Emerging multidrug-resistant organisms challenge the medical community to search for new, effective antimicrobial agents to combat infection. Antimicrobial peptides (AMPs) offer a solution for this challenge and could play a major role in the search for new therapeutic regimens against MDR organisms. These peptides can be utilized in their natural or in synthetic forms, or modulated by agents increasing their natural production in vivo via altered gene regulation. Combinations of AMPs with conventional antibiotics and duplicate and triplicate combinations of AMPs are effective in combating Gram-positive and Gramnegative bacteria, as well as parasites and fungi. AMPs of different classes as well as a common class can be combined to induce synergy, enhancing the antimicrobial activity of each peptide or antibiotic compared with its activity alone. Although some specific triple AMP combinations are more effective than specific double AMP combinations, enhancement is generally not a simple stoichiometric relationship. The synergy between AMPs is complex and depends on the concentration and the combination of specific AMPs. Mechanisms include combining membrane-permeabilizing activities as well as modulating the innate immune system to combat inflammatory activity induced by the microorganisms. Mechanisms of AMP-enhanced antibiotic activity are not well studied, although it is postulated that the membrane altering effects allow for increased permeabilization of the membrane to the antibiotic, enhancing antimicrobial activity. Combinations of AMPs with conventional antibiotics serve the advantage of overcoming microbial resistance to the antibiotic as well as decreasing some of the toxicity of certain antibiotics in the patient. Creation of chemical compounds, termed AMP mimetics, that could replace AMPs known to combine with antibiotics to enhance activity would be advantageous in solving the problem of economically feasible AMP production. The examination of synergy with this new class of antibiotics is needed, for the pharmacodynamics of synergy and antagonism between combinations of these agents is complex and varies with the specific combination of agents. So far, research results demonstrate that synergy between AMPs or their mimetics, between themselves or with existing antibiotics offers a solution to the antibiotic resistance problem.

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Background and Aims Initial WHO guidance advised cautious fluid administration for patients with COVID-19 due to concern about the development of acute respiratory distress syndrome (ARDS). However, as the pandemic unfolded it became apparent that patients who were admitted to hospital had high rates of AKI and this initiated a change in local clinical guidelines during early April 2020. We aimed to ascertain the impact of judicious intravenous fluid use on mortality, length of hospitalisation and AKI. Method An observational cohort study of 158 adults admitted with confirmed SARS-Cov-2 between 18th March and 9th May 2020 was conducted in a teaching hospital and designated centre for infectious diseases, London, UK. Key clinical and demographic data collected included clinical severity markers on admission, biochemical and haematological parameters as well as radiological findings. Primary outcomes were inpatient mortality, mortality at 6-weeks post discharge, length of hospitalisation and intensive care (ICU) admission. We also measured requirement for kidney replacement therapy (KRT) and AKI recovery rate at discharge. Using tests of difference, we compared key outcomes between patients treated with varying fluid regimens and then identified risk factors for AKI and mortality using multivariate logistic regression with results expressed as odds ratios (OR) with corresponding 95% confidence interval (CI). Results The median age was 74.4 (IQR 59.90 - 84.35) years, 66% were male, 53% white with hypertension and diabetes being the commonest co-morbidities. The median duration of illness prior to admission was 7 days (IQR 2 – 10) with respiratory symptoms and fever most prevalent. The people who presented with AKI on admission were more likely to receive fluids (34% vs 15%, p=0.02). 118 patients (75%) received fluids within 24-hours of admission with no difference in volume administered after local guidance change (p=0.78). Comparing patients receiving fluids with those who did not, we observed no difference in mortality (p=0.97), duration of hospital stays (p=0.26) or requirement for ICU admission (p=0.70). 18% died as an inpatient, and 52 patients were either admitted with or developed AKI. Of these 52 patients, 43 received fluids and 9 did not with no difference in KRT requirement (p=0.34), mortality (p=0.50) or AKI recovery (p=0.63). Peak AKI stage was greater among participants who received fluids though stage of AKI at presentation was also greater (p=0.04). Mortality rate in patients with an AKI is higher compared to overall inpatient mortality (31% vs 18%). Of the 36 patients with AKI who were discharged home, 25 patients (69.4%) had renal recovery by the time of discharge. Increasing age and clinical severity on admission were associated with higher mortality (see Figure 1). Older age was associated with 34 - 53 times higher risk of death compared with those aged ≤ 65 years (age 76 - 85 years: OR 34.26, 95% CI: 3.94 - 297.48, p=0.001; age > 85 years: OR 53.07, 95% CI: 5.23 - 539.03, p=0.001). Patients with NEWS2 >4 on admission has 5-fold increased risk of death than those with a score ≤4 (OR 5.26, 95% CI: 1.32 - 20.92). Black ethnicity was associated with a 16-fold increased risk of developing AKI (OR 15.86, 95% CI: 1.67 - 150.99). Conclusion To our knowledge, this is the first study to examine the impact of fluid management on inpatient mortality as well as on renal-associated outcomes of COVID-19 admission. Fluid administration regimen did not have an impact on mortality, length of hospitalisation or ICU admission, nor did it affect renal outcomes. Given the high rates of AKI and KRT in COVID-19 disease, early fluid administration is likely to be an important cornerstone of future management. Further adequately powered prospective studies are required to identify whether early fluid administration can reduce renal injury.