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>Magister Scientiae - MSc / Combating antimicrobial resistant infections caused by nosocomial pathogens poses a major public health problem globally. The widespread use of broad-spectrum antibiotics for the treatment of wound infections has led to the appearance of multidrug-resistant (MDR) microbes which further exacerbates the growth of microbes amongst patients. It may result in prolonged debility of the patient and an increase in healthcare costs due to prolonged hospital stays and expensive treatment regimens to avoid patient-patient transmission. Therefore, it is imperative that alternative sources of treatment to antimicrobial use in wound infections needs to be developed in order to inhibit or kill resistant microbes and to provide point of care medical treatment to the less fortunate at an affordable cost. / 2021-08-30

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Increased prevalence of antimicrobial resistance, treatment failure, and financial losses have been reported in dairy cattle with coagulase-negative Staphylococcus (CoNS) clinical mastitis. However, studies on CoNS are limited in South Africa. Therefore, the objectives of this study were to investigate the antimicrobial resistance patterns and biofilm formation in CoNS isolated from cow milk samples submitted to the Onderstepoort Milk Laboratory. A total of 142 confirmed CoNS isolates were used for this study. Isolates were subjected to the tissue culture plate method for biofilm formation testing and antimicrobial susceptibility testing against a panel of 11 antimicrobials using the disk diffusion method. Biofilm formation was identified in 18% of CoNS tested. Staphylococcus chromogenes (11%) had the highest proportion of biofilm formation followed by S. haemolyticus 4.0% and S. epidermidis, S. hominis, S. xylosus, and S. simulans with 1% respectively. Ninety percent (90%) of CoNS isolates were resistant to at least one antimicrobial (AMR) and 51% were multidrug-resistant (MDR). Resistance among CoNS was the highest to ampicillin (90%) and penicillin (89%), with few isolates resistant to cefoxitin and vancomycin, 9% respectively. The most common resistance patterns among the CoNS was penicillin-ampicillin (16%) and penicillin-ampicillin-erythromycin (10%). Forty-two percent (42%) of biofilm positive CoNS were MDR. At the species level, MDR was common among S. epidermis (65%), S. chromogenes (52%) and S. haemolyticus (44%). In conclusion, biofilm formation was uncommon among the MDR-CoNS isolates in this study suggesting that biofilm formation is not a major contributing factor to antimicrobial resistance in this study. In addition, most CoNS isolates in this study were _-lactams resistant. This is concerning as penicillins are used commonly by dairy farmers in treatment of mastitis in South Africa. Nonetheless, the role of antimicrobial use practice in the development of resistance in subclinical mastitis in the dairy industry should be investigated. / Dissertation (MSc)--University of Pretoria, 2019. / Paraclinical Sciences / MSc / Unrestricted

Background: Antimicrobial resistance (AMR) is a global public health challenge since infection with resistant organisms may cause death, can spread across the community, and increase health care costs at individual, community and government level as more expensive antimicrobials will have to be made available for the treatment of infections caused by resistant bacteria. This calls for urgent and consolidated efforts in order to effectively curb this growing crisis, to prevent the world from slipping back to the pre-antibiotic era. The World Health Organization made a call in 2011 advocating for strengthening of surveillance and laboratory capacity as one-way of detecting and monitoring trends and patterns of emerging AMR. Knowledge of AMR guides clinical decisions regarding choice of antimicrobial therapy, during an episode of bacteraemia and forms the basis of key strategies in containing the spread of resistant bacteria. The current study focused on Staphylococcus aureus (SA), Klebsiella pneumoniae (KP), and Pseudomonas aeruginosa (PA), as they are common hospital acquired infections which are prone to developing resistance to multiple antibiotics. Aim: The aim of this project was to assess and utilize the laboratory information system (LIS) at the National Health Laboratory Services (NHLS), as a tool for reporting AMR and monitoring resistance patterns and trends over time of clinical isolates of SA, KP and PA, cultured from the blood of patients admitted to seven tertiary public hospitals in three provinces in South Africa. Methods: A retrospective and prospective analysis was done on isolates of SA, KP, PA from blood specimens collected from patients with bacteraemia and submitted to diagnostic microbiology laboratories of the NHLS at seven tertiary public hospitals in three provinces in South Africa. These hospitals comprised the Charlotte Maxeke Johannesburg Academic Hospital (CMJAH), Chris Hani Baragwanath Hospital (CBH), Helen Joseph Hospital (HJH), Steve Biko Pretoria Academic Hospital (SBPAH), Groote Schuur Hospital (GSH), Tygerberg Hospital (TH) and the Universitas Hospital of the Free State (UH). For retrospective analysis, data submitted during the period July 2005 to December 2009 were used and for prospective analysis, data relating to AMR in SA, KP, PA, collected by the Group for Enteric, Respiratory and Meningeal disease Surveillance in South Africa, (GERMS-SA) from July 2010 to June 2011 were used. AMR in these three pathogens to commonly used antimicrobial drugs was systematically investigated. Multivariate logistic regressions models were used to assess factors associated with AMR. In addition, a systematic review of research done to date on AMR in bacterial pathogens commonly associated with hospital-acquired infections was conducted in order to understand the existing antimicrobial surveillance systems and baseline resistance patterns in South Africa. Results: A total of 9969 isolates were reported from the retrospective dataset. These were 3942 (39.5%) SA, 4466 (44.8%) KP and 1561 (15.7%) PA. From the prospective dataset, a total of 3026 isolates were reported, 1494 (49.4%) SA and 1532 (50.6%) KP isolates respectively. The proportion of invasive bacteraemia was higher in the <5 year old children. Nearly all strains of SA in South Africa were resistant to penicillin, and >30% up to as high as 80% were resistant to methicillin-related drugs among~560 invasive SA isolates over the two year period. Methicillin resistant Staphylococcus aureus (MRSA) rates significantly differed between hospitals (p=<0.001). The proportion of MRSA isolates in relation to methicillin-susceptible strains showed a declining trend from 22.2% in 2005 to 10.5% in 2009 (p=0.042). Emerging resistance was observed for vancomycin: 1 isolate was identified in 2006 and 9 isolates between July 2010-June 2011, and all except 1 were from Gauteng hospitals. The study found increasing rates of carbapenem-resisant KP of 0.4% in 2005 to 4.0% in 2011 for imipenem. The mean rate of extended spectrum beta lactamase (ESBL-KP) producing KP was 74.2%, with the lowest rate of 62.4% in SBPAH and the highest rate of 81.3% in UH, showing a significant geographical variation in rates of resistance (p=0.021). PA showed a tendency for multi-drug resistance with resistance rates of >20% to extended spectrum cephalosporins, fluoroquinolones and aminoglycosides respectively. Emerging resistance in PA isolates was observed to colistin, showing a resistance rate of 1.9% over the 5 years period. In the multivariate model, age <5 years, male gender, and hospital location were factors significantly associated with MRSA, while ESBL-KP was significantly associated with age <5 years and hospital location. Concluding remarks: The study has clearly demonstrated that AMR is relatively common in South Africa among children <5 years. Enhancement of continued surveillance of nosocomial infections through use of routine laboratory data should be reinforced as this will facilitate effective interpretation and mapping of trends and patterns of AMR. Therefore, the LIS as a tool for gathering such data should be strengthened to provide reliable AMR data for improved understanding of the extent of the AMR, and present evidence on which future policies and practices aimed at containing AMR could be based. Key words: Laboratory information system, Trends, Patterns, Antimicrobial resistance, Bacterial pathogens, Nosocomial infections, Surveillance, Bacteraemia, Blood culture.

The increase of antibiotic resistance against antibiotics (AB) is an alarming phenomenon threatening the human well being and heading back to the pre-antibiotic era where many infectious diseases may become again untreatable with antibiotics. There is a strong correlation between AB use and occurrence of resistances which suggests anthropogenically-driven environments as reservoirs of antibiotic resistant bacteria (ARB). Among anthropogenically - driven environments, wastewater treatment plants (WWTPs), have been linked with the increased incidence of pathogens and ARB in freshwater ecosystems. Principal goal of the study was to evaluate the role of WWTPs as environmental reservoirs for antibiotic resistance and pathogenic bacteria. In this thesis, classical and molecular microbiology methods were applied to analyse resistance levels of bacterial communities from wastewater and wastewater-polluted environments at different geographical locations of developed (German and Switzerland) and developing (Nigeria) countries. Additionally, a novel approach which makes use of a combination of quantitative genomics, Next Generation Sequencing and drug-related health data was applied to quantitatively detect antibiotic resistance genes (ARG) in wastewater and assess their seasonal dynamics. The relative abundance of ARG was not reduced by the WWTPs in the treated effluent. Effluents were responsible for significantly high levels of ARB and ARG in the receiving environment because capable of introducing and/or selecting ARB carrying ARG on genetic mobile elements. The ARG levels differed between seasons independently from the water sanitation. High ARG levels were displayed in autumn and winter in coincidence with the higher uptake of antibiotics by the outpatients of the municipality.Contrary to the ARG, the abundance of bacteria was reduced by WWTPs processes in the effluent of developed countries. The WWTPs were also responsible for the changes of the microbial community from the wastewater to the effluent. Contrary to developed countries, the poor treatment of wastewater in Nigeria facilitated the spread of multi-drug resistant pathogens in the freshwater ecosystem. These bacteria were also carriers of clinically relevant ARG contributing to the accumulation of multiresistant pathogens in the environment. All in all, this thesis shows that well established WWTP technologies are not capable to prevent or reduce the abundance of ARG in the freshwater ecosystem and poorly treated wastewater enriches the environmental reservoirs of ARG. Antibiotic resistance can spread across taxonomically distant bacteria and therefore explain the strong dispersal of ARG in wastewater effluents. These results show that antibiotic resistances are also ubiquitous in the freshwater environment and that anthropogenically - driven environments determine the incidence of antibiotic resistance. As for the clinic, tackling the problem of antibiotic resistance in the environment is fundamental. Without any action, the environmental reservoirs of resistance will increase and therapeutic failure in the clinic will irreversibly compromise the biggest progress in medicine of the 20th century.

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ACKNOWLEDGEMENTS I would like to take this moment to extend my utmost appreciation for all the support provided by my supervisor, Dr. Russell de Souza. He assisted me along the way and ensured that I was always on the right path to achieve all my goals and checkpoints in every circumstance. I would also like to thank my committee for providing me with fantastic support: Ms. Laura Banfield for always being there to help solve any problem in this process, and Dr. Zain Chagla for providing a plethora of knowledge from the technical perspective of infectious disease and being so patient. Special thanks to Dr. Alexandra Mayhew for her support in our prevalence meta-analysis. Finally, I would like to thank my family, my wife, Dr. Sanjida Rowshan Anannya, for whom I am here today, and my parents, siblings, and in-laws; you are always there for me in every walk of life. You are why I have gotten to where I am today and are my daily inspiration. / Background: Bacteria is a major cause of many infectious diseases, and the treatment for these diseases is antibiotics designed to kill or subdue the growth of the bacteria. However, bacteria evolve, and if an antibiotic prescription is not the right antibiotic for the right patient at the right time with the correct dose and the right route, Antimicrobial Resistance (AMR) may result. During this pandemic, the use of antibiotics to treat hospitalized COVID-19 patients without any bacterial coinfection threatens the effectiveness of antibiotic treatment for current and future bacterial infections. Methods: A systematic search was conducted of the Embase, Medline, Web of Science, and Cochrane Library databases by generating search terms using the concepts of “COVID-19,” “Bacterial Coinfection,” “Secondary bacterial infection,” and “Antimicrobial resistance” to identify studies that reported the prevalence of antibiotic prescription for the treatment of COVID-19 in hospitalized patients with and without bacterial coinfection. The pooled estimate of the percentage of the total and confirmed appropriate antibiotic prescriptions provided to hospitalized COVID-19 patients was generated using a random effect meta-analysis with inverse variance weighting. Result: Of 157,623 participants from 29 studies included in our review, 67% (CI 64% to 71%, P<0.00001) were prescribed antibiotics, among which 80% (CI 76% to 83%, P<0.00001) prescriptions were given for the COVID-19 patients without any bacterial coinfections. The use of antibiotics varied during the pre-immunosuppressive period (before 16 June 2020) and post-immunosuppressive period of the pandemic and between the High-Income Countries and Upper and Lower Middle-Income Countries. Conclusion: This Systematic Review and Meta-analysis finds greater than expected use of antibiotics to treat hospitalized COVID-19 patients without bacterial coinfections, which can worsen AMR globally. Clear and concrete guidelines for the use of antibiotic prescriptions to treat COVID-19 patients, strict monitoring, and compliance with Antimicrobial Stewardship are needed to prevent over-prescription. / Thesis / Master in Advanced Studies (MAS) / Bacteria is a major cause of many infectious diseases. Before the discovery of Antibiotics in 1928, hundreds of thousands of people used to die due to infectious diseases caused by bacteria. While Antibiotics are essential to treat bacterial infectious diseases, overuse or misuse can accelerate Antibiotic Resistance, a phenomenon when bacteria change and/or develop the ability to escape the drugs designed to kill them. Self-medication, availability of antibiotics without a prescription, and inappropriate dosing of antibiotics can worsen the situation. During the COVID-19 pandemic, antibiotics were commonly prescribed as part of the treatment regime for COVID-19, even when a clear bacterial infection was not identified. In our Systematic Review and Meta-analysis, we aimed to see the frequency of antibiotic prescriptions to treat hospitalized COVID-19 patients without any bacterial coinfections.

Abstract Background: Surgical site infections (SSIs) remain a challenge for the healthcare system. During the last 30 years, the literature has shown an increase of gram-negative bacterial strains in multiple infectious sites and that cephalosporins have replaced penicillin as the gold standard in peri-operative antibiotic prophylaxis. This study aims to examine the recent bacterial spectrum in orthopedic early SSIs and to compare it with a historical cohort. Patients and Methods: Patients in a level 1 trauma center with an SSI within six weeks after open fixation of a fracture were analyzed in two adjacent periods from 2007 to 2012 (data pool 1; DP1) and 2013 to 2017 (data pool 2; DP2), retrospectively. The detected microbiologic pathogens and the associated resistograms from both time periods were compared. Results: Six hundred eighty-one smear tests and respective pathogens from the wounds of 463 patients (mean age, 62.6 – 20 years) with SSIs were analyzed. The following pathogens were found most frequent: Staphylococcus epidermidis (DP1, 20.6%; DP2, 26.3%), Staphylococcus aureus (DP1, 27.1%; DP2, 16.5%), Enterococcus faecalis (DP1, 13.7%; DP2, 11.1%), Bacillus sp. (DP1, 3.0%; DP2, 5.3%), Escherichia coli (DP1, 5.1%; DP2, 4.1%), Pseudomonas aeruginosa (DP1, 3.7%; DP2, 2.5%). In DP2, there were lower primary early infection rates with Staphylococcus aureus than in DP1 (p = 0.002). In DP2, Staphylococcus epidermidis showed an oxacillin resistance in 90.6% and an increased resistance (79.8%; p = 0.069) to several classes of antibiotic agents compared to DP1. Conclusions: No bacterial shift toward gram-negative species was observed in this investigation. However, Staphylococcus epidermidis showed an increased antibiotic resistance in the more recent patient cohort. The incidence of SSIs with Staphylococcus aureus decreased substantially.:Inhaltsverzeichnis ....................................................................................................................... 2 Abkürzungsverzeichnis .............................................................................................................. 3 Einleitung ................................................................................................................................... 4 Definition & Klassifikation der FRI .................................................................................................... 5 Epidemiologie & Pathogenese ............................................................................................................ 7 Risikofaktoren ..................................................................................................................................... 7 Prävention ............................................................................................................................................ 8 Perioperative Antibiotikaprophylaxe (PAP) ................................................................................................... 8 Mikrobiologie .................................................................................................................................... 10 Biofilme ........................................................................................................................................................ 11 Antibiotika Resistenzen ................................................................................................................................ 13 Resistenzmechanismen ................................................................................................................................. 14 Diagnosestellung ............................................................................................................................... 16 Therapie ............................................................................................................................................. 17 Chirurgisches Therapieregime ...................................................................................................................... 18 Empirische Antibiotikatherapie .................................................................................................................... 20 Zielstellung der Arbeit ............................................................................................................. 22 Publikation ............................................................................................................................... 23 Zusammenfassung der Arbeit ................................................................................................... 32 Abbildungsverzeichnis ............................................................................................................. 34 Tabellenverzeichnis .................................................................................................................. 34 Literaturverzeichnis .................................................................................................................. 35 Anlagen .................................................................................................................................... 46 Spezifizierung des eigenen Beitrags .................................................................................................. 46 Erklärung über die eigenständige Abfassung der Arbeit ................................................................... 48 Lebenslauf und wissenschaftlicher Werdegang ................................................................................ 49 Publikationsverzeichnis ..................................................................................................................... 51 Danksagung ....................................................................................................................................... 52

Yes / It is estimated that 5-10% of hospitalised patients in developed countries contract hospital acquired infections (HAI). Increasing levels of antimicrobial resistance manifested by many HAI-causing pathogens such as Acinetobacter spp in the intensive care unit (ICU) setting present a significant challenge to those managing these infections. Consequently, much attention has been focused on the prevention of HAIs. Particular emphasis has been placed on interventions intended to interrupt patient-to-patient transmission of pathogens, such as enhanced hand hygiene and identification of patients colonised with methicillin-resistant Staphylococcus aureus (MRSA) using rapid DNA-based screening techniques. However, comparatively little attention has been given to the hospital environment, including water supplies, as a source of nosocomial pathogens of importance for patients on the critical care unit. This article reviews the role of hospital water sources in the epidemiology of HAI and new technologies which can be employed in the prevention and control of such infections.