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Ventilator-associated pneumonia remains commonplace in critically ill patients and is associated with an increased morbidity and mortality. Multidrug-resistant Gram-negative bacillary pathogens, such as Pseudomonas aeruginosa, are commonly implicated in the pathogenesis of ventilator-associated pneumonia. Increasing rates of antibiotic resistance have led to increasing interest in repurposing old antibiotics with alternative administration methods and the development of new antibiotics that have activity against these multidrug-resistant isolates. Moreover, ensuring that the optimal dose is used is of paramount importance to improve patient outcomes and prevent resistance emergence to these novel antibiotic therapies. Amikacin, an aminoglycoside antibiotic, is of interest in the management of ventilator-associated pneumonia given that it retains activity in up to 70% of multi-drug resistant P. aeruginosa isolates. However, amikacin penetrates poorly into the infection site in patients with ventilator-associated pneumonia, resulting in subtherapeutic exposures when administered intravenously. Therefore, there has been renewed interest in dosing for innovative administration methods, such as inhaled dosing for direct drug delivery to the site of infection. Alternatively, new agents such as ceftolozane/tazobactam, have been developed and are increasingly used clinically, particularly for multidrug-resistant P. aeruginosa. However, a paucity of pharmacodynamic studies exist to assist clinicians with prescribing a dose that both increases the probability of treatment success and minimises the emergence of resistance. Therefore, the primary aims of this thesis are to describe the infection site pharmacodynamics of amikacin and ceftolozane/tazobactam against P. aeruginosa, to determine the likely dosing strategies for both agents that will achieve maximal bacterial killing and minimise the risk of resistance emerging. A series of in vitro studies and in silico simulations, Thesis (PhD Doctorate), Doctor of Philosophy (PhD), School of Medicine & Dentistry, Griffith Health, Full Text

Full Text, Thesis (PhD Doctorate), Doctor of Philosophy (PhD), School of Pharmacy & Med Sci, Griffith Health, The placenta is a transient organ, essential for the growth and development of the fetus throughout pregnancy. This temporary organ brings maternal and fetal blood circulation into close proximity, which allows for the exchange of oxygen, carbon dioxide, waste, and other essential nutrients. Despite constant influences by internal and external factors, the human placenta has a defined life span of approximately 280 days. From conception, through to term, the placenta undergoes chronological aging, which is regulated by a range of cellular processes. Advanced placental aging and cellular senescence have been known to contribute to the pathophysiology of preterm birth, fetal growth restriction and may cause an increased risk of stillbirth. However, the molecular mechanisms behind placental aging are still poorly understood. As a key regulator of cell homeostasis, mitochondria have been recognised as an important mediator of age-related disease processes through the production of reactive oxygen species which activate mechanisms that induce cellular senescence. Currently, we do not understand the molecular link between cellular aging processes and the role of mitochondria in chronological and pathological placental aging. Therefore, this research aimed to, 1) identify key areas of mitochondrial physiology that change with placental development, 2) characterise a set of markers that define aging in the human placenta, 3) assess the role of the mitochondria in the placenta as it develops throughout a healthy pregnancy, 4) to measure the chosen markers of aging in placentas complicated by pregnancy pathologies. Chapter 1 presents a comprehensive review of the literature to date and highlights key gaps in our current knowledge. It sets the scene for the experimental chapters to follow. Chapter 2 provides the details of the methods and materials that have been used in the laboratory to generate the data presented in the results chapters. Chapter 3 explored the molecular cha

Objective: Stillbirth investigations incur healthcare costs, but these investigations are necessary to provide information that will help reduce the risk of a recurrent stillbirth, as well as advice regarding family planning and future pregnancies. The aims of this study were to determine the healthcare costs of investigations for stillbirths, identify drivers and assess cost differences between explained and unexplained stillbirths. Methods: Data from 697 stillbirths were extracted from the Stillbirth Causes Study covering the period 2013-18. The dataset comprised all investigations related to stillbirth on the mother, baby and placenta. Unit costs applied were sourced from the Australian Medicare Benefits Schedule, local hospital estimates and published literature. Multivariable regression analyses were used to assess key factors in cost estimates. Results: In all, 200 (28.7%) stillbirths were unexplained and 76.8% of these had between five and eight core investigations. Unexplained stillbirths were twice as likely to have eight core investigations as explained stillbirths (16.5% vs 7.7%). The estimated aggregated cost of stillbirth investigations for 697 stillbirths was A$2.13 million (mean A$3060, median A$4246). The main cost drivers were autopsies or cytogenetic screening. Mean costs were similar when stillbirths had known or unknown causes and by reason for stillbirth among cases with definable causes. Conclusion: Investigations for stillbirth in Australia cost approximately A$4200 per stillbirth on average and are critical for managing future pregnancies and preventing more stillbirths. These findings improve our understanding of the costs that may be averted if stillbirths can be prevented through primary prevention initiatives. What is known about the topic?: Approximately 2000 stillbirths occur each year in Australia, and this trend has not changed for several decades. Stillbirth investigations incur healthcare costs, but these investigations are neces

To characterise the demographic and clinical characteristics of women who died by suicide in the perinatal period to inform and improve suicide prevention strategies. Retrospective analysis of maternal suicides during and within 1 year after the end of pregnancy in Queensland between January 2004 and December 2017. Outcomes measured included timing of death in relation to pregnancy, sociodemographic and clinical characteristics and health service use prior to death. There were 65 deaths by suicide in the study period; six occurred during pregnancy, 30 occurred after a live birth, 22 occurred after a termination of pregnancy and seven followed a miscarriage or stillbirth. Most suicides were late maternal deaths. Women were younger, and more likely to identify as Aboriginal or Torres Strait Islander, when compared to all women giving birth for the same time period. Most women had a prior mental health diagnosis, most commonly depression. Over half of women had recent relationship separation or conflict prior to death. Perinatal women had higher rates of death by violent means than all women in Queensland who died by suicide during the same time period. The demographic, psychosocial and clinical characteristics of a group of women who died by suicide have been described, and this shows a high proportion of women with a prior mental health diagnosis. To reduce maternal mortality, psychosocial screening must be implemented broadly and continued until the end of the first year postpartum. Similar screening attention is needed for women who had a termination of pregnancy, miscarriage or stillbirth.

Background The United States (US) spends more on health care than any other high‐resource country. Despite this, their maternal and newborn outcomes are worse than all other countries with similar levels of economic development. Our purpose was to describe maternal and newborn outcomes and organization of care in four high‐resource countries (Australia, Canada, the Netherlands, and United Kingdom) with consistently better outcomes and lower health care costs, and to identify opportunities for emulation and improvement in the United States. Method We examined resources that described health care organization and financing, provider types, birth settings, national, clinical guidelines, health care policies, surveillance data, and information for consumers. We conducted interviews with country stakeholders representing the disciplines of obstetrics, midwifery, pediatrics, neonatology, epidemiology, sociology, political science, public health, and health services. The results of the analysis were compared and contrasted with the US maternity system. Results The four countries had lower rates of maternal mortality, low birthweight, and newborn and infant death than the United States. Five commonalities were identified as follows: (1) affordable/ accessible health care, (2) a maternity workforce that emphasized midwifery care and interprofessional collaboration, (3) respectful care and maternal autonomy, (4) evidence‐based guidelines on place of birth, and (5) national data collections systems. Conclusions The findings reveal marked differences in the other countries compared to the United States. It is critical to consider the evidence for improved maternal and newborn outcomes with different models of care and to examine US cultural and structural failures that are leading to unacceptable and substandard maternal and infant outcomes.

Objective: Develop a core outcome set of international consensus definitions for severe maternal morbidities. Design: Electronic Delphi study. Setting: International. Population: Eight expert panels. Methods: All 13 high-income countries represented in the International Network of Obstetric Surveillance Systems (INOSS) nominated five experts per condition of morbidity, who submitted possible definitions. From these suggestions, a steering committee distilled critical components: eclampsia: 23, amniotic fluid embolism: 15, pregnancy-related hysterectomy: 11, severe primary postpartum haemorrhage: 19, uterine rupture: 20, abnormally invasive placentation: 12, spontaneous haemoperitoneum in pregnancy: 16, and cardiac arrest in pregnancy: 10. These components were assessed by the expert panel using a 5-point Likert scale, following which a framework for an encompassing definition was constructed. Possible definitions were evaluated in rounds until a rate of agreement of more than 70% was reached. Expert commentaries were used in each round to improve definitions. Main outcome measures: Definitions with a rate of agreement of more than 70%. Results: The invitation to participate in one or more of eight Delphi processes was accepted by 103 experts from 13 high-income countries. Consensus definitions were developed for all of the conditions. Conclusion: Consensus definitions for eight morbidity conditions were successfully developed using the Delphi process. These should be used in national registrations and international studies, and should be taken up by the Core Outcomes in Women's and Newborn Health initiative. Tweetable abstract: Consensus definitions for eight morbidity conditions were successfully developed using the Delphi process.