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Proactive Prophylaxis With Azithromycin and HydroxyChloroquine in Hospitalised Patients With COVID-19 (ProPAC-COVID): A structured summary of a study protocol for a randomised controlled trial.
Sivapalan, P, Ulrik, CS, Bojesen, RD, Lapperre, TS, Eklöf, JV, Håkansson, KEJ, Browatzki, A, Tidemansen, C, Wilcke, JT, Janner, J, et al
Trials. 2020;(1):513
Abstract
OBJECTIVES The aim of this randomised GCP-controlled trial is to clarify whether combination therapy with the antibiotic azithromycin and hydroxychloroquine via anti-inflammation/immune modulation, antiviral efficacy and pre-emptive treatment of supra-infections can shorten hospitalisation duration for patients with COVID-19 (measured as "days alive and out of hospital" as the primary outcome), reduce the risk of non- invasive ventilation, treatment in the intensive care unit and death. TRIAL DESIGN This is a multi-centre, randomised, Placebo-controlled, 2-arm ratio 1:1, parallel group double-blind study. PARTICIPANTS 226 participants are recruited at the trial sites/hospitals, where the study will take place in Denmark: Aalborg, Bispebjerg, Gentofte, Herlev, Hillerød, Hvidovre, Odense and Slagelse hospitals. INCLUSION CRITERIA • Patient admitted to Danish emergency departments, respiratory medicine departments or internal medicine departments • Age≥ 18 years • Hospitalized ≤48 hours • Positive COVID-19 test / diagnosis during the hospitalization (confirmed). • Men or non-fertile women. Fertile women* must not be pregnant, i.e. negative pregnancy test must be available at inclusion • Informed consent signed by the patient *Defined as after menarche and until postmenopausal (no menstruation for 12 months) Exclusion criteria: • At the time of recruitment, the patient uses >5 LO2/min (equivalent to 40% FiO2 if measured) • Known intolerance/allergy to azithromycin or hydroxychloroquine or hypersensitivity to quinine or 4-aminoquinoline derivatives • Neurogenic hearing loss • Psoriasis • Retinopathy • Maculopathy • Visual field changes • Breastfeeding • Severe liver diseases other than amoebiasis (INR> 1.5 spontaneously) • Severe gastrointestinal, neurological and hematological disorders (investigator-assessed) • eGFR <45 ml/min/1.73 m2 • Clinically significant cardiac conduction disorders/arrhythmias or prolonged QTc interval (QTc (f) of> 480/470 ms). • Myasthenia gravis • Treatment with digoxin* • Glucose-6-phosphate dehydrogenase deficiency • Porphyria • Hypoglycaemia (Blood glucose at any time since hospitalization of <3.0 mmol/L) • Severe mental illness which significantly impedes cooperation • Severe linguistic problems that significantly hinder cooperation • Treatment with ergot alkaloids *The patient must not be treated with digoxin for the duration of the intervention. For atrial fibrillation/flutter, select according to the Cardiovascular National Treatment Guide (NBV): Calcium antagonist, Beta blocker, direct current (DC) conversion or amiodarone. In case of urgent need for digoxin treatment (contraindication for the aforementioned equal alternatives), the test drug should be paused, and ECG should be taken daily. INTERVENTION AND COMPARATOR Control group: The control group will receive the standard treatment + placebo for both types of intervention medication at all times. If part or all the intervention therapy being investigated becomes standard treatment during the study, this may also be offered to the control group. Intervention group: The patients in the intervention group will also receive standard care. Immediately after randomisation to the intervention group, the patient will begin treatment with: Azithromycin: Day 1-3: 500 mg x 1 Day 4-15: 250 mg x 1 If the patient is unable to take the medication orally by themselves, the medication will, if possible, be administered by either stomach-feeding tube, or alternatively, temporary be changed to clarithromycin 500 mg x 2 (this only in agreement with either study coordinator Pradeesh Sivapalan or principal investigator Jens-Ulrik Stæhr Jensen). This will also be done in the control group if necessary. The patient will switch back to azithromycin when possible. Hydroxychloroquine: Furthermore, the patient will be treated with hydroxychloroquine as follows: Day 1-15: 200 mg x 2 MAIN OUTCOMES • Number of days alive and discharged from hospital within 14 days (summarises both whether the patient is alive and discharged from hospital) ("Days alive and out of hospital") RANDOMISATION The sponsor (Chronic Obstructive Pulmonary Disease Trial Network, COP:TRIN) generates a randomisation sequence. Randomisation will be in blocks of unknown size and the final allocation will be via an encrypted website (REDCap). There will be stratification for age (>70 years vs. <=70 years), site of recruitment and whether the patient has any of the following chronic lung diseases: COPD, asthma, bronchiectasis, interstitial lung disease (Yes vs. No). BLINDING (MASKING): Participants and study personnel will both be blinded, i.e. neither will know which group the participant is allocated to. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): This study requires 226 patients randomised 1:1 with 113 in each group. TRIAL STATUS Protocol version 1.8, from April 16, 2020. Recruitment is ongoing (first patient recruited April 6, 2020; final patient expected to be recruited October 31, 2020). TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04322396 (registered March 26, 2020) FULL PROTOCOL The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).
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Procalcitonin-guided Antibiotic Treatment in Patients With Positive Blood Cultures: A Patient-level Meta-analysis of Randomized Trials.
Meier, MA, Branche, A, Neeser, OL, Wirz, Y, Haubitz, S, Bouadma, L, Wolff, M, Luyt, CE, Chastre, J, Tubach, F, et al
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2019;(3):388-396
Abstract
BACKGROUND Whether procalcitonin (PCT)-guided antibiotic management in patients with positive blood cultures is safe remains understudied. We performed a patient-level meta-analysis to investigate effects of PCT-guided antibiotic management in patients with bacteremia. METHODS We extracted and analyzed individual data of 523 patients with positive blood cultures included in 13 trials, in which patients were randomly assigned to receive antibiotics based on PCT levels (PCT group) or a control group. The main efficacy endpoint was duration of antibiotic treatment. The main safety endpoint was mortality within 30 days. RESULTS Mean duration of antibiotic therapy was significantly shorter for 253 patients who received PCT-guided treatment than for 270 control patients (-2.86 days [95% confidence interval [CI], -4.88 to -.84]; P = .006). Mortality was similar in both arms (16.6% vs 20.0%; P = .263). In subgroup analyses by type of pathogen, we noted a trend of shorter mean antibiotic durations in the PCT arm for patients infected with gram-positive organisms or Escherichia coli and significantly shorter treatment for subjects with pneumococcal bacteremia. In analysis by site of infection, antibiotic exposure was shortened in PCT subjects with Streptococcus pneumoniae respiratory infection and those with E. coli urogenital infections. CONCLUSIONS This meta-analysis of patients with bacteremia receiving PCT-guided antibiotic management demonstrates lower antibiotic exposure without an apparent increase in mortality. Few differences were demonstrated in subgroup analysis stratified by type or site of infection but notable for decreased exposure in patients with pneumococcal pneumonia and E. coli urogenital infections.
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Clinical characteristics and lipid lowering treatment of patients initiated on proprotein convertase subtilisin-kexin type 9 inhibitors: a nationwide cohort study.
Jensen, JS, Weeke, PE, Bang, LE, Høfsten, DE, Ripa, MS, Schjerning, AM, Theilade, JE, Køber, LV, Gislason, GH, Pallisgaard, J
BMJ open. 2019;(4):e022702
Abstract
OBJECTIVES Given the novelty of proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i), little is known regarding overall implementation or clinical characteristics among patients who initiate treatment. We aimed to assess the total number of patients initiated on PCSK9i along with a description of the clinical characteristics and lipid lowering treatment (LLT) of such patients. SETTING A register-based descriptive cohort study of patients receiving a PCSK9i in the time period from 01 January 2016 to 31 March 2017 using a cross linkage between three nationwide Danish registers. Information regarding PCSK9i prescriptions, patient demographics, concurrent pharmacotherapy, comorbidities and previous coronary procedures was identified. RESULTS Overall, 137 patients initiated treatment with PCSK9i in the study period from 11 in the first quarter of 2016 to 40 in the first quarter of 2017. The majority had a history of ischaemic heart disease (IHD) (67.9%) with ischaemic stroke and diabetes mellitus being present in 7.3% and 16.8% of patients, respectively. All patients initiated on PCSK9i had been previously prescribed statin treatment with atorvastatin and simvastatin being most frequently prescribed in 53% and 36% of patients, respectively. The majority of patients had received both statins and ezetimibe (94.9%) and approximately half of these patients had also received bile acid sequestrant (45.3%). Clinical characteristics mainly differed in patients receiving triple LLT compared with patients not receiving triple LLT in the regards of heart failure. CONCLUSION Patients treated with PCSK9i were rare, characterised by having IHD and had received various and intensive conventional LLT prior to PCSK9i initiation in agreement with current international guidelines.
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Procalcitonin-guided antibiotic therapy algorithms for different types of acute respiratory infections based on previous trials.
Schuetz, P, Bolliger, R, Merker, M, Christ-Crain, M, Stolz, D, Tamm, M, Luyt, CE, Wolff, M, Schroeder, S, Nobre, V, et al
Expert review of anti-infective therapy. 2018;(7):555-564
Abstract
Although evidence indicates that use of procalcitonin to guide antibiotic decisions for the treatment of acute respiratory infections (ARI) decreases antibiotic consumption and improves clinical outcomes, algorithms used within studies had differences in PCT cut-off points and frequency of testing. We therefore analyzed studies evaluating procalcitonin-guided antibiotic therapy and propose consensus algorithms for different respiratory infection types. Areas covered: We systematically searched randomized-controlled trials (search strategy updated on February 2018) on procalcitonin-guided antibiotic therapy of ARI in adults using a pre-specified Cochrane protocol and analyzed algorithms from 32 trials that included 10,285 patients treated in primary care settings, emergency departments (ED), and intensive care units (ICU). We derived consensus algorithms for use of procalcitonin by the type of ARI including community-acquired pneumonia, bronchitis, chronic obstructive pulmonary disease or asthma exacerbation, sepsis, and post-operative sepsis due to respiratory infection. Consensus algorithm recommendations differ with regard to timing of treatment (i.e. timing of initiation in low-risk patients or discontinuation in high-risk patients) and procalcitonin cut-off points for the recommendation/strong recommendation to discontinue antibiotics (≤ 0.25/≤ 0.1 µg/L in ED and inpatients, ≤ 0.5/≤ 0.25 µg/L in ICU patients, and reduction by ≥ 80% from peak levels in sepsis patients). Expert commentary: Our proposed algorithms may facilitate safe and efficient implementation of procalcitonin-guided antibiotic protocols in diverse healthcare settings. Still, the decision about initiation and cessation of antibiotic treatment remains a clinical decision based on the patient assessment and the severity of illness and use of procalcitonin should not delay empirical treatment in high risk situations.
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Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a patient level meta-analysis.
Schuetz, P, Wirz, Y, Sager, R, Christ-Crain, M, Stolz, D, Tamm, M, Bouadma, L, Luyt, CE, Wolff, M, Chastre, J, et al
The Lancet. Infectious diseases. 2018;(1):95-107
Abstract
BACKGROUND In February, 2017, the US Food and Drug Administration approved the blood infection marker procalcitonin for guiding antibiotic therapy in patients with acute respiratory infections. This meta-analysis of patient data from 26 randomised controlled trials was designed to assess safety of procalcitonin-guided treatment in patients with acute respiratory infections from different clinical settings. METHODS Based on a prespecified Cochrane protocol, we did a systematic literature search on the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase, and pooled individual patient data from trials in which patients with respiratory infections were randomly assigned to receive antibiotics based on procalcitonin concentrations (procalcitonin-guided group) or control. The coprimary endpoints were 30-day mortality and setting-specific treatment failure. Secondary endpoints were antibiotic use, length of stay, and antibiotic side-effects. FINDINGS We identified 990 records from the literature search, of which 71 articles were assessed for eligibility after exclusion of 919 records. We collected data on 6708 patients from 26 eligible trials in 12 countries. Mortality at 30 days was significantly lower in procalcitonin-guided patients than in control patients (286 [9%] deaths in 3336 procalcitonin-guided patients vs 336 [10%] in 3372 controls; adjusted odds ratio [OR] 0·83 [95% CI 0·70 to 0·99], p=0·037). This mortality benefit was similar across subgroups by setting and type of infection (pinteractions>0·05), although mortality was very low in primary care and in patients with acute bronchitis. Procalcitonin guidance was also associated with a 2·4-day reduction in antibiotic exposure (5·7 vs 8·1 days [95% CI -2·71 to -2·15], p<0·0001) and a reduction in antibiotic-related side-effects (16% vs 22%, adjusted OR 0·68 [95% CI 0·57 to 0·82], p<0·0001). INTERPRETATION Use of procalcitonin to guide antibiotic treatment in patients with acute respiratory infections reduces antibiotic exposure and side-effects, and improves survival. Widespread implementation of procalcitonin protocols in patients with acute respiratory infections thus has the potential to improve antibiotic management with positive effects on clinical outcomes and on the current threat of increasing antibiotic multiresistance. FUNDING National Institute for Health Research.
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Effect of exercise combined with glucagon-like peptide-1 receptor agonist treatment on cardiac function: A randomized double-blind placebo-controlled clinical trial.
Jørgensen, PG, Jensen, MT, Mensberg, P, Storgaard, H, Nyby, S, Jensen, JS, Knop, FK, Vilsbøll, T
Diabetes, obesity & metabolism. 2017;(7):1040-1044
Abstract
In patients with type 2 diabetes, both supervised exercise and treatment with the glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA) liraglutide may improve cardiac function. We evaluated cardiac function before and after 16 weeks of treatment with the GLP-1RA liraglutide or placebo, combined with supervised exercise, in 33 dysregulated patients with type 2 diabetes on diet and/or metformin. Early diastolic myocardial tissue velocity was improved by exercise in the placebo group (mean ± standard deviation [s.d.] -7.1 ± 1.6 to -7.7 ± 1.8 cm/s, P = .01), but not in the liraglutide group (-7.1 ± 1.4 to -7.0 ± 1.4 cm/s, P = .60; between groups, P = .02). Similarly, the mean ± s.d. ratio of early and atrial mitral annular tissue velocities improved in the placebo group (1.0 ± 0.4 to 1.2 ± 0.4, P = .003), but not in the liraglutide group (1.0 ± 0.3 to 1.0 ± 0.3, P = .87; between groups, P = .03). We found no significant differences in heart rate, left ventricular (LV) structure or function within or between the groups. In conclusion, the addition of liraglutide to exercise in sedentary patients with dysregulated type 2 diabetes may blunt the suggested beneficial effect of exercise on LV diastolic function.
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Use of diagnostic coronary angiography in women and men presenting with acute myocardial infarction: a matched cohort study.
Bjerking, LH, Hansen, KW, Madsen, M, Jensen, JS, Madsen, JK, Sørensen, R, Galatius, S
BMC cardiovascular disorders. 2016;:120
Abstract
BACKGROUND Based on evident sex-related differences in the invasive management of patients presenting with acute myocardial infarction (AMI), we sought to identify predictors of diagnostic coronary angiography (DCA) and to investigate reasons for opting out an invasive strategy in women and men. METHODS The study was designed as a matched cohort study. We randomly selected 250 female cases from a source population of 4000 patients hospitalized with a first AMI in a geographically confined region of Denmark from January 2010 to November 2011. Each case was matched to a male control on age and availability of cardiac invasive facilities at the index hospital. We systematically reviewed medical records for risk factors, comorbid conditions, clinical presentation, and receipt of DCA. Clinical justifications, as stated by the treating physician, were noted for the subset of patients who did not receive a DCA. RESULTS Overall, 187 women and 198 men received DCA within 60 days (75 % vs. 79 %, hazard ratio: 0.82 [0.67-1.00], p = 0.047).In the subset of patients who did not receive a DCA (n = 114), clinical justifications for opting out an invasive strategy was not documented for 21 patients (18.4 %). Type 2 myocardial infarction was noted in 11 patients (women versus men; 14.5 % vs. 3.8 %, p = 0.06) and identified as a potential confounder of the sex-DCA relationship. Receipt of DCA was predicted by traditional risk factors for ischaemic heart disease (family history of cardiovascular disease, hypercholesterolemia, and smoking) and clinical presentation (chest pain, ST-segment elevations). Although prevalent in both women and men, the presence of relative contraindications did not prohibit the use of DCA. CONCLUSION In this matched cohort of patients with a first AMI, women and men had different clinical presentations despite similar age. However, no differences in the distribution of relative contraindications for DCA were found between the sexes. Type 2 MI posed a potentiel confounder for the sex-related differences in the use of DCA. Importantly,clinical justification for opting out an invasive strategy was not documented in almost one fifth of patients not receiving a DCA.
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Treatment of bacterial vaginosis in pregnancy in order to reduce the risk of spontaneous preterm delivery - a clinical recommendation.
Haahr, T, Ersbøll, AS, Karlsen, MA, Svare, J, Sneider, K, Hee, L, Weile, LK, Ziobrowska-Bech, A, Østergaard, C, Jensen, JS, et al
Acta obstetricia et gynecologica Scandinavica. 2016;(8):850-60
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Abstract
INTRODUCTION Bacterial vaginosis (BV) is characterized by a dysbiosis of the vaginal microbiota with a depletion of Lactobacillus spp. In pregnancy, prevalence's between 7 and 30% have been reported depending on the study population and the definition. BV may be associated with an increased risk of spontaneous preterm delivery (sPTD). However, it is controversial whether or not BV-positive pregnant women will benefit from treatment to reduce the risk of sPTD. We could not identify any good-quality guideline addressing this issue. Consequently we aimed to produce this clinical recommendation based on GRADE. MATERIAL AND METHODS Systematic literature searches were conducted in the following databases: Guidelines International Network: G-I-N, Medline, Embase, The Cochrane Database of Systematic Reviews, Web of Science and http://www.clinicaltrials.gov from 1999 to 3 October 2014. Hence, nine guidelines, 34 reviews, 18 randomized controlled trials and 12 observational studies were included. RESULTS The GRADE quality of evidence was consistently low or very low, primarily because none of the risk ratios (RR) for the risk of sPTD at <37 weeks were statistically significant. Concerning treatment with metronidazole, RR was 1.11 (95% CI 0.93-1.34) in low-risk pregnancies and 0.96 (95% CI 0.78-1.18) in high risk pregnancies. Concerning treatment with clindamycin at any gestational age, the RR was 0.87 (95% CI 0.73-1.05). CONCLUSION This systematic review gives a strong recommendation against treatment with metronidazole and a weak recommendation against treatment with clindamycin to reduce the sPTD rate in both high-risk and low-risk pregnancies with BV.
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Experimental determination of thermodynamic equilibrium in biocatalytic transamination.
Tufvesson, P, Jensen, JS, Kroutil, W, Woodley, JM
Biotechnology and bioengineering. 2012;(8):2159-62
Abstract
The equilibrium constant is a critical parameter for making rational design choices in biocatalytic transamination for the synthesis of chiral amines. However, very few reports are available in the scientific literature determining the equilibrium constant (K) for the transamination of ketones. Various methods for determining (or estimating) equilibrium have previously been suggested, both experimental as well as computational (based on group contribution methods). However, none of these were found suitable for determining the equilibrium constant for the transamination of ketones. Therefore, in this communication we suggest a simple experimental methodology which we hope will stimulate more accurate determination of thermodynamic equilibria when reporting the results of transaminase-catalyzed reactions in order to increase understanding of the relationship between substrate and product molecular structure on reaction thermodynamics.
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The microbiology of alkaline-fermentation of indigenous seeds used as food condiments in Africa and Asia.
Parkouda, C, Nielsen, DS, Azokpota, P, Ouoba, LI, Amoa-Awua, WK, Thorsen, L, Hounhouigan, JD, Jensen, JS, Tano-Debrah, K, Diawara, B, et al
Critical reviews in microbiology. 2009;(2):139-56
Abstract
Alkaline-fermented food condiments play an important role in the diets of many people in developing and a few developed countries. The rise in pH during production of these foods is due to the ability of the dominant microorganisms, Bacillus spp., to hydrolyze proteins into amino acids and ammonia. Studies have been undertaken which have investigated a number of these products like dawadawa, ugba, bikalga, kinema, natto, and thua-nao. In this review, current knowledge about the principal microbiological activities and biochemical modifications which occur during the processing of the alkaline condiments including nutritional, antimicrobial, and probiotic aspects are discussed. The current use of molecular biology methods in microbiological research has allowed unambiguous and more reliable identification of microorganisms involved in these fermentations generating sufficient knowledge for the selection of potential starter cultures for controlled and better production procedures for alkaline-fermented seeds condiments.