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The usage of antibiotics in paediatric patients while admitted to the intensive care unit at a public tertiary hospital

The usage of antibiotics in paediatric patients while admitted to the intensive care unit at a public tertiary hospital Sinyela, Nkhumiseni Background: The overuse and misuse of antibiotics decreases their effectiveness and results in increasing bacterial resistance which is considered an international public health crisis. Antibiotics are one of the most commonly used groups of medicines in peadiatric patients however there are limited data available on the usage of antibiotics in paediatrics globally but especially in South Africa. The aim of this study was to conduct a retrospective review of antibiotics used in paediatric patients in intensive care. Method: This study reviewed antibiotic therapy from patient charts in the Intensive Care Unit at Charlotte Maxeke Johannesburg Academic hospital. The review was done from 15 January 2016 to 15 February 2016 and 15 January 2017 to 15 February 2017. Results: There were 40 files reviewed for 2016 and 55 files for 2017. Most patients (2016: 78% and 2017: 60%) were neonates aged between 0 -3 months. There were 15 antibiotics prescribed in 2016 and 2017 that differed between the two study periods. The most frequently prescribed antibiotics in 2016 were: vancomycin (19%), imipenem (18%), ampicillin (11%) and gentamycin (11%). In comparison in 2017, the most frequently prescribed antibiotics were meropenem (21.7%) vancomycin (20.8%) and co-amoxiclav (11.7%). In both periods majority of patients received two antibiotics as therapy during their ICU stay, 47.5% in 2016 and 40% in 2017. The average numbers of days in ICU were 5 days in 2016 and 4 days in 2017. Diagnosis classifications were similar between the two study periods. Cultures (blood) were ordered in 73% (2016) compared to 75% (2017). C-reactive protein samples were taken from 85% of patients in 2016 and 82% in 2017. In 2017, there were 46.2% (n=36) of doses with a hang time less than 60 minutes and 32.5% (n=26) in 2016. Conclusion: This study showed that most antibiotics were prescribed empirically with imipenem and vancomycin the most used combination antibiotic therapy in 2016, meropenem and vancomycin in 2017. Majority of patients received two antibiotic therapies during their ICU stay. CRP and cultures (blood) were frequently ordered and hang time mostly documented. Prescription of antibiotics was mostly compliant with the unit antibiotic prescription guidelines. A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, in partial fulfillment for the degree of Masters of Science in Medicines: Pharmaceutical Affairs. June 2018.


Investigating a BIR-containing plasmodium falciparum protein and identifying its binding partners

Investigating a BIR-containing plasmodium falciparum protein and identifying its binding partners Liebenberg, Dale The majority of the worldwide malaria deaths are caused by the Plasmodium falciparum parasite and unfortunately parasite strains are emerging that are resistant to not only artemisinin, but also the partner drugs used in current antimalarial combination therapy. The intraerythrocytic P. falciparum life stage is characterised by exponential, asexual proliferation that could cause the premature death of the human host before the sexual gametocytes have had enough time to develop and be taken up by the mosquito vector to continue its lifecycle. It is hypothesised that P. falciparum maintains its population at a level low enough to allow for the transmission of these gametocytes by using a form of regulated cell death (RCD). The molecular members of this cell death pathway are currently unclear, but a putative P. falciparum inhibitor of apoptosis protein (PfIAP; PF3D7_0519600) has previously been identified. Metazoan IAP proteins play anti-apoptotic roles in cells by interacting and inhibiting pro-apoptotic caspases, but also perform other functions. Analysis of the PfIAP protein using bioinformatic tools revealed that it contains one conserved baculoviral IAP repeat (BIR) domain and that this P. falciparum BIR domain is structurally similar to the BIR domains of various human IAP proteins. mRNA extracted from asexual P. falciparum parasites was used to construct a biotin-tagged phage display library, which was used in biopanning experiments with two regions of the PfIAP protein, expressed as recombinant GST-tagged proteins. Four binding partners were identified for the N-terminal BIR domain of the protein, while two proteins were identified as interacting partners for the C-terminal region of PfIAP. Of these, a double C2-like domain-containing protein (PfDOC2) and the high molecular weight rhoptry protein 3 (PfRhopH3) were expressed as recombinant His-tagged proteins and verified as PfIAP binding partners by in vitro binding assays. Transgenic P. falciparum parasites were generated expressing a GFP-tagged PfIAP BIR domain, which localised to the cytoplasm under both normal and high temperature conditions which mimic febrile malaria, a physiological trigger of RCD. Knockout experiments of the pfiap gene using the CRISPR-Cas9 genome editing tool suggested that this gene could be essential for the survival of asexual P. falciparum parasites. This study offers the first details of a putative P. falciparum inhibitor of apoptosis protein and suggests that it could have non-apoptotic roles in the parasite, given the diverse functions of the binding partners that comprise the PfIAP protein-protein network. A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Doctor of Philosophy. Johannesburg, 2018.


The attitudes and opinions of intensive care nurses on the use of physical restraints

The attitudes and opinions of intensive care nurses on the use of physical restraints Maleho, Mabona Ednah Background: Despite the uncertainty over the ability of physical restraints to maintain patient safety, as well as the potential for undesirable psychological and physical patient outcomes and ethical concerns, physical restraints use is still common in many ICUs in different countries. Physical restraints are prescribed by the physician but the ICU nurse remains the decision maker responsible in assessing the need, application and removal of physical restraints on patients in the ICU setting. Purpose of the study: The purpose of this study was to describe nurses’ attitudes and opinions on the use of physical restraints in adult ICUs of a tertiary academic hospital in Johannesburg, with the intention to suggest and create awareness to nurse educators on what needs to be included in the curriculum on topic of physical restraints. This may also provide guidance to policy makers on the best practice that need to be considered when implementing a policy in the clinical setting. Method: A descriptive, non-experimental, quantitative survey design was used. Data was collected using an eighteen (18) item questionnaire developed by Freeman, Hallett and McHugh (2015) titled “Attitudes and opinions of ICU nurses on the use of physical restraints’’. The questionnaire was divided into four sections. Convenience sampling was used and a sample size of 113 was used. Descriptive and comparative statistics were used for data analysis. The statistical test used includes Chi-square test and Fisher’s exact test and testing was set at 5% level of significance Results: Most nurses indicated that there is a need for physical restraints use in the ICU setting in order to provide an environment that is safe for the patient. Physical restraints as a management option were preferred over sedation. There was no consensus about the maximum time that an individual patient can be restraint, agitated behaviors such as pulling of endotracheal tubes and medical devices has been noted as the most reason for exceeding the maximum time that an individual patient can be restraint. Nurses were happy to discuss the use of physical restraints with relatives. There was a perceived need for training on use of physical restraints, availing a written policy on physical restraints and support from the medical staff. There was association between ICU nurses’ years of experience, report on availability of written policy on the use of physical restraints, reports on having training on the application of physical restraints and their attitudes and opinions on the use of physical restraints in some statements regarding such. Conclusion: Nurses need support and guidance from other health care workers in cases of using physical restraints. There is need for availability of physical restraints policy to aid nurses’ clinical decision making. Relevance to clinical Practice: There have to be alternative methods and thorough patient assessment of managing agitated patients before implementation of physical restraints, these methods can be pain management and allowing relatives to be at the patient bed side. Key words: Physical restraints, Attitudes, Opinions, Intensive Care, Nurses, Clinical decision making A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg In partial fulfilment of the requirements for the degree of Master of Science in Nursing. Johannesburg, 2018.


Characterisation of mycobacterial amidases and their role in bacterial growth and physiology

Characterisation of mycobacterial amidases and their role in bacterial growth and physiology Senzani, Sibusiso The genus Mycobacterium represents a complex family containing a number of clinically significant pathogens such as Mycobacterium ulcerans, Mycobacterium leprae and Mycobacterium tuberculosis (Mtb), the latter known to be the etiological agent of tuberculosis (TB). TB remains a global health issue, claiming approximately two million lives annually, with much of this burden being carried in the developing world in countries such as India and South Africa. The emergence of drug-resistant strains of Mtb and the synergistic relationship between TB and HIV/AIDS has crippled efforts to eradicate this disease by rendering many of the current therapeutics ineffective. This has created an urgent need for new drugs with novel modes of action and in this regard, peptidoglycan (PG)-associated enzymes constitute attractive targets for drug development. This study focused on a group of PG hydrolysing enzymes, the N-acetylmuramyl-L-alanine amidases (amidases), which have been linked to a number of essential cellular processes including cell division, antibiotic tolerance and pathogenicity in other organisms. Using the gene sequences of previously characterised cell wall amidases as queries, our bioinformatics analysis revealed that Mtb and Mycobacterium smegmatis contained 4 amidases, designated ami1-ami4. Analysis of an ami1 deficient M. smegmatis strain highlighted a role for this enzyme in cell division, cell elongation, cell shape maintenance and antibiotic tolerance. Deletion of ami1 resulted in the formation of chains consisting of 3 to 8 cells in approximately 20 % of the bacterial population assessed. Growth in these chains was characterised by ectopic mis-localisation of DivIVA, which resulted in the formation of lateral branches and Y-formed cell division. Single-cell localisation of the -sliding clamp (DnaN) and ParB, required for chromosome segregation, revealed that these ectopic branches were able to coordinate chromosome replication and partitioning. Additionally, increased cell permeability was noted in the Δami1 strain, which was associated with increased antibiotic susceptibility. These cell division defects were not observed in the Mtb Δami1 mutant. However, in this case, lateral growth appendages were observed under nutrient limited conditions. Deletion of ami1 in Mtb also resulted in a reduction in bacterial persistence upon challenge with isoniazid. In contrast, loss of ami4 in Mtb did not appear to have an impact on bacterial growth or survival rather, the mutant displayed increased survival under oxidative stress. The ami2 gene has been predicted to be essential, a hypothesis that was confirmed herein through the generation of a merodiploid strain wherein ami2 could be deleted. As such, characterisation of the role of Ami2 was conducted using a previously generated gene depletion strain. Depletion of Ami2 resulted in retarded growth, altered colony morphology, defective sliding motility, the formation of short cells and cells which contain bulges at the pole. Single-cell time lapse microscopy revealed that depletion of ami2 resulted in cessation of growth. Analysis of the localisation pattern of Ami2 revealed a polar localisation pattern, confirming a role for this enzyme in bacterial elongation. Collectively, these data highlight novel, specialist functions for mycobacterial amidases in cell elongation and division. The essentiality of Ami2 for mycobacterial growth also validates this enzyme as a possible drug target for TB. A thesis submitted to the Faculty of Health Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Doctor of Philosophy on medicine. Johannesburg, 2018.


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