Reducing broad-spectrum antibiotic use in intensive care unit between first and second waves of COVID-19 did not adversely affect mortality

Background: The COVID-19 pandemic increased the use of broad-spectrum antibiotics due to diagnostic uncertainty, particularly in critical care. Multi-professional communication became more difficult, weakening stewardship activities. Aim: To determine changes in bacterial co-/secondary infections and antibiotics used in COVID-19 patients in critical care, and mortality rates, between the first and second waves. Methods: Prospective audit comparing bacterial co-/secondary infections and their treatment during the first two waves of the pandemic in a single-centre teaching hospital intensive care unit. Data on demographics, daily antibiotic use, clinical outcomes, and culture results in patients diagnosed with COVID-19 infection were collected over 11 months. Findings: From March 9th, 2020 to September 2nd, 2020 (Wave 1), there were 156 patients and between September 3rd, 2020 and February 1st, 2021 (Wave 2) there were 235 patients with COVID-19 infection admitted to intensive care. No significant difference was seen in mortality or positive blood culture rates between the two waves. The proportion of patients receiving antimicrobial therapy (93.0% vs 81.7%; P < 0.01) and the duration of meropenem use (median (interquartile range): 5 (2–7) vs 3 (2–5) days; P = 0.01) was lower in Wave 2. However, the number of patients with respiratory isolates of Pseudomonas aeruginosa (4/156 vs 21/235; P < 0.01) and bacteraemia from a respiratory source (3/156 vs 20/235; P < 0.01) increased in Wave 2, associated with an outbreak of infection. There was no significant difference between waves with respect to isolation of other pathogens. Conclusion: Reduced broad-spectrum antimicrobial use in the second wave of COVID-19 compared with the first wave was not associated with significant change in mortality

The cardiovascular toxicity of antimalarial drugs

Malaria is an ancient mosquito-borne parasitic disease from which over a thousand – mostly children in sub-Saharan Africa – still die of needlessly every day. For half a millennium, quinine and quinine-like antimalarial drugs have been the mainstay of malaria treatment and prevention. In the 18th century, the chance observation of their ability to quell palpitations led to their becoming the first anti-arrhythmic agents. Some of these anti-arrhythmic antimalarials later came to define the adverse drug reaction of repolarisation-related cardiotoxicity as sudden deaths, ventricular tachyarrhythmias, and electrocardiographic QT interval prolongation were in turn causally associated with their use. With increasing population-level use of antimalarials for malaria elimination, there has been renewed global interest in defining the cardiovascular toxicity of key members of this drug class to guide antimalarial choice and dosage for development and deployment. In this thesis, I investigate the repolarisation-related cardiotoxicity of the quinoline and structurally-related oral antimalarials mostly widely used in malaria treatment, prevention, and drug development. In Chapter 3, I find that the risk of sudden unexplained death after dihydroartemisinin-piperaquine, a leading candidate for mass drug administration and intermittent preventive therapy for malaria, is no higher than baseline. In Chapter 4, I report how torsade de pointes and other clinically significant arrhythmias have not been documented after front-line antimalarials at standard malaria doses despite extensive use. In Chapter 5, I identify independent effects of malaria severity and fever on the QT interval accounting for the greater post-drug prolongation in malaria patients compared to healthy individuals. In Chapter 6, I present the QT interval prolongation and heart rate reduction from artesunate-amodiaquine compared with other front-line antimalarials and propose bradycardia may underlie amodiaquine-associated asthenia. I conclude that chloroquine, piperaquine, amodiaquine, and lumefantrine remain safe at World Health Organization-recommended doses and combinations for the treatment, prevention, and global eradication of malaria.</p

The Study of Earthquakes in the South-East of Europe

Background Several quinoline and structurally related antimalarial drugs are associated with cardiovascular side effects, particularly hypotension and electrocardiographic QT interval prolongation. A prolonged QT interval is a sensitive but not specific risk marker for the development of Torsade de Pointes—a potentially lethal polymorphic ventricular tachyarrhythmia. The increasing use of quinoline and structurally related antimalarials in mass treatments to eliminate malaria rapidly highlights the need to review their cardiovascular safety profiles. Methods The primary objective of this systematic review was to describe the documented clinical and electrocardiographic cardiovascular side effects of quinine, mefloquine, lumefantrine, piperaquine, halofantrine, chloroquine, sulfadoxine-pyrimethamine, amodiaquine, and primaquine. Trials in healthy subjects or patients with Plasmodium falciparum or P. vivax infection were included if at least two ECGs were conducted during the trial. All trial designs were included except case reports and pooled analyses. Secondary outcomes were the methods adopted by trials for measuring and reporting the QT interval. Results Data from trials published between 1982 and July 2016 were included. A total of 177 trials met the inclusion criteria. 35,448 participants received quinoline antimalarials in these trials, of which 18,436 participants underwent ECG evaluation. Subjects with co-medication use or comorbidities including cardiovascular disease were excluded from the majority of trials. Dihydroartemisinin-piperaquine was the drug most studied (5083 participants). Despite enormous use over the past 60 years, only 1076, 452, and 150 patients had ECG recordings reported in studies of chloroquine, amodiaquine, and primaquine respectively. Transiently high concentrations of quinine, quinidine, and chloroquine following parenteral administration have all been associated with hypotension, but there were no documented reports of death or syncope attributable to a cardiovascular cause, nor of electrocardiographic recordings of ventricular arrhythmia in these trials. The large volume of missing outcome information and the heterogeneity of ECG interval reporting and measurement methodology did not allow pooled quantitative analysis of QT interval changes. Conclusion No serious cardiac adverse effects were recorded in malaria clinical trials of 35,548 participants who received quinoline and structurally related antimalarials with close follow-up including 18,436 individuals who underwent ECG evaluation. While these findings provide further evidence of the rarity of serious cardiovascular events after treatment with these drugs, they also underscore the need for continued strengthening of pharmacovigilance systems for robust detection of rare drug adverse events in real-world populations. A standardised approach to measurement and reporting of ECG data in malaria trials is also needed.</p

HIV - lessons from a late diagnosis

Late HIV diagnosis is the most important predictor of HIV-related morbidity and mortality in the UK and often results from missed testing opportunities during earlier contact with health services. The HPA now recommends routine HIV testing be commissioned as a priority for all general medical admissions in high prevalence areas, such as Milton Keynes. We present the case of a patient admitted to our Medical Admissions Unit (MAU) managed initially for presumed septic complications of metastatic disease who was later found to have terminal HIV disease. In keeping with UK-wide experience which we review, a local audit following this case found MAU HIV test coverage increased after routine testing but not after staff education alone, and resulted in implementation of routine HIV testing in our MAU

Aortic thrombosis in COVID-19

Background Venous thrombo-embolism is now well-recognised as a common complication of severe COVID-19 disease. Arterial thrombosis has been less well recognised, although it is increasingly reported, mostly in the context of myocardial infarction and stroke. Case report A 63-year-old man developed a pale, cold foot with an absent dorsalis pedis pulse 7 days into his admission with COVID-19. A CT angiogram demonstrated a large thrombus in the lower thoracic aorta, which had not been present on CT pulmonary angiogram the preceding week, along with occlusion of both popliteal arteries. He was managed with therapeutic dose of low molecular weight heparin (LMWH) for 6 weeks. Results This case adds to the growing list of potential sites and consequences of thrombosis in COVID-19. Conclusion This case underscores the urgent need for pathophysiological studies and clinical trials to target treatments and guidelines for thromboprophylaxis in COVID-19

Risk of sudden unexplained death after use of dihydroartemisinin-piperaquine for malaria: A systematic review and Bayesian meta-analysis

Background Dihydroartemisinin–piperaquine is an effective and well tolerated artemisinin-based combination therapy that has been assessed extensively for the prevention and treatment of malaria. Piperaquine, similar to several structurally related antimalarials currently used, can prolong cardiac ventricular repolarisation duration and the electrocardiographic QT interval, leading to concerns about its proarrhythmic potential. We aimed to assess the risk of potentially lethal iatrogenic ventricular arrhythmias in individuals receiving dihydroartemisinin–piperaquine. Methods We did a systematic review and Bayesian meta-analysis. We searched clinical bibliographic databases (last on May 24, 2017) for studies of dihydroartemisinin–piperaquine in human beings. Further unpublished studies were identified with the WHO Evidence Review Group on the Cardiotoxicity of Antimalarials. We searched for articles containing “dihydroartemisinin-piperaquine” as title, abstract, or subject heading keywords, with synonyms and variant spellings as additional search terms. We excluded animal studies, but did not apply limits on language or publication date. Eligible studies were prospective, randomised, controlled trials or cohort studies in which individuals received at least one 3-day treatment course of dihydroartemisinin–piperaquine for mass drug administration, preventive therapy, or case management of uncomplicated malaria, with follow-up over at least 3 days. At least two independent reviewers screened titles, abstracts, and full texts, agreed study eligibility, and extracted information about study and participant characteristics, adverse event surveillance methodology, dihydroartemisinin–piperaquine exposures, loss-to-follow up, and any deaths after dihydroartemisinin–piperaquine treatment into a standardised database. The risk of sudden unexplained death after dihydroartemisinin–piperaquine with 95% credible intervals (CI) generated by Bayesian meta-analysis was compared with the baseline rate of sudden cardiac death. Findings Our search identified 94 eligible primary studies including data for 197 867 individuals who had received dihydroartemisinin–piperaquine: 154 505 in mass drug administration programmes; 15 188 in 14 studies of repeated courses in preventive therapies and case management of uncomplicated malaria; and 28 174 as single-course treatments of uncomplicated malaria in 76 case-management studies. There was one potentially drug-related sudden unexplained death: a healthy woman aged 16 in Mozambique who developed heart palpitations several hours after the second dose of dihydroartemisinin–piperaquine and collapsed and died on the way to hospital (no autopsy or ECG was done). The median pooled risk estimate of sudden unexplained death after dihydroartemisinin–piperaquine was 1 in 757 950 (95% CI 1 in 2 854 490 to 1 in 209 114). This risk estimate was not higher than the baseline rate of sudden cardiac death (0·7–11·9 per 100 000 person-years or 1 in 1 714 280 to 1 in 100 835 over a 30-day risk period). The risk of bias was low in most studies and unclear in a few. Interpretation Dihydroartemisinin–piperaquine was associated with a low risk of sudden unexplained death that was not higher than the baseline rate of sudden cardiac death. Concerns about repolarisation-related cardiotoxicity need not limit its current use for the prevention and treatment of malaria.</p

Risk of sudden unexplained death after use of dihydroartemisinin-piperaquine for malaria: A systematic review and Bayesian meta-analysis

Background Dihydroartemisinin–piperaquine is an effective and well tolerated artemisinin-based combination therapy that has been assessed extensively for the prevention and treatment of malaria. Piperaquine, similar to several structurally related antimalarials currently used, can prolong cardiac ventricular repolarisation duration and the electrocardiographic QT interval, leading to concerns about its proarrhythmic potential. We aimed to assess the risk of potentially lethal iatrogenic ventricular arrhythmias in individuals receiving dihydroartemisinin–piperaquine. Methods We did a systematic review and Bayesian meta-analysis. We searched clinical bibliographic databases (last on May 24, 2017) for studies of dihydroartemisinin–piperaquine in human beings. Further unpublished studies were identified with the WHO Evidence Review Group on the Cardiotoxicity of Antimalarials. We searched for articles containing “dihydroartemisinin-piperaquine” as title, abstract, or subject heading keywords, with synonyms and variant spellings as additional search terms. We excluded animal studies, but did not apply limits on language or publication date. Eligible studies were prospective, randomised, controlled trials or cohort studies in which individuals received at least one 3-day treatment course of dihydroartemisinin–piperaquine for mass drug administration, preventive therapy, or case management of uncomplicated malaria, with follow-up over at least 3 days. At least two independent reviewers screened titles, abstracts, and full texts, agreed study eligibility, and extracted information about study and participant characteristics, adverse event surveillance methodology, dihydroartemisinin–piperaquine exposures, loss-to-follow up, and any deaths after dihydroartemisinin–piperaquine treatment into a standardised database. The risk of sudden unexplained death after dihydroartemisinin–piperaquine with 95% credible intervals (CI) generated by Bayesian meta-analysis was compared with the baseline rate of sudden cardiac death. Findings Our search identified 94 eligible primary studies including data for 197 867 individuals who had received dihydroartemisinin–piperaquine: 154 505 in mass drug administration programmes; 15 188 in 14 studies of repeated courses in preventive therapies and case management of uncomplicated malaria; and 28 174 as single-course treatments of uncomplicated malaria in 76 case-management studies. There was one potentially drug-related sudden unexplained death: a healthy woman aged 16 in Mozambique who developed heart palpitations several hours after the second dose of dihydroartemisinin–piperaquine and collapsed and died on the way to hospital (no autopsy or ECG was done). The median pooled risk estimate of sudden unexplained death after dihydroartemisinin–piperaquine was 1 in 757 950 (95% CI 1 in 2 854 490 to 1 in 209 114). This risk estimate was not higher than the baseline rate of sudden cardiac death (0·7–11·9 per 100 000 person-years or 1 in 1 714 280 to 1 in 100 835 over a 30-day risk period). The risk of bias was low in most studies and unclear in a few. Interpretation Dihydroartemisinin–piperaquine was associated with a low risk of sudden unexplained death that was not higher than the baseline rate of sudden cardiac death. Concerns about repolarisation-related cardiotoxicity need not limit its current use for the prevention and treatment of malaria.</p

Zinc supplementation for preventing mortality, morbidity, and growth failure in children aged 6 months to 12 years of age

Background Zinc deficiency is prevalent in low‐ and middle‐income countries, and contributes to significant diarrhoea‐, pneumonia‐, and malaria‐related morbidity and mortality among young children. Zinc deficiency also impairs growth. Objectives To assess the effects of zinc supplementation for preventing mortality and morbidity, and for promoting growth, in children aged six months to 12 years of age. Search methods Between December 2012 and January 2013, we searched CENTRAL, MEDLINE, MEDLINE In‐Process and Other Non‐Indexed Citations, Embase, African Index Medicus, Conference Proceedings Citation Index, Dissertation Abstracts, Global Health, IndMED, LILACS, WHOLIS, metaRegister of Controlled Trials, and WHO ICTRP. Selection criteria Randomised controlled trials of preventive zinc supplementation in children aged six months to 12 years compared with no intervention, a placebo, or a waiting list control. We excluded hospitalised children and children with chronic diseases or conditions. We excluded food fortification or intake, sprinkles, and therapeutic interventions. Data collection and analysis Two authors screened studies, extracted data, and assessed risk of bias. We contacted trial authors for missing information. Main results We included 80 randomised controlled trials with 205,401 eligible participants. We did not consider that the evidence for the key analyses of morbidity and mortality outcomes were affected by risk of bias. The risk ratio (RR) for all‐cause mortality was compatible with a reduction and a small increased risk of death with zinc supplementation (RR 0.95, 95% confidence interval (CI) 0.86 to 1.05, 14 studies, high‐quality evidence), and also for cause‐specific mortality due to diarrhoea (RR 0.95, 95% CI 0.69 to 1.31, four studies, moderate‐quality evidence), lower respiratory tract infection (LRTI) (RR 0.86, 95% CI 0.64 to 1.15, three studies, moderate‐quality evidence), or malaria (RR 0.90, 95% CI 0.77 to 1.06, two studies, moderate‐quality evidence). Supplementation reduced diarrhoea morbidity, including the incidence of all‐cause diarrhoea (RR 0.87, 95% CI 0.85 to 0.89, 26 studies, moderate‐quality evidence), but the results for LRTI and malaria were imprecise: LRTI (RR 1, 95% CI 0.94 to 1.07, 12 studies, moderate‐quality evidence); malaria (RR 1.05, 95% 0.95 to 1.15, four studies, moderate‐quality evidence). There was moderate‐quality evidence of a very small improvement in height with supplementation (standardised mean difference (SMD) ‐0.09, 95% CI ‐0.13 to ‐0.06; 50 studies), but the size of this effect might not be clinically important. There was a medium to large positive effect on zinc status. Supplementation was associated with an increase in the number of participants with at least one vomiting episode (RR 1.29, 95% CI 1.14 to 1.46, five studies, high‐quality evidence). We found no clear evidence of benefit or harm of supplementation with regard to haemoglobin or iron status. Supplementation had a negative effect on copper status. Authors' conclusions In our opinion, the benefits of preventive zinc supplementation outweigh the harms in areas where the risk of zinc deficiency is relatively high. Further research should determine optimal intervention characteristics such as supplement dose