Background/Objectives: The overuse and misuse of antibiotics contribute to antimicrobial resistance (AMR) globally. The appropriateness of antibiotic prescribing at the primary healthcare (PHC) level must be urgently addressed to reduce high levels of inappropriate antibiotic prescribing and associated AMR. This study aimed to develop quality indicators, based on the World Health Organization (WHO)'s Access, Watch, Reserve (AWaRe) guidance, to assess the appropriateness and quality regarding antibiotic prescribing in public PHC settings in South Africa. Methods: Potential indicators were identified from indicators developed by City St George's, University of London (SGUL); a review of AWaRe-based indicators; and the results from point prevalence surveys at PHC clinics in South Africa. The indicators were developed using the RAND/UCLA Appropriateness Method. In Round 1, 12 experts individually rated 78 indicators for clarity and appropriateness. In Round 2, 10 experts rated 89 indicators for appropriateness and feasibility during an interactive online meeting. Results: The final set had 61/89 indicators (68.5%) that were rated both appropriate and feasible with agreement. Dental infections (9/9; 100%) alongside skin and soft tissue infections (11/13; 84.6%) had the highest percentage of indicators that were rated appropriate and feasible with agreement. Lower urinary tract infections (6/11; 54.5%) and general (4/8; 50%) categories had the lowest percentage of indicators rated appropriate and feasible with agreement. Conclusions: The process proved valuable in developing potential indicators for use in future antimicrobial stewardship programmes to improve antibiotic prescribing in public sector PHC facilities in South Africa and beyond.
Abstract:Calcium-channel blockers (CCBs) are widely prescribed in South Africa and are frequently implicated in overdose-related morbidity and mortality. We report a case of amlodipine overdose in a teenager. Her management is notable for the exceptionally high dose of insulin used as part of high dose insulin euglycaemic therapy (HIET), far exceeding standard protocol. Despite the aggressive dosing, no clinically significant hypoglycaemia or hypokalaemia occurred. The patient showed progressive improvement and was discharged from the intensive care unit on day 3, making a full recovery. This case demonstrates that insulin doses significantly exceeding conventional protocols may be safe and effective in resource-limited settings when supported by experienced staff and close monitoring. More research is needed to guide optimal HIET dosing and safe discontinuation protocols. Contribution of study:This case demonstrates that concentrated insulin formulations, combined with appropriate monitoring and level of care, can safely deliver higher than usual insulin doses. The use of concentrated insulin significantly reduces its contribution to total fluid administration, providing a practical approach to fluid stewardship. The report highlights a clinical management gap: the absence of standardised protocols for discontinuing insulin and dextrose infusions after high-dose insulin euglycaemic therapy. This case provides data on successful weaning and cessation of HIE and dextrose therapy following unconventionally high insulin dosing. High insulin doses may warrant consideration in severe calcium channel blocker toxicity when conventional haemodynamic support is unavailable or deemed insufficient.
RATIONALE:Globally, there are 1.3 million new HIV infections annually, with a disproportionate burden on young women and girls, especially in sub-Saharan Africa (63% of new infections). Despite the demonstrated effectiveness of pre-exposure prophylaxis (PrEP), global uptake remains low, reaching only 16.5% of the UNAIDS 2025 target. PrEP adherence is suboptimal in vulnerable populations. There is an urgent need to develop and implement alternative, user-friendly PrEP strategies like long-acting formulations that minimise reliance on daily dosing or frequent injections. Lenacapavir is a first-in-class, long-acting capsid inhibitor that disrupts HIV replication at multiple stages. Following an oral loading dose, lenacapavir administered by subcutaneous injection provides six months of protection against HIV. OBJECTIVES:To evaluate the benefits and harms of long-acting injectable lenacapavir for HIV PrEP compared to oral fixed-dose combination PrEP (tenofovir disoproxil fumarate plus emtricitabine (F/TDF) and/or oral tenofovir alafenamide plus emtricitabine (F/TAF)), long-acting injectable cabotegravir (CAB-LA), or placebo or no prophylaxis. SEARCH METHODS:We searched CENTRAL, PubMed, and two trial registers and conducted reference checking to identify eligible studies. The search is current to May 2025. ELIGIBILITY CRITERIA:We included randomised controlled trials (RCTs) with no date or language restrictions in any HIV-negative person at risk of acquiring HIV through sexual contact or exposure to blood, comparing long-acting injectable lenacapavir with oral PrEP, long-acting injectable cabotegravir, placebo or no prophylaxis. OUTCOMES:Our critical outcomes were: new HIV infections or relative risk of HIV infection; serious adverse events (SAEs); adverse events (AEs); adverse drug reactions: injection site reactions; and all-cause mortality. We included data at 26- and 52-week time points. RISK OF BIAS:We used the Cochrane RoB 2 tool to assess risk of bias in the included studies. SYNTHESIS METHODS:We meta-analysed data for each outcome where possible, using the inverse variance statistical method with a random-effects model. We reported risk ratios (RR) with 95% confidence intervals (CIs) for dichotomous data. Where this was not possible, we synthesised results using the direction of effect, guided by the Synthesis Without Meta-analysis (SWiM) reporting guidelines. We used GRADE to assess the certainty of evidence. INCLUDED STUDIES:We included two studies with 8660 participants. The first trial, conducted in South Africa and Uganda, included adolescent girls and young women (16 to 25 years) and compared injectable lenacapavir with daily oral PrEP consisting of F/TAF in one comparator arm and F/TDF in the other. The second trial, conducted in the USA, Brazil, Thailand, South Africa, Peru, Argentina, and Mexico, included cisgender gay, bisexual and other men, transgender women, transgender men, and gender-nonbinary persons of any age who have condomless, receptive anal sex with partners assigned male at birth. It compared injectable lenacapavir with F/TDF. In both trials, participants in the lenacapavir group received placebo tablets that matched the oral PrEP, and participants in the oral PrEP group received placebo injections that matched lenacapavir. SYNTHESIS OF RESULTS:New HIV infections Lenacapavir results in a large reduction in new HIV infections at 52 weeks compared to oral PrEP (RR 0.07, 95% CI 0.02 to 0.22; 2 studies, 8660 participants; high-certainty evidence). There were 14 fewer new HIV infections per 1000 (ranging from 15 fewer to 12 fewer), with a number needed to treat for an additional beneficial outcome (NNTB) of 70. Serious adverse events Lenacapavir results in a slight reduction in SAEs at 52 weeks compared to oral PrEP (RR 0.78, 95% CI 0.61 to 0.99; 2 studies, 8660 participants; high-certainty evidence). There were 8 fewer SAEs per 1000 (ranging from 15 fewer to 0 fewer), NNTB of 128. Adverse events Lenacapavir results in little to no difference in AEs at 52 weeks compared to oral PrEP (RR 0.99, 95% CI 0.96 to 1.01; 2 studies, 8660 participants; high-certainty evidence). There were 8 fewer AEs per 1000 (ranging from 31 fewer to 8 more), NNTB of 55. Adverse drug reactions: injection site reactions Lenacapavir likely increases adverse drug reactions: injection site reactions compared to oral PrEP at 52 weeks (RR 1.68, 95% CI 1.20 to 2.33; 2 studies, 8660 participants; moderate-certainty evidence). There were 295 more adverse drug reactions per 1000 (ranging from 87 more to 577 more), number needed to treat for an additional harmful outcome of 4. All-cause mortality Lenacapavir results in little to no difference in all-cause mortality at 52 weeks compared to oral PrEP (RR 0.57, 95% CI 0.11 to 3.06; 2 studies, 8660 participants; high-certainty evidence). There were 1 fewer deaths per 1000 (ranging from 2 fewer to 4 more), NNTB of 1073. We rated all critical outcomes as low risk of bias in both studies. We found no difference on subgroup analysis between comparators F/TDF and F/TAF. AUTHORS' CONCLUSIONS:When compared to oral PrEP, lenacapavir results in a large reduction in new HIV infections at 52 weeks, with one HIV infection prevented for every 70 people receiving lenacapavir rather than oral PrEP, that is 14 fewer HIV infections per 1000 people treated with lenacapavir. Lenacapavir results in a slight reduction in SAEs and little to no difference in AEs compared to oral PrEP. Lenacapavir likely increases the risk of injection site reactions compared with oral PrEP, but discontinuation of lenacapavir in the included trials due to injection site reactions was rare. There is little to no difference in mortality between lenacapavir and oral PrEP. No studies compared lenacapavir to injectable long-acting cabotegravir, placebo or no prophylaxis. Within the included trials, there was a non-randomised comparison of lenacapavir with background HIV incidence in the screened population as a proxy for a no-PrEP arm. There was a large reduction in HIV incidence in the lenacapavir study arms compared to background HIV incidence in the screened populations. FUNDING:This Cochrane review was part-funded by the South African National Department of Health (NDoH) through the Evidence to Decision (E2D) Collaboration project. The E2D Collaboration is a partnership between the NDoH, the South African Medical Research Council, and Stellenbosch University (2024 to 2028). The views expressed in this review do not necessarily represent the views of the funder. REGISTRATION:PROSPERO (2025) CRD420251080791.
OBJECTIVES:The COVID-19 pandemic highlighted an urgent need to more efficiently identify patients at highest risk for developing respiratory failure. We investigated whether plasma levels of lung injury biomarkers are associated with progression to respiratory failure among adults hospitalized with COVID-19 pneumonia without respiratory failure at admission. DESIGN:This was a nested case-control study of COVID-19 patients enrolled in the Accelerating COVID-19 Therapeutic Interventions and Vaccines-3 (ACTIV-3)/Therapeutics for Inpatients with COVID-19 (TICO) platform trial who were on less than 20 L/min supplemental oxygen at enrollment. We compared baseline measurements of lung injury biomarkers between participants who progressed to respiratory failure or died by study day 10 (cases) and matched controls who did not progress to respiratory failure or death. Cases and controls were matched 1:1 on age, baseline oxygen requirement, immunomodulator use, and study arm. SETTING:Hospitals enrolling in the ACTIV-3/TICO trials. PATIENTS:Four hundred five cases and 405 matched controls. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:Baseline levels of plasma interleukin (IL)-6, IL-8, IL-18, tumor necrosis factor receptor, angiopoietin-2, soluble receptor for advanced glycation end-products (sRAGE), C-reactive protein (CRP), and surfactant protein D (SPD) were compared between cases and controls using matched logistic regression. Forward variable selection was used to identify biomarkers that were independently associated with progression to respiratory failure or death in a multivariate model. All lung injury biomarkers with the exception of SPD were significantly associated with progression to respiratory failure or death, with sRAGE demonstrating the highest odds ratio (OR) for each doubling of biomarker level (OR, 1.85; 95% CI, 1.61-2.12). In multivariate regression analysis, sRAGE, IL-6, and CRP were independently associated with progression, with sRAGE as the biomarker with the strongest association. CONCLUSIONS:Baseline levels of plasma lung injury biomarkers are significantly associated with progression to respiratory failure or death among hospitalized COVID-19 patients without respiratory failure at admission. These findings support the potential utility of measuring lung injury biomarkers in patients hospitalized without respiratory failure and should be tested in more heterogeneous patient groups including non-COVID-19 cohorts.
