 mg/L). The concentration-response was characterized by the sigmoid inhibitory maximum effect (Emax) model. The best-fit parameter values were used to predict %T > MICi associated with CAZ/AVI exposures expected in peritoneal fluid after standard dosing (2.5g q8h). These CAZ/AVI exposures were simulated in the hollow-fiber infection model (HFIM), and the bacterial responses were correlated to observed clinical outcomes. Results The AVI-dependent reduction in CAZ MIC was well characterized in both strains (R2 > 0.98). In HFIM, sustained suppression of KP118 (T > MICi = 100%) was observed over 5 days, but not with KP286 (T > MICi < 100%). These observations are consistent with the clinical courses of the patients. Conclusion The discordant patient outcomes could be explained by MIC profiling of CAZ/AVI. This method appears to be more robust than conventional susceptibility testing, and the clinical utility of this approach should be further investigated. Disclosures All Authors: No reported disclosures

In western Kazakhstan there are several world class hydrocarbon fields, including the onshore Karachaganak Field. The geological setting is very challenging for the seismic imaging techniques where deep carbonate platform targets underlie a complex overburden including diapiric and detached salt structures. Furthermore, the extensive oil field infrastructure generates a noisy environment for seismic acquisition and reduced access for vibroseis trucks. KPO conducted an extensive integrated feasibility study for a new survey, complemented by a seismic acquisition test in 2008 which confirmed the need for dense source and receiver coverage, long offsets and wide azimuths to optimize imaging of the pre-salt targets. The survey was acquired in 2009 and survey execution exceeded local and international standards. It was the highest channel survey acquired in Kazakhstan and when fully depth image processed it will yield a high spatially sampled seismic volume, with improved resolution and structural definition. The application of the latest technology and techniques will enable better characterization of this complex carbonate reservoir, adding future value by better placement of wells and reducing overall costs for the ongoing development of the field.

The Karachaganak Field is an oil and gas condensate supergiant field located in the western Kazakhstan Pricaspian Basin. As part of the challenge to improve reservoir knowledge, KPO has been continuously monitoring the reservoir using a microseismic array deployed downhole since February 2009. Continuous deep recording of microseismic activity is an innovative technique for reservoir monitoring; progressive refinements were made to fine-tune the acquisition and processing techniques. By December 2010, 8074 events had been detected and, from this group, 2556 events have been located. Events within the reservoir were recorded up to 8 km from the array to a depth of 5 km with moment magnitudes (Mw) ranging from −2.4 to +1. Microseismic events are continuously located and their spatial and temporal distribution analysed. This basic analysis is the input to an integrated study that considers the static model for the reservoir, in addition to dynamic and operational aspects such as production and injection rates, pressure baffles, drilling behaviour and casing perforations. The results to date indicate valuable reservoir information concerning the location of lateral and vertical reservoir pressure baffles and delineation of zones of instability at the reservoir–seal interface, important for well integrity issues. This new information is helping to improve dynamic and geomechanical reservoir models and also wellbore stability predictions. This article presents the details of the Karachaganak microseismic array and how microseismic events were located. Discussion follows on the interpretation and the possible impact on reservoir monitoring and drilling. The Karachaganak array is one of the deepest installations of a passive microseismic monitoring system and also represents one of the longer periods of continuous monitoring, with two years of data available.

[Extract] Currently Brucella suis is the only causative agent of endemic brucellosis in Australia. The incidence of human brucellosis in Australia is 0.2 per 100 000. This equates to approximately 40–50 cases each year including occasional imported cases caused by Brucella melitensis. Of the cases reported, 80% occur in Queensland. The clinical manifestations of human brucellosis are protean and non-specific, posing a diagnostic challenge to clinicians. Delay in time to diagnosis and poor management of brucellosis may result in serious, sometimes life-threatening complications. Chronic brucellosis is not uncommon and can have an enormous impact on the patient's physical, mental and occupational health. A recent study in North Queensland has described the clinical and psychological impact of this disease.

SUMMARYThe aims of this study were to define the basic epidemiology of serologically confirmed acute Q fever in patients tested via the Townsville Hospital laboratory from 2000 to 2010 and to determine the impact of geographical location and seasonality on the incidence of acute cases in the Townsville region. Seven Statistical Local Areas (SLA) were identified as having an incidence higher than the average Queensland incidence over the study period. The SLA with the highest incidence was Woodstock-Ross with 24·9 cases/100 000. A clear seasonal peak was found, with the greatest number of cases observed in May, 3 months following the peak in rainfall in February. We hypothesize that an increase in wildlife numbers and drier conditions seen immediately following the wet season is the reason for the seasonal peak of human acute Q fever cases in Townsville.

We investigated modifications to the reservoir tube usually used in drawover anaesthetic breathing systems as a method of improving its efficiency and performance. The resulting oxygen concentration was recorded at different oxygen flow rates whilst an artificial lung was being ventilated over a range of minute volumes. Addition of a reservoir bag and valves significantly increased the measured percentage of oxygen at the common gas outlet when compared to a 300-ml reservoir tube. There was no difference in the percentage of oxygen when comparing a reservoir bag and a 600-ml reservoir tube.

Introduction In 2007 the Mental Health Act in England and Wales was amended and the definition of Mental Disorder was broadened. This change affected people with Personality Disorders who now can be admitted for hospital treatment without consent, often for prolonged period of time. Objectives This poster reviews clinicians’ attitudes towards the new legislation and its consequences and also presents the research on the different perspectives about the new law. Aims To review clinicians’ attitudes with regard to interfaces between Personality Disorders and the new law. Methods Use of the specifically designed questionnaire for clinicians providing hospital care for patients with Borderline Personality Disorders. MEDLINE and PsycINFO databases were also searched for all English-language articles published between 2008 and 2012 containing the keywords “rsonality Disorder”, “Mental Health Act” and “clinicians view on compulsory treatment of persons with Borderline Personality Disorder”. Additional key articles published before 2008 were reviewed. The most relevant articles were selected for the review. Results and conclusions There is still no common consensus in regard to the benefit of compulsory hospital admission of persons with Borderline Personality Disorders. Results from questionnaires are under review.

DNA mapping of the alpha globin gene cluster in cord blood from Polynesians has shown an increased frequency of alpha thalassaemia and triplicated alpha genes. Reduced levels of haemoglobin, mean corpuscular haemoglobin or mean corpuscular volume in these neonates may indicate alpha thalassaemia. Recognition of this will avoid unnecessary haematological investigations and iron supplementation.

The electrochemical quartz crystal microbalance (EQCM) and ellipsometry have been used to study directly the movement of ions and solvent into/out of electroactive polymer films. The systems studied were polyvinylferrocene (PVF), polybithiophene (PBT) and polythionine (PTh). The overall mass changes accompanying oxidation/reduction indicate that film sources of counter-ions (required to maintain electroneutrality) can be significant. The extent of participation of these species depends on the nature and concentration of the bathing electrolyte solution. In the case of PVF, optical data also indicate a structural change: reduced PVF appears to be a homogeneous compact film, whilst oxidised PVF+ is a more diffuse, inhomogeneous film, whose polymer content decreases with distance from the electrode. Voltammetric experiments at rapid (and in some cases even moderate) scan rates show that transport of mobile species can be quite slow. It was generally observed that ingress into the polymer was slower than egress of the same species from the polymer. Charged species, notably proton in hydrated systems, move faster than neutral species, such as solvent, due to the influence of the field.