Optimizing beta-lactam antibiotic dosing in critically ill patients: Prolonged infusion versus intermittent bolus administration

Severe sepsis is a major burden in the intensive care unit (ICU) with persistently high mortality rates. Optimization of antibiotic dosing has been suggested as an intervention to improve clinical outcomes for critically ill patients with severe sepsis. However, current antibiotic dosing guidelines may not be appropriate for these patients, as they rarely consider the altered physiology and illness severity associated with this population. Optimizing antibiotic dosing using pharmacokinetic (PK) and pharmacodynamic (PD) principles can address these critical illness-related changes and promote therapeutic success. Due to their wide spectrum of antibiotic activity and excellent safety profile, beta-lactam antibiotics are commonly used for severe infections in the ICU. Two alternative dosing approaches to traditional intermittent bolus (IB) dosing, namely continuous infusion (CI) and extended infusion (EI), have been suggested to maximize the therapeutic potential of these antibiotics in critically ill patients. Collectively, the two dosing approaches can also be referred as prolonged infusion (PI). This Thesis aims to better characterize the pharmacokinetics/pharmacodynamics (PK/PD) of beta-lactam antibiotics to determine whether there is any therapeutic advantage associated with PI dosing (CI and/or EI) as compared to IB dosing. This Thesis comprises of eight chapters. Chapter 1 is an introductory chapter which provides an overview of the published literature on the area of research. The discussion in Chapter 1 presents a theoretical framework behind the Thesis objectives. Chapter 1 concludes with the specific aims of this Thesis. Chapter 2 reports the findings of a prospective PK study which aimed to describe the population PK of doripenem in critically ill patients with sepsis and perform dosing simulations to develop clinically relevant dosing guidelines for these patients. Twelve critically ill participants receiving 500 mg of doripenem 8-hourly as a 1-hr infusion were enrolled. The volume of distribution (Vd) and clearance (CL) of doripenem in this patient cohort were substantially different than those usually described in non-critically patients. As current dosing guidelines were mostly derived from the non-critically ill, findings from this study suggest that the licensed “one-dose-fits-all” dosing for doripenem is unlikely to achieve optimal exposures in critically ill patients. Empirical use of PI dosing should be considered to account for PK and illness severity differences, particularly when less-susceptible pathogens are involved. Chapter 3 incorporates a published systematic review which compares the PK/PD data and clinical outcomes between CI and IB dosing to describe any potential merits supporting either of the two dosing approaches for critically ill patients. The findings suggest that beta-lactam CI may not be advantageous for all critically ill patients and may be beneficial in patients with severe infections. Chapter 4 describes the findings of a post hoc analysis on the Defining Antibiotic Levels in Intensive care unit patients (DALI) study, which recruited critically ill patients from 68 ICUs across 10 countries. The analysis aimed to compare the PK/PD target attainment and clinical outcomes between PI (CI and EI) and IB dosing of meropenem and piperacillin/tazobactam in 182 critically ill patients. In this analysis, PI dosing significantly increased the target attainment for most PK/PD end-points. Data from this chapter also suggest that the critically ill patients who are most likely to benefit from altered dosing strategies are those with severe pneumonia and not receiving renal replacement therapy (RRT). Chapter 5 is a published review article which scrutinizes the methodology of clinical studies comparing CI versus IB dosing of beta-lactam antibiotics. Several issues and problems in the interpretation of results obtained from these studies are discussed. This finally led to a proposal of how a methodologically robust study should be performed to test the clinical outcome differences of CI versus IB dosing of beta-lactam antibiotics in critically ill patients. Chapter 6 reports the findings of the Beta-Lactam In Severe Sepsis (BLISS) study, which was a two-centre, randomized controlled trial of CI versus IB dosing of beta-lactam antibiotics, enrolling 140 critically ill participants with severe sepsis who were not on RRT. This study aimed to determine if CI is associated with better clinical outcomes and PK/PD target attainment in critically ill patients, as opposed to IB dosing. In this study, CI of beta-lactam antibiotics demonstrated higher clinical cure rates and better PK/PD target attainment than IB dosing. The findings suggest that beta-lactam CI may be most beneficial for critically ill patients with severe infections, who are infected with less-susceptible microorganisms. Chapter 7 incorporates a published review article which systematically analyses the relevance of PK/PD characteristics of antibiotics and their potential roles in maximizing patient outcomes and preventing the emergence of antibiotic resistance. Based on the collated data, dosing approaches which are likely to reduce the risk of antibiotic resistance in the ICU were also proposed. Chapter 8 will be the final chapter in this Thesis and summarizes the clinical findings of all the work and highlight potential areas of future research

Child in car alarm system using various sensors

The network service system is increasingly extended as the demand from various of usage is growing. Although many products had been invented, there are still the incidents that involve to death of children which been left in cars often occur. The system is designed in order to overcome this unwanted incident from happening. The proposed system is designed to detect sound or voice and any movement made by the children that had been left behind in a vehicle. The main target of the system is to create a complete system which uses Global System for Mobile Communication (GSM) that can communicate with human. GSM modem is the medium to interact and communicate with the module. It is used to send and receive Short Messaging System (SMS) based on which appropriate actions taken by the user. PIC microcontroller performs as heart of whole controlling system. The system at the final stage can be used to detect the sound that had been produced by a human at optimum strength. In addition, it was also able to detect motion that performed by a person and can detect any sounds that produced from inside the car. The system that has generated is expected to continue to expand with concomitant change in time with the developed and equipped with a great technology

Prolonged administration of beta-lactam antibiotics - a comprehensive review and critical appraisal

Prolonged infusion of β-lactam antibiotics as either extended (over at least 2 hours) or continuous infusion is increasingly applied in intensive care units around the world in an attempt to optimise treatment with this most commonly used class of antibiotics, whose effectiveness is challenged by increasing resistance rates. The pharmacokinetics of β-lactam antibiotics in critically ill patients is profoundly altered secondary to an increased volume of distribution and the presence of altered renal function, including augmented renal clearance. This may lead to a significant decrease in plasma concentrations of β-lactam antibiotics. As a consequence, low pharmacokinetic/pharmacodynamic (PK/PD) target attainment, which is described as the percentage of time that the free drug concentration is maintained above the minimal inhibitory concentration (MIC) of the causative organism (fT>MIC), has been documented for β-lactam treatment in these patients when using standard intermittent bolus dosing, even for the most conservative target (50% fT>MIC). Prolonged infusion of β-lactams has consistently been shown to improve PK/PD target attainment, particularly in patients with severe infections. However, evidence regarding relevant patient outcomes is still limited. Whereas previous observational studies have suggested a clinical benefit of prolonged infusion, results from two recent randomised controlled trials of continuous infusion versus intermittent bolus administration of β-lactams are conflicting. In particular, the larger, double-blind placebo-controlled randomised controlled trial including 443 patients did not demonstrate any difference in clinical outcomes. We believe that a personalised approach is required to truly optimise β-lactam treatment in critically ill patients. This may include therapeutic drug monitoring with real-time adaptive feedback, rapid MIC determination and the use of antibiotic dosing software tools that incorporate patient parameters, dosing history, drug concentration and site of infection. Universal administration of β-lactam antibiotics as prolonged infusion, even if supported by therapeutic drug monitoring, is not yet ready for "prime time", as evidence for its clinical benefit is modest. There is a need for prospective randomised controlled trials that assess patient-centred outcomes (e.g. mortality) of a personalised approach in selected critically ill patients including prolonged infusion of β-lactams compared with the current standard of care

An investigation of geometrical defect of cold embossing part utilizing FEM and image processing technique

Accuracy of the forging parts becomes critical as the process depends on many factors. Defect may harm the assembly and tends to affect the performance of the parts. Therefore, it must be understood and detected as soon as the manufacturing begins. The size and complexity of the part limit the defect to be assessed. This study intent to investigate the defect of the cold embossing pin located at the head of a propeller blade. This is to ensure accurate assembly of the blade. In this work, the effects of design and process parameters on the formation of defect are studied using 2-D finite element analysis. The defect can be measured based on the incomplete filling of the region using the captured images from the FE result. The results seem to show that there is less effect from the diameter of punch and internal cavity, but more obvious due to the distance to the edge. The FE results are in good agreement with the experimental results

Intestinal myiasis in a Malaysian patient caused by larvae of Clogmia albipunctatus (Diptera: Psychodidae)

Clogmia albipunctatus (Duckhouse) is a cosmopolitan fly belonging to the family Psychodidae and is one of the medically important insects associated with urban environments ( Smith and Thomas 1979 ). Psychodid larvae can cause myiasis in humans through infestation of healthy or traumatized tissues ( Hall and Smith 1993 ). Human myiasis can be presented in various forms with cutaneous myiasis the most common form ( Tu et al. 2007 ). Other infestation sites include nasal, aural, pulmonary, ophthalmic cavities, body cavities, and the gastrointestinal and urogenital systems ( Tu et al. 2007 , El-Badry et al. 2014 ). Intestinal myiasis may result from accidental ingestion of larvae. Subsequently, this form of myiasis presents symptoms such as nausea, vomiting, abdominal pain and distention, loss of appetite, weight loss, and episodic diarrhea ( Ramana 2012 ). This is the second reported case of human intestinal myiasis in Malaysia caused by larvae of C. albipunctatus . Microscopic examination revealed the structure of the larvae and DNA barcoding established the species identity

Analysis of road accident fatality in malaysia: body part injury

Over the decade, the number of road crashes in Malaysia has kept increasing whilst the number of fatalities has not experienced any dramatic increase, hovering over 6,700 cases yearly. Speeding while driving, fatigue, and reckless driving are the causes of car accidents in Malaysia. The fatality rate of car accidents in this country is high as cars are a means of family transport. This becomes a challenge for this country to reduce the likelihood of road deaths and injuries due to reliance on these vehicles. Moreover, the causes of death in relation to bodily injuries are vaguely discussed. This hampers the vehicles safety programme initiatives meant to prevent accident fatalities. One of the established road safety programmes that highlights the above issue is ASEAN New Car Assessment Programme (NCAP) for verifying compliance with vehicle standards by implementing the NCAP star rating for Malaysian-produced cars. Accordingly, this study was commissioned to evaluate body regions that are the most vulnerable in frontal and/or side collisions. Results showed that head, neck, and chest are the most severely-affected body regions in frontal collisions. As for side collisions, chest is leading the overall results. In line with NCAP, all the above body regions are covered under Adult Occupant Protection (AOP) domain with three main assessments: Offset Frontal Test (OFT); Side Impact Test (SIT); and Head Protection Technology (HPT). Based on the findings, ASEAN NCAP star rating program could ensure manufacturing of safer cars, suitable to current need

Characterization of Enzyme Produced from Pseudomonas Putida for BTX (Benzene, Toluene & Xylene) Treatment in Petrochemical Industry Wastewater System

One of the big challenges in petrochemical industries is waste management. Currently, huge money was spending on the disposal of the waste. Industries are trying hard to find an alternative method to reduce the cost and improve the effectiveness of current waste management including treatment efficiency. Most of petrochemical wastes are containing benzene, toluene and xylene (BTX) which are very harmful to environment and living organisms. Common method used to separate the BTX from the waste are by using liquid-liquid and stripping process. One of the alternative to treat BTX is biological treatment method that used the natural capability of microorganisms to degrade to less harmful product is been applied. Some of examples are Pseudomonas Putida. (P. putida), Rhizobium, and Agrobacterium. P. putida is selected in this study for the biological treatment of BTX in petrochemical wastewater because it can produce an enzyme that has the capability of breakdown the aromatic hydrocarbon to carbon dioxide (CO2) and water (H2O). The main objective of this study is to produce and extract the enzymes produce, characterised the enzymes. This study also to investigate the effect of different concentration on the treatment as well as the growth of the bacteria. The enzyme is purified using salt precipitation and analysed using SDS_PAGE technique. UV-Vis is used to study the growth of the bacteria in the culture stock by measuring its optical density. The concentration of BTX was varied to determine the effect of the concentration on the percentage removal and the growth of P. putida. Enzymes detected or purified in this study was benzene reductase. Other expected enzymes were not able to be purified or analysed. It was found that in this experimental study, the removal of benzene is at 74% to 80%. The removal of toluene is at 62% to 75%. The removal of xylene is at 23% to 42%. Increasing the concentration of contaminants will reduce the removal capabilities

Identification of the genomic mutation in Epha4rb-2J/rb-2J mice

The EphA4 receptor tyrosine kinase is involved in numerous cell-signalling activities during embryonic development. EphA4 has the ability to bind to both types of ephrin ligands, the ephrinAs and ephrinBs. The C57BL/6J-Epha4rb-2J/GrsrJ strain, denoted Epha4rb-2J/rb-2J, is a spontaneous mouse mutant that arose at The Jackson Laboratory. These mutants exhibited a synchronous hind limb locomotion defect or “hopping gait” phenotype, which is also characteristic of EphA4 null mice. Genetic complementation experiments suggested that Epha4rb-2J corresponds to an allele of EphA4, but details of the genomic defect in this mouse mutant are currently unavailable. We found a single base-pair deletion in exon 9 resulting in a frame shift mutation that subsequently resulted in a premature stop codon. Analysis of the predicted structure of the truncated protein suggests that both the kinase and sterile α motif (SAM) domains are absent. Definitive determination of genotype is needed for experimental studies of mice carrying the Epha4rb-2J allele, and we have also developed a method to ease detection of the mutation through RFLP. Eph-ephrin family members are reportedly expressed as numerous isoforms. Hence, delineation of the specific mutation in EphA4 in this strain is important for further functional studies, such as protein–protein interactions, immunostaining and gene compensatory studies, investigating the mechanism underlying the effects of altered function of Eph family of receptor tyrosine kinases on phenotype

Determination of leg injury criteria subjected to frontal impacts

The leg injury criteria subjected to frontal impact is presented and discussed. The aim is to analyze the effect of steel material of bumper shell on pedestrian leg injury criteria of front bumper system. The front bumper beam is made of mild steel and characterized by impact modeling using LS-DYNA V971, according to United States New Car Assessment Program (US-NCAP) frontal impact velocity and based on European Enhanced Vehicle-safety Committee. The most important variable of this structure are mass, material, internal energy, and Leg Injury Criterion (LIC). In order to evaluate the protective performance of the baseline hood, the Finite Element Models (FEM) of legform of an adult pedestrian is used. The result shows that the acceleration of 91.5 g, shear displacement of 4.2 mm and bending angle of 12.0˚ graphs are performing below the danger limit. The reason found to be there were no contact between the front bumper beam and the legform, so that the injury is less. This is shows that the clearance between the bumper shell and front bumper beam are sufficient