Browsing by Subject "Antibiotics"
Now showing 1 - 9 of 9
Results Per Page
Sort Options
- ItemOpen AccessAddressing the ongoing threat of antimicrobial resistance: synthetic investigations of novel amicetin and B-lactam antibiotics(2025) Bhana, Ashlyn; Veale, Clinton; Petersen, WadeAntimicrobial resistance (AMR) poses a significant risk to global health security and threatens to undermine a century of healthcare gains. Within this thesis, we attempt to address the ongoing threat of AMR through performing synthetic investigations of amicetin and novel -lactam therapeutics. Chapter 1 essentially highlights the role and importance of synthesizing complex chiral scaffolds and heterocycles in discovering new antibiotics by providing a brief historical context and background of disease etiology and medicine (chemotherapy), AMR, -lactam antibiotics, heterocyclic chemistry, and green chemistry techniques such as organocatalysis and visible-light photocatalysis, which were utilized to synthesize the relevant compounds described in this study. Chapter 2 provides background on the natural antibiotic, amicetin, and a current literature review on the synthesis of -tertiary amines (ATAs), focusing mainly on the electrophilic amination strategy, which was relevant to this study. Chapter 2 also provides the aims and objectives for Chapter 3. Chapter 3 discusses the results obtained within the first project of this study, namely the attempted synthesis of p-aminobenzoic acid (PABA)--methyl-L-serine substructure of amicetin, from PABA as the starting point. Synthetic access to the PABA--methyl-L-serine moiety would allow for structure-activity relationship (SAR) studies to be performed on the natural antibiotic. This synthetic route involved a Cinchona alkaloid organocatalyzed electrophilic hydrazination of a novel -dicarbonyl system, namely -formylamides (AFAs), with azodicarboxylates. Novel AFAs are synthesized via a Ti-Claisen condensation between methyl formate, a methodology also previously developed within our research group. Unfortunately, due to difficulties encountered within the initial synthetic route and time constraints, we could not reach the PABA--methyl-L-serine end-target. However, the adjusted synthetic route devised to reach the end-target seems highly feasible and forms part of the future work for this project. Instead, we showcased the synthetic utility of our aminated products by functionalizing them into N-amino oxazolidinones and oxazolidinones, which may find applications in asymmetric synthesis. Chapter 4 provides a brief introduction to monobactams and a brief current literature review of the synthesis of 2-azetidinones. Chapter 4 also provides the aims and objectives for Chapter 5. Chapter 5 discusses the results obtained within the second project of this study, namely the synthesis of novel 2-azetidinones via a radical photocyclization of acrylamides enabled by triplet energy transfer visible-light photocatalysis, a methodology which was also previously developed within our research group, and investigation into their antimicrobial activity. Although the preliminary bioactivity data of the synthesized 2-azetidinones against WT Staphylococcus aureus ATCC 49775 was disappointing, it should be noted that the project is still well in its infancy, and further investigation and evaluation is warranted to assess whether the scaffold is worth pursuing for potential antimicrobial activity or other biological applications.
- ItemOpen AccessThe anti-Pseudomonas aeruginosa antibody Panobacumab is efficacious on acute pneumonia in neutropenic mice and has additive effects with meropenem(Public Library of Science, 2013) Secher, Thomas; Fas, Stefanie; Fauconnier, Louis; Mathieu, Marieke; Rutschi, Oliver; Ryffel, Bernhard; Rudolf, MichaelPseudomonas aeruginosa ( P. aeruginosa ) infections are associated with considerable morbidity and mortality in immunocompromised patients due to antibiotic resistance. Therefore, we investigated the efficacy of the anti- P. aeruginosa serotype O11 lipopolysaccharide monoclonal antibody Panobacumab in a clinically relevant murine model of neutropenia induced by cyclophosphamide and in combination with meropenem in susceptible and meropenem resistant P. aeruginosa induced pneumonia. We observed that P. aeruginosa induced pneumonia was dramatically increased in neutropenic mice compared to immunocompetent mice. First, Panobacumab significantly reduced lung inflammation and enhanced bacterial clearance from the lung of neutropenic host. Secondly, combination of Panobacumab and meropenem had an additive effect. Third, Panobacumab retained activity on a meropenem resistant P. aeruginosa strain. In conclusion, the present data established that Panobacumab contributes to the clearance of P. aeruginosa in neutropenic hosts as well as in combination with antibiotics in immunocompetent hosts. This suggests beneficial effects of co-treatment even in immunocompromised individuals, suffering most of the morbidity and mortality of P. aeruginosa infections.
- ItemOpen AccessAntibiotic stewardship ward rounds and a dedicated prescription chart reduce antibiotic consumption and pharmacy costs without affecting inpatient mortality or re-admission rates(Public Library of Science, 2013) Boyles, Tom H; Whitelaw, Andrew; Bamford, Colleen; Moodley, Mischka; Bonorchis, Kim; Morris, Vida; Rawoot, Naazneen; Naicker, Vanishree; Lusakiewicz, Irena; Black, JohnBACKGROUND: Antibiotic consumption is a major driver of bacterial resistance. To address the increasing burden of multi-drug resistant bacterial infections, antibiotic stewardship programmes are promoted worldwide to rationalize antibiotic prescribing and conserve remaining antibiotics. Few studies have been reported from developing countries and none from Africa that report on an intervention based approach with outcomes that include morbidity and mortality. METHODS: An antibiotic prescription chart and weekly antibiotic stewardship ward round was introduced into two medical wards of an academic teaching hospital in South Africa between January-December 2012. Electronic pharmacy records were used to collect the volume and cost of antibiotics used, the patient database was analysed to determine inpatient mortality and 30-day re-admission rates, and laboratory records to determine use of infection-related tests. Outcomes were compared to a control period, January-December 2011. RESULTS: During the intervention period, 475.8 defined daily doses were prescribed per 1000 inpatient days compared to 592.0 defined daily doses/1000 inpatient days during the control period. This represents a 19.6% decrease in volume with a cost reduction of 35% of the pharmacy's antibiotic budget. There was a concomitant increase in laboratory tests driven by requests for procalcitonin. There was no difference in inpatient mortality or 30-day readmission rate during the control and intervention periods. CONCLUSIONS: Introduction of antibiotic stewardship ward rounds and a dedicated prescription chart in a developing country setting can achieve reduction in antibiotic consumption without harm to patients. Increased laboratory costs should be anticipated when introducing an antibiotic stewardship program.
- ItemOpen AccessBacterial disease and antimicrobial susceptibility patterns in HIV-infected, hospitalized children: a retrospective cohort study(Public Library of Science, 2008) Jaspan, Heather B; Huang, Lyen C; Cotton, Mark F; Whitelaw, Andrew; Myer, LandonBACKGROUND: Serious bacterial infections are a major source of morbidity and mortality in HIV-infected children. The spectrum of disease is wide, and responsible organisms vary according to setting. The use of antibiotic prophylaxis and the emergence of multi-drug resistant bacteria necessitate examination of responsible organisms and their antibiotic susceptibility. METHODOLOGY/PRINCIPAL FINDINGS: A retrospective cohort study of all HIV-positive pediatric admissions at an urban public sector hospital in Cape Town between January 2002 and June 2006 was conducted. Children between the ages of one month and nine years with laboratory confirmed HIV status, serious bacterial infection, and a hospital length of stay of 5 days or more, were eligible for inclusion. Organisms isolated from blood, urine, and cerebral spinal fluid cultures and their antimicrobial susceptibility were examined, and compared according to timing of isolation to distinguish nosocomial versus community-acquired. One hundred and forty-one children were identified (median age 1.2 years), 39% of whom were on antiretrovirals started before or during this hospitalization. Bacterial infections involved all organ systems, however pneumonia was most common (67%). S. pneumoniae and S. aureus were the most common gram positive and K. pneumoniae was the most common gram negative organism. K pneumoniae isolates were resistant to many first and second line antibiotics, and were all considered nosocomial. All S. aureus isolates were methicillin resistant, some of which were community-acquired. Conclusions/Significance Bacterial infections are an important source of co-morbidity in HIV-infected children in resource-limited settings. Clinicians should have a low threshold to initiate antibiotics in children requiring hospitalization. Broad-spectrum antibiotics should be used judiciously. Clinicians caring for HIV-infected children should be cognizant of the most common organisms affecting such children, and of their local antimicrobial susceptibilities, when treating empirically for serious bacterial infections.
- ItemOpen AccessEpidemiology of Staphylococcus aureus bacteraemia at a tertiary children's hospital in Cape Town, South Africa(Public Library of Science, 2013) Naidoo, Reené; Nuttall, James; Whitelaw, Andrew; Eley, BrianBACKGROUND: Staphylococcus aureus is an important pathogen in paediatric patients with bloodstream infections. The epidemiology of S. aureus bacteraemia, however, has not been well documented in children in South Africa. METHODS: A retrospective study was conducted at a children's hospital in Cape Town, South Africa, to investigate the epidemiology of S. aureus bacteraemia from 2007-2011. The incidence, clinical presentation, risk factors, management and outcomes of methicillin sensitive S. aureus (MSSA) and methicillin resistant S. aureus (MRSA) bacteraemia were compared. RESULTS: Over the five year study period, 365 episodes of S. aureus bacteraemia were identified. The annual incidence was 3.28 cases per 1000 hospital admissions. MRSA was responsible for 26% of S. aureus bacteraemia and 72% of nosocomial infections. Only six possible cases of community-acquired MRSA infections were described. MSSA bacteraemia was more likely to present as pulmonary and bone or joint infections, while bacteraemia without a source was the most common presentation with MRSA. Infants, children with malnutrition, and residents of long-term care facilities were at highest risk for MRSA bacteraemia. The overall case fatality rate for S. aureus bacteraemia was 8.8% over five years, with MRSA being the only significant risk factor for mortality. CONCLUSION: The incidence of S. aureus bacteraemia and MRSA bacteraemia in children has remained stable over the past five years. MRSA is a predominantly nosocomial pathogen in children with S. aureus bacteraemia in Cape Town, South Africa.
- ItemOpen AccessICU-Associated Acinetobacter baumannii Colonisation/Infection in a High HIV-Prevalence Resource-Poor Setting(Public Library of Science, 2012) Ntusi, Ntobeko B A; Badri, Motasim; Khalfey, Hoosain; Whitelaw, Andrew; Oliver, Stephen; Piercy, Jenna; Raine, Richard; Joubert, Ivan; Dheda, KeertanBACKGROUND: There are hardly any data about the incidence, risk factors and outcomes of ICU-associated A.baumannii colonisation/infection in HIV-infected and uninfected persons from resource-poor settings like Africa. METHODS: We reviewed the case records of patients with A.baumannii colonisation/infection admitted into the adult respiratory and surgical ICUs in Cape Town, South Africa, from January 1 to December 31 2008. In contrast to colonisation, infection was defined as isolation of A.baumannii from any biological site in conjunction with a compatible clinical picture warranting treatment with antibiotics effective against A.baumannii . RESULTS: The incidence of A.baumannii colonisation/infection in 268 patients was 15 per 100 person-years, with an in-ICU mortality of 26.5 per 100 person-years. The average length of stay in ICU was 15 days (range 1-150). A.baumannii was most commonly isolated from the respiratory tract followed by the bloodstream. Independent predictors of mortality included older age (p = 0.02), low CD4 count if HIV-infected (p = 0.038), surgical intervention (p = 0.047), co-morbid Gram-negative sepsis (p = 0.01), high APACHE-II score (p = 0.001), multi-organ dysfunction syndrome (p = 0.012), and a positive blood culture for A.baumannii (p = 0.017). Of 21 A.baumannii colonised/infected HIV-positive persons those with clinical AIDS (CD4<200 cells/mm 3 ) had significantly higher in-ICU mortality and were more likely to have a positive blood culture. Conclusion In this resource-poor setting A.baumannii infection in critically ill patients is common and associated with high mortality. HIV co-infected patients with advanced immunosuppression are at higher risk of death.
- ItemOpen AccessOutbreak of multi-drug resistant Pseudomonas aeruginosa bloodstream infection in the haematology unit of a South African academic hospital(Public Library of Science, 2013) Mudau, Maanda; Jacobson, Rachael; Minenza, Nadia; Kuonza, Lazarus; Morris, Vida; Engelbrecht, Heather; Nicol, Mark P; Bamford, ColleenObjective: To describe an outbreak of multi-resistant Pseudomonas aeruginosa bloodstream infections (MRPA-BSI) that occurred in the haematology ward of a tertiary academic hospital in Cape Town, South Africa, and determine risk factors for acquisition of MRPA-BSI. METHODS: The outbreak investigation included a search for additional cases, review of patient records, environmental and staff screening, molecular typing using pulsed-field gel electrophoresis (PFGE) and Multi-locus sequencing (MLST) and a retrospective case-control study. RESULTS: Ten MRPA-BSI cases occurred in the haematology ward between January 2010 and January 2011. The case fatality rate was 80%. Staff screening specimens were negative for MRPA and an environmental source was not identified. PFGE showed that 9/10 isolates were related. MLST showed that 3 of these 9 isolates belonged to Sequence type (ST) 233 while the unrelated isolate belonged to ST260. CONCLUSION: We have described an outbreak of MRPA-BSI occurring over an extended period of time among neutropenic haematology patients. Molecular typing confirms that the outbreak was predominantly due to a single strain. The source of the outbreak was not identified, but the outbreak appears to have been controlled following intensive infection control measures.
- ItemOpen AccessStreptococcus pneumoniae Serotypes and Mortality in Adults and Adolescents in South Africa: Analysis of National Surveillance Data, 2003 - 2008(Public Library of Science, 2015) Cohen, Cheryl; Naidoo, Nireshni; Meiring, Susan; de Gouveia, Linda; van Mollendorf, Claire; Walaza, Sibongile; Naicker, Preneshni; Madhi, Shabir A; Feldman, Charles; Klugman, Keith P; Dawood, Halima; von Gottberg, Anne; GERMS-SABACKGROUND: An association between pneumococcal serotypes and mortality has been suggested. We aimed to investigate this among individuals aged ≥15 years with invasive pneumococcal disease (IPD) in South Africa. METHODS: IPD cases were identified through national laboratory-based surveillance at 25 sites, pre-pneumococcal conjugate vaccine (PCV) introduction, from 2003-2008. We assessed the association between the 20 commonest serotypes and in-hospital mortality using logistic regression with serotype 4 (the third commonest serotype with intermediate case-fatality ratio (CFR)) as referent. RESULTS: Among 3953 IPD cases, CFR was 55% (641/1166) for meningitis and 23% (576/2484) for bacteremia (p<0.001). Serotype 19F had the highest CFR (48%, 100/207), followed by serotype 23F (39%, 99/252) and serotype 1 (38%, 246/651). On multivariable analysis, factors independently associated with mortality included serotype 1 (OR 1.9, 95%CI 1.1-3.5) and 19F (OR 2.9, 95%CI 1.4-6.1) vs. serotype 4; increasing age (25-44 years, OR 1.8, 95%CI 1.0-3.0; 45-64 years, OR 3.6, 95%CI 2.0-6.4; ≥65 years, OR 5.2, 95%CI 1.9-14.1; vs. 15-24 years); meningitis (OR 4.1, 95%CI 3.0-5.6) vs. bacteremic pneumonia; and HIV infection (OR1.7, 95%CI 1.0-2.8). On stratified multivariate analysis, serotype 19F was associated with increased mortality amongst bacteremic pneumococcal pneumonia cases, while no serotype was associated with increased mortality in meningitis cases. CONCLUSION: Mortality was increased in HIV-infected individuals, which may be reduced by increased antiretroviral therapy availability. Serotypes associated with increased mortality are included in the 10-and-13-valent PCV and may become less common in adults due to indirect effects following routine infant immunization.
- ItemOpen AccessThe skin microbiome: impact of modern environments on skin ecology, barrier integrity, and systemic immune programming(2017) Prescott, Susan L; Larcombe, Danica-Lea; Logan, Alan C; West, Christina; Burks, Wesley; Caraballo, Luis; Schoeman, Johan; Etten, Eddie Van; Horwitz, Pierre; Kozyrskyj, Anita; Campbell, Dianne ESkin barrier structure and function is essential to human health. Hitherto unrecognized functions of epidermal keratinocytes show that the skin plays an important role in adapting whole-body physiology to changing environments, including the capacity to produce a wide variety of hormones, neurotransmitters and cytokine that can potentially influence whole-body states, and quite possibly, even emotions. Skin microbiota play an integral role in the maturation and homeostatic regulation of keratinocytes and host immune networks with systemic implications. As our primary interface with the external environment, the biodiversity of skin habitats is heavily influenced by the biodiversity of the ecosystems in which we reside. Thus, factors which alter the establishment and health of the skin microbiome have the potential to predispose to not only cutaneous disease, but also other inflammatory non-communicable diseases (NCDs). Indeed, disturbances of the stratum corneum have been noted in allergic diseases (eczema and food allergy), psoriasis, rosacea, acne vulgaris and with the skin aging process. The built environment, global biodiversity losses and declining nature relatedness are contributing to erosion of diversity at a micro-ecological level, including our own microbial habitats. This emphasises the importance of ecological perspectives in overcoming the factors that drive dysbiosis and the risk of inflammatory diseases across the life course.