Addressing the aftermath of the COVID-19 pandemic: A quality improvement collaborative to optimize the use of antibacterials in Argentine Intensive Care Units (preprint)

BackgroundReducing antimicrobial resistance is a global priority that become even more important after the COVID-19 pandemic. To date there is a scarce volume of evidence from antimicrobial stewardship programs from less resourced settings where this phenomenon is bigger. Our aim was to improve the quality of antibacterials prescription in intensive care units (ICUs) in a middle-income country. MethodsWe established a quality improvement collaborative (QIC) model involving nine ICUs over an 11-month period, with a 16-week baseline (BP) and 32-week Intervention (IP) periods. Our co-designed intervention package included audits and feedback on antibacterial use, facility-specific treatment guidelines, antibacterial timeouts, pharmacy-based interventions, and education. The intervention was delivered in two learning sessions with three action periods, along with coaching support and basic quality improvement training. ResultsWe enrolled 912 patients, with 357 in baseline period (BP) and 555 in implementation period (IP). The latter had higher APACHE II (17 (12, 21) vs. 15 (11, 20); p=0.036) and SOFA scores (6 (4, 9) vs. 5 (3, 8); p=0.006), sepsis (36.1% vs. 31.6%, p<0.001), and septic shock (40.0% vs. 33.8%, p<0.001). Days of antibacterial therapy were similar between groups (IP 1112.2, BP 1133.4, RR 0.98 (0.95-1.02); p=0.2973) and the antibacterial Daily Define Dose was lower in IP group (IP, 1193.0; BP, 1301.0; RR, 0.92 (0.89, 0.95); p=0.0001). The rate of adequate antibacterial adjustment was higher during the IP (62.0% vs. 45.3%, p<0.001). We observed a lower rate of ventilation-associated pneumonia and catheter-associated urinary tract infections related to multidrug-resistant organisms (MDRO) in the IP. There was a noticeable improvement in the Infection Prevention and Control (IPC) Assessment Framework compared to baseline. ConclusionThe implementation of a post pandemic antimicrobial stewardship program in ICUs via a QIC demonstrated success in improving antibacterials utilization, reducing HAIs related to MDRO while also enhancing IPC measures. What is already known on this topicO_LIHealthcare-associated infections represent a global healthcare issue, particularly prevalent in low- and middle-income countries, where their occurrence is nearly three times higher. C_LIO_LIApproximately 50% of antimicrobial use is deemed unnecessary or inappropriate, necessitating the development of widely accessible stewardship methods. C_LIO_LIThe misuse and overuse of antibacterials adversely affect patients admitted to intensive care units (ICUs). C_LIO_LIFurther research is urgently required to determine the most effective ways to implement ASPs in LMICs. C_LI What this study addsO_LIBy establishing a quality improvement collaborative (QIC), we showcased an improvement in antibacterial utilization within ICUs in a low- to middle-income country. C_LIO_LIAdditionally, a reduction in healthcare-associated infections is evident. C_LIO_LIMoreover, the QIC effectively strengthened the capabilities of infection control and prevention in participating ICUs. C_LI How this study might affect research, practice, or policyO_LIThis study is among the initial endeavors in a middle-income country to evaluate the efficacy and essential strategies for establishing antimicrobial stewardship programs. C_LIO_LIThis study could serve as a foundational reference for upcoming teams aiming to introduce similar programs in the region. C_LI

A Poor and Delayed Anti-SARS-CoV2 IgG Response is Associated to Severe COVID-19 in Children (preprint)

Background: Most children and youth develop mild or asymptomatic disease during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, a very small number of patients suffer severe Coronavirus induced disease 2019 (COVID-19). The reasons underlying these different outcomes remain unknown.Methods: We analyzed three different cohorts: children with acute infection (n=550), convalescent children (n=138), and MIS-C (multisystem inflammatory syndrome in children, n=42). IgG and IgM antibodies to the spike protein of SARS-CoV-2, serum-neutralizing activity, plasma cytokine levels, and the frequency of circulating Follicular T helper cells (cTfh) and plasmablasts were analyzed by conventional methods.Findings: Fifty-eight percent of the children in the acute phase of infection had no detectable antibodies at the time of sampling while a seronegative status was found in 25% and 12% of convalescent and MIS-C children, respectively. When children in the acute phase of the infection were stratified according disease severity, we found that contrasting with the response of children with asymptomatic, mild and moderate disease, children with severe COVID-19 did not develop any detectable response. A defective antibody response was also observed in the convalescent cohort for children with severe disease at the time of admission. This poor antibody response was associated to both, a low frequency of cTfh and a high plasma concentration of inflammatory cytokines.Interpretation: A weak and delayed kinetic of antibody response to SARS-CoV-2 together with a systemic pro-inflammatory profile characterize to pediatric severe COVID-19.Funding Information: National Agency for Scientific and Technological Promotion from Argentina (IP-COVID-19-0277 and PMO-BID-PICT2018-2548).Declaration of Interests: The authors have declared that no conflict of interest exists.Ethics Approval Statement: This study was conducted in accordance with the Declaration of Helsinki. The Institutional Review Board at institutions participants reviewed and approved the sample collection and the overall study (Hospital General de Niños Pedro de Elizalde protocol reference 1226/20, Hospital Universitario Austral protocol reference 2147/2020 and Hospital General de Agudos Dr. J. A Fernández protocol reference 1720/20). Parents or legal guardians from children under 8 years provided written, informed consent. Children older than 8 years old provided written, informed assent and their parents or legal guardians also provided written, informed consent.

Blood Neutrophils from Children with COVID-19 Exhibit Both Inflammatory and Anti-Inflammatory Markers (preprint)

Background: Perhaps reflecting that children with COVID-19 rarely exhibit severe respiratory symptoms and often remain asymptomatic, little attention has been paid to explore the immune response in pediatric COVID-19. Here, we analyzed the phenotype and function of circulating neutrophils from children with COVID-19.Methods: One seventy-four children with COVID-19, 21 children with multisystem inflammatory syndrome (MIS-C), and 40 healthy children were studied. Neutrophil phenotype was analyzed by flow cytometry in blood samples. Cytokine production and plasma levels of IgG antibodies directed to the spike protein of SARS-CoV-2 were measured by ELISA. Cell-free DNA was quantified by fluorometry.Findings: Compared with healthy controls, neutrophils from children with COVID-19 showed a lower expression of CD11b, CD66b, and L-selectin but a higher expression of the activation markers HLA-DR, CD64 and PECAM-1 and the inhibitory receptors LAIR-1 and PD-L1. No differences in the pattern of cytokine production and NETs were observed when neutrophils from healthy children were compared with neutrophils from children with COVID-19. Interestingly, the expression of CD64 not only distinguished asymptomatic from mild and moderate COVID-19, but also positively correlated with the serum concentration of IgG antibodies directed to the spike protein of SARS-CoV-2.Interpretation: Acute lung injury is a prominent feature of severe COVID-19 in adults. A low expression of adhesion molecules together with a high expression of inhibitory receptors in neutrophils from children with COVID-19 might prevent tissue infiltration by neutrophils preserving lung function.Funding: FONCyT- ANPCyT, UBA, Argentina.Declaration of Interests: The authors have declared that no conflict of interest exists.Ethics Approval Statement: The Institutional Review Board at institutions participants reviewed and approved the sample collection and overall study.