ISSUES IN MEDICINE: Models for increasing the health workforce

A stable human resource base in the health sector is critical to achieving health-related Millennium Development Goals. There is a severe quantitative and qualitative shortfall of healthcare professionals in South Africa, and the existing and future health workforce production is inadequate for our healthcare needs. The production model must include all healthcare disciplines because the quadruple burden of disease necessitates multi-professional healthcare teams working synergistically to improve healthoutcomes and life expectancy

Antibiotic, Heavy Metal, and Biocide Concentrations in a Wastewater Treatment Plant and Its Receiving Water Body Exceed PNEC Limits: Potential for Antimicrobial Resistance Selective Pressure

Data Availability Statement: All data have been added to the manuscript and the Supplementary Material available onlione at: https://www.mdpi.com/2079-6382/12/7/1166#app1-antibiotics-12-01166 ..Copyright © 2023 by the authors. Although the rise in antimicrobial resistance has been attributed mainly to the extensive and indiscriminate use of antimicrobials such as antibiotics and biocides in humans, animals and on plants, studies investigating the impact of this use on water environments in Africa are minimal. This study quantified selected antibiotics, heavy metals, and biocides in an urban wastewater treatment plant (WWTP) and its receiving water body in Kwazulu-Natal, South Africa, in the context of the predicted no-effect concentrations (PNEC) for the selection of antimicrobial resistance (AMR). Water samples were collected from the WWTP effluent discharge point and upstream and downstream from this point. Heavy metals were identified and quantified using the United States Environmental Protection Agency (US EPA) method 200.7. Biocides and antibiotic residues were determined using validated ultra-high-performance liquid chromatography with tandem mass spectrometry-based methods. The overall highest mean antibiotic, metal and biocide concentrations were observed for sulfamethoxazole (286.180 µg/L), neodymium (Nd; 27.734 mg/L), and benzalkonium chloride (BAC 12) (7.805 µg/L), respectively. In decreasing order per sampling site, the pollutant concentrations were effluent > downstream > upstream. This implies that the WWTP significantly contributed to the observed pollution in the receiving water. Furthermore, most of the pollutants measured recorded values exceeding the recommended predicted no-effect concentration (PNEC) values, suggesting that the microbes in such water environments were at risk of developing resistance due to the selection pressure exerted by these antimicrobials. Further studies are required to establish such a relationship.South African Research Chair Initiative of the Department of Science and Technology and National Research Foundation of South Africa (Grant No. 98342); South African Medical Research Council (SAMRC); SAMRC Self-Initiated Research Grant

Environmental concentrations of antibiotics, biocides, and heavy metals fail to induce phenotypic antimicrobial resistance in Escherichia coli

Data availability: Data will be made available on request.Supplementary data are available online at: https://www.sciencedirect.com/science/article/pii/S0048969723043449?via%3Dihub#s0090 .Copyright © 2023 The Authors. Most anthropogenically affected environments contain mixtures of pollutants from different sources. The impact of these pollutants is usually the combined effect of the individual polluting constituents. However, how these stressors contribute to the development of antimicrobial resistance in environmental microorganisms is poorly understood. Thus, a 30-day exposure experiment to environmental and sub-inhibitory concentrations of oxytetracycline, amoxicillin, zinc, copper, BAC (benzalkonium chloride) 10 and DADMAC (diallyldimethylammonium chloride) 12, was conducted using fully susceptible E. coli ATCC 25922 to ascertain any development of phenotypic or genotypic resistance. Furthermore, wild-type isolates were collected from the same aquatic environment as the stressors, analysed for phenotypic resistance using the disk diffusion method and genotypically through whole genome sequencing. Exposure to the various concentrations and combinations of the stressors did not trigger phenotypic resistance in the experimental bacteria. Furthermore, genotypic analysis of the WGS on the exposed isolates only found the macrolide resistance mdf(A) gene (also present in the control strain) and the disinfectant resistance gene sitABCD. With further analysis for single nucleotide variants (SNV), mutations were detected for 19 genes that encoded for oxidative stress, DNA repair, membrane proteins efflux systems, growth and persister formations except for the robA, a transcription protein subset of the ArcC/XylS family of proteins, which confer multidrug resistance in E. coli. This indicates that exposure to sub-inhibitory concentrations of antibiotics, heavy metals and biocide residues in the aquatic environmental concentrations of the stressors identified in the current study could not induce phenotypic or genotypic resistance but encoded for genes responsible for the development of persistence and tolerance in bacteria, which could be a precursor to the development of resistance in environmental bacteria.The South African Research Chair Initiative of the Department of Science and Technology and National Research Foundation of South Africa (Grant No. 98342); South African Medical Research Council (SAMRC) Self-Initiated Research Grant

Impact of Environmental Sub-Inhibitory Concentrations of Antibiotics, Heavy Metals, and Biocides on the Emergence of Tolerance and Effects on the Mutant Selection Window in E. coli

Data Availability Statement: All data have been added to the manuscript. Any further data would be provided by the authors upon responsible request.Copyright © 2023 by the authors. Bacteria’s ability to withstand the detrimental effects of antimicrobials could occur as resistance or tolerance with the minimum inhibitory concentration, the mutant prevention concentration, and the mutant selection window as salient concepts. Thus, this study assessed the impact of exposure to extremely high doses of ampicillin on the level of persistence and tolerance development in isolates previously exposed to different concentrations of selected antibiotics, biocides, and heavy metals. These isolates were previously exposed to oxytetracycline (OXYTET), amoxicillin (AMX), copper (Cu), zinc (Zn), benzalkonium chloride (BAC) 10, dimethylammonium chloride (DADMAC) 12 and a combination of all the individual pollutants (ALL). The isolates were exposed to very high concentrations (25 × MIC) of ampicillin, and their tolerance was calculated as the time required to kill 99.9% of the bacterial population (MDK99.9). The MDK99.9 increased by 30 to 50% in test isolates (DADMAC, OXYTET, Zinc = 28 h; BAC, Copper = 30 h; amoxycillin, ALL = 26 h) compared to the untreated control. BAC-exposed isolates decreased from 2.5 × 108 CFU/mL to 2.5 × 104 CFU/mL on the second day, displaying the highest tolerance increase. The tolerance appeared to originate from two sources, i.e., stochastic persistence and genetic-induced persistence, involving multiple genes with diverse mechanisms. The mutant selection window of the isolates to ampicillin, amoxicillin, and oxytetracycline also slightly increased compared to the control, indicating the selective survival of persister cells during the 30-day exposure. These findings indicate that bacterial exposure to sub-inhibitory concentrations of environmental chemical stressors may not always result in the development of antimicrobial resistance but could initiate this process by selecting persisters that could evolve into resistant isolates.South African Research Chair Initiative of the Department of Science and Technology and the National Research Foundation of South Africa (Grant No. 98342); South African Medical Research Council (SAMRC); SAMRC Self-Initiated Research Grant

Ongoing strategies to improve the management of upper respiratory tract infections and reduce inappropriate antibiotic use particularly among lower and middle-income countries: findings and implications for the future

Introduction: Antibiotics are indispensable to maintaining human health; however, their overuse has resulted in resistant organisms, increasing morbidity, mortality and costs. Increasing antimicrobial resistance (AMR) is a major public health threat, resulting in multiple campaigns across countries to improve appropriate antimicrobial use. This includes addressing the overuse of antimicrobials for self-limiting infections, such as upper respiratory tract infections (URTIs), particularly in lower- and middle-income countries (LMICs) where there is the greatest inappropriate use and where antibiotic utilization has increased the most in recent years. Consequently, there is a need to document current practices and successful initiatives in LMICs to improve future antimicrobial use. Methodology: Documentation of current epidemiology and management of URTIs, particularly in LMICs, as well as campaigns to improve future antimicrobial use and their influence where known. Results: Much concern remains regarding the prescribing and dispensing of antibiotics for URTIs among LMICs. This includes considerable self-purchasing, up to 100% of pharmacies in some LMICs. However, multiple activities are now ongoing to improve future use. These incorporate educational initiatives among all key stakeholder groups, as well as legislation and other activities to reduce self-purchasing as part of National Action Plans (NAPs). Further activities are still needed however. These include increased physician and pharmacist education, starting in medical and pharmacy schools; greater monitoring of prescribing and dispensing practices, including the development of pertinent quality indicators; and targeted patient information and health education campaigns. It is recognized that such activities are more challenging in LMICs given more limited resources and a lack of healthcare professionals. Conclusion: Initiatives will grow across LMICs to reduce inappropriate prescribing and dispensing of antimicrobials for URTIs as part of NAPs and other activities, and these will be monitored

Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials.

BACKGROUND: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4-12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered. METHODS: We present data from three single-blind randomised controlled trials-one phase 1/2 study in the UK (COV001), one phase 2/3 study in the UK (COV002), and a phase 3 study in Brazil (COV003)-and one double-blind phase 1/2 study in South Africa (COV005). As previously described, individuals 18 years and older were randomly assigned 1:1 to receive two standard doses of ChAdOx1 nCoV-19 (5 × 1010 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2 × 1010 viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005). FINDINGS: Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4-74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3-85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59-0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3-91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0-69·9] at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18-55 years (GMR 2·32 [2·01-2·68]). INTERPRETATION: The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose. FUNDING: UK Research and Innovation, National Institutes of Health Research (NIHR), The Coalition for Epidemic Preparedness Innovations, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D'Or, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

NATED vs NSC

The challenge of translating equity of access into equity of outcome with students from a differentially resourced secondary education system which may have advantaged or disadvantaged them in demonstrating their academic ability in the conventional matriculation/national senior certificate (NSC) examinations necessitated that Universities undertake a review of selection and admissions criteria within the “achievement vs. aptitude” as well as the “NATED vs. NCS” discourses. The Faculty of Health Sciences conducted a longitudinal cohort study correlating matriculation/NSC scores, composite and component Alternative Admissions Research Project (AARP) scores and Standardized Assessment Test for Access and Placement (SATAP) English for Academic Purposes scores with average first year performance of all first entry students admitted into programmes offered in the Faculty of Health Sciences in 2008 (matriculants of the NATED curriculum) and 2009 (NSC holders of the OBE curriculum). Results allow the Faculty to confidently use NSC scores as the primary selection tool for students who have received quality secondary education and students whose first language is English. The RT and PTEEP as well as composite AARP scores may be used to inform selection in the L2 and AA cohorts respectively noting that the AARP has since been replaced by the National Benchmark Test (NBT) which consists of commensurate components; thereby addressing equity and redress imperatives while ensuring throughput and success. Keywords: selection, aptitude, NATED, OBE, NS

Strategies for the prevention and containment of antibiotic resistance

Antibiotic resistance may emerge by antibiotic selection pressure but is perpetuated by diverse risk factors and maintained within environments as a result of poor infection control. Population-specific drug pharmacokinetics and pharmacodynamics also play a role. The WHO, US, UK and EU have initiated strategies for the containment of resistance, with surveillance and delineation of the cause(s) cited as essential. Surveillance of antibiotic efficacy should be disease-based, establishing sensitivity profiles of common causative organisms to inform the development of or amendment to standard treatment guidelines and essential drugs lists adopted within the national drug policy. The manner of antimicrobial use (overuse, underuse, inadequate dosing) associated with resistance should be established for appropriate intervention in terms of rational drug use, a reduction in use and dosing regimens based on population-specific pharmacokinetics and pharmacodynamics. Risk factors unique to South African communities (poverty, HIV) and hospitals (duration of hospitalisation, location within the hospital, intensive care unit stay, surgery, wounds, previous and current antimicrobial therapy, mechanical ventilation, urinary catherterisation, nasogastric intubation, central venous and peripheral catheters, previous hospitalisation and transfer from another unit or hospital) must be determined and due vigilance exercised in patients exhibiting classical risk factors for the acquisition of or colonisation with resistant pathogens. Hygiene and sanitation (in communities) and infection control (in hospitals) status must be determined and interventions initiated to prevent the spread of resistance. Pharmacokinetics and pharmacodynamics specific to diverse populations must be devised to optimise antimicrobial therapy. South Africa has unique needs in the antimicrobial resistance arena, needs to be addressed in the context of severe financial, human resources and technological challenges. Keywordsantibiotic resistance, rational drug use, infection control, risk factors, pharmacokinetics, pharmacodynamics For full text, click here:SA Fam Pract 2006;48(1):51-51