Use of Cefiderocol in the Management of Children With Infection or Colonization With Multi-drug Resistant Gram-negative Bacteria: A Retrospective, Single-center Case Series.

Cefiderocol, a novel siderophore cephalosporin, represents a treatment option for infections with multidrug-resistant Gram-negative bacteria, of which rates are rising worldwide. Clinical data on its use in children is limited. In our pediatric case series, the largest reported to date, cefiderocol seems safe and well tolerated, with more favorable clinical outcomes when compared to the literature reviewing adult cases.

Socioeconomic and Demographic Risk Factors for SARS-CoV-2 Seropositivity Among Healthcare Workers in a UK Hospital: A Prospective Cohort Study.

BACKGROUND: To protect healthcare workers (HCWs) from the consequences of disease due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is necessary to understand the risk factors that drive exposure and infection within hospitals. Insufficient consideration of key socioeconomic variables is a limitation of existing studies that can lead to bias and residual confounding of proposed risk factors for infection. METHODS: The Co-STARs study prospectively enrolled 3679 HCWs between April 2020 and September 2020. We used multivariate logistic regression to comprehensively characterize the demographic, occupational, socioeconomic, and environmental risk factors for SARS-CoV-2 seropositivity. RESULTS: After adjusting for key confounders, relative household overcrowding (odds ratio [OR], 1.4 [95% confidence interval {CI}, 1.1-1.9]; P = .006), Black, Black British, Caribbean, or African ethnicity (OR, 1.7 [95% CI, 1.2-2.3]; P = .003), increasing age (ages 50-60 years: OR, 1.8 [95% CI, 1.3-2.4]; P < .001), lack of access to sick pay (OR, 1.8 [95% CI, 1.3-2.4]; P < .001). CONCLUSIONS: Socioeconomic and demographic factors outside the hospital were the main drivers of infection and exposure to SARS-CoV-2 during the first wave of the pandemic in an urban pediatric referral hospital. Overcrowding and out-of-hospital SARS-CoV-2 contact are less amenable to intervention. However, lack of access to sick pay among externally contracted staff is more easily rectifiable. Our findings suggest that providing easier access to sick pay would lead to a decrease in SARS-CoV-2 transmission and potentially that of other infectious diseases in hospital settings. CLINICAL TRIALS REGISTRATION: NCT04380896.

Cefiderocol Red Wine Urine Syndrome in Pediatric Patients: A Multicenter Case Series.

Cefiderocol is a novel cephalosporin antibiotic with activity against multidrug-resistant gram-negative bacteria and limited pediatric experience. This case series describes 3 immunocompromised children receiving blood transfusion who developed benign red or purple urine with administration of cefiderocol. Interaction with iron from blood products is a possible mechanism. It is important to recognize this phenomenon and distinguish it from hematuria to avoid unnecessary diagnostic testing.

Within-host diversity improves phylogenetic and transmission reconstruction of SARS-CoV-2 outbreaks.

Accurate inference of who infected whom in an infectious disease outbreak is critical for the delivery of effective infection prevention and control. The increased resolution of pathogen whole-genome sequencing has significantly improved our ability to infer transmission events. Despite this, transmission inference often remains limited by the lack of genomic variation between the source case and infected contacts. Although within-host genetic diversity is common among a wide variety of pathogens, conventional whole-genome sequencing phylogenetic approaches exclusively use consensus sequences, which consider only the most prevalent nucleotide at each position and therefore fail to capture low-frequency variation within samples. We hypothesized that including within-sample variation in a phylogenetic model would help to identify who infected whom in instances in which this was previously impossible. Using whole-genome sequences from SARS-CoV-2 multi-institutional outbreaks as an example, we show how within-sample diversity is partially maintained among repeated serial samples from the same host, it can transmitted between those cases with known epidemiological links, and how this improves phylogenetic inference and our understanding of who infected whom. Our technique is applicable to other infectious diseases and has immediate clinical utility in infection prevention and control.

During an infectious disease outbreak, tracing who infected whom allows public health scientists to see how a pathogen is spreading and to establish effective control measures. Traditionally, this involves identifying the individuals an infected person comes into contact with and monitoring whether they also become unwell. However, this information is not always available and can be inaccurate. One alternative is to track the genetic data of pathogens as they spread. Over time, pathogens accumulate mutations in their genes that can be used to distinguish them from one another. Genetically similar pathogens are more likely to have spread during the same outbreak, while genetically dissimilar pathogens may have come from different outbreaks. However, there are limitations to this approach. For example, some pathogens accumulate genetic mutations very slowly and may not change enough during an outbreak to be distinguishable from one another. Additionally, some pathogens can spread rapidly, leaving less time for mutations to occur between transmission events. To overcome these challenges, Torres Ortiz et al. developed a more sensitive approach to pathogen genetic testing that took advantage of the multiple pathogen populations that often coexist in an infected patient. Rather than tracking only the most dominant genetic version of the pathogen, this method also looked at the less dominant ones. Torres Ortiz et al. performed genome sequencing of SARS-CoV-2 (the virus that causes COVID-19) samples from 451 healthcare workers, patients, and patient contacts at participating London hospitals. Analysis showed that it was possible to detect multiple genetic populations of the virus within individual patients. These subpopulations were often more similar in patients that had been in contact with one another than in those that had not. Tracking the genetic data of all viral populations enabled Torres Ortiz et al. to trace transmission more accurately than if only the dominant population was used. More accurate genetic tracing could help public health scientists better track pathogen transmission and control outbreaks. This may be especially beneficial in hospital settings where outbreaks can be smaller, and it is important to understand if transmission is occurring within the hospital or if the pathogen is imported from the community. Further research will help scientists understand how pathogen population genetics evolve during outbreaks and may improve the detection of subpopulations present at very low frequencies.

Increasing rhinovirus prevalence in paediatric intensive care patients since the SARS-CoV2 pandemic.

BACKGROUND: Rhinovirus (HRV) is a significant seasonal pathogen in children. The emergence of SARS-CoV2, and the social restrictions introduced in, disrupted viral epidemiology. Here we describe the experience of Great Ormond Street Hospital (GOSH), where HRV almost entirely disappeared from the paediatric intensive care units (PICU) during the first national lockdown and then rapidly re-emerged with a fast-increasing incidence, leading to concerns about possible nosocomial transmission in a vulnerable population. OBJECTIVES: To describe alterations in HRV infection amongst PICU patients at GOSH since the emergence of SARS-COV2 STUDY DESIGN: 10,950 nasopharyngeal aspirate viral PCR samples from GOSH PICU patients from 2019 to 2023 were included. 3083 returned a positive result for a respiratory virus, with 1530 samples positive for HRV. 66 HRV isolates from August 2020 - Jan 2021, the period of rapidly increasing HRV incidence, were sequenced. Electronic health record data was retrospectively collected for the same period. RESULTS: Following a reduction in the incidence of HRV infection during the first national lockdown, multiple genotypes of HRV emerged amongst GOSH PICU patients, with the incidence of HRV infection rapidly surging to levels higher than that seen prior to the emergence of SARS-CoV2 and continuing to circulate at increased incidence year-round. CONCLUSIONS: The incidence of HRV infection amongst GOSH PICU patients is markedly higher than prior to the emergence of SARS-CoV2, a pattern not seen in other respiratory viruses. The increased burden of HRV-infection in vulnerable PICU patients has both clinical and infection prevention and control Implications.

Trends in coagulase-negative staphylococci (CoNS), England, 2010-2021.

Objective: To review the epidemiology of coagulase-negative staphylococci (CoNS) in England over the recent 12 year period. Methods: Laboratory-confirmed CoNS reported from sterile sites in patients in England to the UK Health Security Agency (UKHSA) between 2010 and 2021 were extracted from the national laboratory database and analysed. Results: Overall, 668 857 episodes of CoNS were reported. Unspeciated CoNS accounted for 56 % (374 228) of episodes, followed by Staphylococcus epidermidis (26 %; 174 050), S. hominis (6.5 %; 43 501) and S. capitis (3.9 %; 25 773). Unspeciated CoNS increased by 8.2 % (95 % CI, 7.1-9.3) annually between 2010 and 2016, then decreased annually by 6.4 % (95 % CI: -4.8 to -7.9) until 2021. Speciated CoNS increased by 47.6 % (95 % CI, 44.5-50.9) annually between 2010 and 2016 and increased annually by 8.9 % (95 % CI: 5.1 to 12.8) until 2021. Antimicrobial susceptibility profiles differed by species. Conclusions: Reports of CoNS from normally sterile body sites in patients in England increased between 2010 and 2016 and remained stable between 2017 and 2021. There has been a striking improvement in species-level identification of CoNS in recent years. Monitoring trends in CoNS epidemiology is crucial for development of observational and clinical intervention studies on individual species.

Quantifying patient- and hospital-level antimicrobial resistance dynamics in Staphylococcus aureus from routinely collected data.

Introduction. Antimicrobial resistance (AMR) to all antibiotic classes has been found in the pathogen Staphylococcus aureus. The reported prevalence of these resistances varies, driven by within-host AMR evolution at the patient level, and between-host transmission at the hospital level. Without dense longitudinal sampling, pragmatic analysis of AMR dynamics at multiple levels using routine surveillance data is essential to inform control measures.Gap Statement. The value and limitations of routinely collected hospital data to gain insight into AMR dynamics at the hospital and individual levels simultaneously are unclear.Methodology. We explored S. aureus AMR diversity in 70 000 isolates from a UK paediatric hospital between 2000-2021, using electronic datasets containing multiple routinely collected isolates per patient with phenotypic antibiograms and information on hospitalization and antibiotic consumption.Results. At the hospital level, the proportion of isolates that were meticillin-resistant (MRSA) increased between 2014-2020 from 25-50 %, before sharply decreasing to 30%, likely due to a change in inpatient demographics. Temporal trends in the proportion of isolates resistant to different antibiotics were often correlated in MRSA, but independent in meticillin-susceptible S. aureus. Ciprofloxacin resistance in MRSA decreased from 70-40 % of tested isolates between 2007-2020, likely linked to a national policy to reduce fluoroquinolone usage in 2007. At the patient level, we identified frequent AMR diversity, with 4 % of patients ever positive for S. aureus simultaneously carrying, at some point, multiple isolates with different resistances. We detected changes over time in AMR diversity in 3 % of patients ever positive for S. aureus. These changes equally represented gain and loss of resistance.Conclusion. Within this routinely collected dataset, we found that 65 % of changes in resistance within a patient's S. aureus population could not be explained by antibiotic exposure or between-patient transmission of bacteria, suggesting that within-host evolution via frequent gain and loss of AMR genes may be responsible for these changing AMR profiles. Our study highlights the value of exploring existing routine surveillance data to determine underlying mechanisms of AMR. These insights may substantially improve our understanding of the importance of antibiotic exposure variation, and the success of single S. aureus clones.

Intracranial invasive group A streptococcus: a neurosurgical emergency in children.

OBJECTIVE: Invasive group A streptococcus (iGAS) infections are associated with a high rate of morbidity and mortality. CNS involvement is rare, with iGAS accounting for only 0.2%-1% of all childhood bacterial meningitis. In 2022, a significant increase in scarlet fever and iGAS was reported globally with a displacement of serotype, causing a predominance of the emm1.0 subtype. Here, the authors report on iGAS-related suppurative intracranial complications requiring neurosurgical intervention and prolonged antibiotic therapy. METHODS: The authors performed a retrospective chart review of consecutive cases of confirmed GAS in pediatric neurosurgical patients. RESULTS: Five children with a median age of 9 years were treated for intracranial complications of GAS infection over a 2-month period between November 2022 and December 2022. All patients had preceding illnesses, including chicken pox and upper respiratory tract infections. Infections included subdural empyema with associated encephalitis (n = 2), extradural empyema (n = 1), intracranial abscess (n = 1), and diffuse global meningoencephalitis (n = 1). Streptococcus pyogenes was cultured from 4 children, and 2 were of the emm1.0 subtype. Antimicrobial therapy in all patients included a third-generation cephalosporin but varied in adjunctive therapy, often including a toxin synthesis inhibitor antibiotic such as clindamycin. Neurological outcomes varied; 3 patients returned to near neurological baseline, 1 had significant residual neurological deficits, and 1 patient died. CONCLUSIONS: Despite the worldwide increased incidence, intracranial complications remain rarely reported resulting in a lack of awareness of iGAS-related intracranial disease. Awareness of intracranial complications of iGAS and prompt referral to a pediatric neurology/neurosurgical center is crucial to optimize neurological outcomes.

Comparison of endoscopic sinus sampling versus intracranial sampling for microbiological diagnosis of intracranial infection in children: a case series and literature review.

INTRODUCTION: Intracranial infection is often associated with contiguous sinus infection, with Streptococcus intermedius being the most common pathogen. Microbiological assessment is possible via sinus or intracranial sampling. While a sinus approach is minimally invasive, it is not clear whether this yields definitive microbiological diagnosis leading to optimized antimicrobial therapy and avoidance of intracranial surgery. METHODS: A retrospective review of a prospectively collected electronic departmental database identified patients between 2019 and 2022. Further demographic and microbiological information was obtained from electronic patient records and laboratory management systems. RESULTS: Thirty-one patients were identified with intracranial subdural and/or epidural empyema and concurrent sinus involvement during the 3-year study period. The median age of onset was 10 years with a slight male predominance (55%). All patients had intracranial sampling with 15 patients undergoing sinus sampling in addition. Only 1 patient (7%) demonstrated identical organism(s) grown from both samples. Streptococcus intermedius was the most common pathogen in intracranial samples. Thirteen patients (42%) had mixed organisms from their intracranial cultures and 57% of samples undergoing bacterial PCR identified additional organisms, predominantly anaerobes. Sinus samples had a significant addition of nasal flora and Staphylococcus aureus which was rarely grown from intracranial samples. Of concern, 7/14 (50%) of sinus samples did not identify the main intracranial pathogen diagnosed on intracranial culture and additional PCR. Literature review identified 21 studies where sinus drainage was used to treat intracranial empyemas, with only 6 authors reporting concurrent microbiology results. This confirmed our cohort to be the largest comparative study in the current literature. No center has observed a greater than 50% concordance in microbiological diagnoses. CONCLUSION: Endoscopic sinus surgery may have therapeutic benefit, but it is not an appropriate approach for microbiological diagnosis in pediatric subdural empyemas. High rates of contaminating nasal flora can lead to misdiagnosis and inappropriate treatment. Routine addition of 16S rRNA PCR to intracranial samples is recommended.

Staphylococcus capitis: Review of Its Role in Infections and Outbreaks.

In June 2021, a national incident team was formed due to an increased detection of Staphylococcus capitis in samples from hospitalised infants. Staphylococcus capitis has been known to cause outbreaks in neonatal units across the globe, but the extent of the UK spread was unclear. A literature review was undertaken to support case identification, clinical management and environmental infection control. A literature search was undertaken on multiple databases from inception to 24 May 2021, using keywords such as "Staphylococcus capitis", "NRCS-A", "S. capitis", "neonate", "newborn" and "neonatal intensive care unit" (NICU). After screening, 223 articles of relevance were included. Results show incidences of S. capitis outbreaks have frequently been associated with the outbreak clone (NRCS-A) and environmental sources. The NRCS-A harbours a multidrug resistance profile that includes resistance to beta-lactam antibiotics and aminoglycosides, with several papers noting resistance or heteroresistance to vancomycin. The NRCS-A clone also harbours a novel SCCmec-SCCcad/ars/cop composite island and increased vancomycin resistance. The S. capitis NRCS-A clone has been detected for decades, but the reasons for the potentially increased frequency are unclear, as are the most effective interventions to manage outbreaks associated with this clone. This supports the need for improvements in environmental control and decontamination strategies to prevent transmission.

Quantifying patient- and hospital-level antimicrobial resistance dynamics in Staphylococcus aureus from routinely collected data.

Antimicrobial resistance (AMR) to all antibiotic classes has been found in the pathogen Staphylococcus aureus . The reported prevalence of these resistances vary, driven by within-host AMR evolution at the patient level, and between-host transmission at the hospital level. Without dense longitudinal sampling, pragmatic analysis of AMR dynamics at multiple levels using routine surveillance data is essential to inform control measures. We explored S. aureus AMR diversity in 70,000 isolates from a UK paediatric hospital between 2000-2020, using electronic datasets containing multiple routinely collected isolates per patient with phenotypic antibiograms, hospitalisation information, and antibiotic consumption. At the hospital-level, the proportion of isolates that were meticillin-resistant (MRSA) increased between 2014-2020 from 25 to 50%, before sharply decreasing to 30%, likely due to a change in inpatient demographics. Temporal trends in the proportion of isolates resistant to different antibiotics were often correlated in MRSA, but independent in meticillin-susceptible S. aureus . Ciprofloxacin resistance in MRSA decreased from 70% to 40% of tested isolates between 2007-2020, likely linked to a national policy to reduce fluoroquinolone usage in 2007. At the patient level, we identified frequent AMR diversity, with 4% of patients ever positive for S. aureus simultaneously carrying, at some point, multiple isolates with different resistances. We detected changes over time in AMR diversity in 3% of patients ever positive for S. aureus . These changes equally represented gain and loss of resistance. Within this routinely collected dataset, we found that 65% of changes in resistance within a patient’s S. aureus population could not be explained by antibiotic exposure or between-patient transmission of bacteria, suggesting that within-host evolution via frequent gain and loss of AMR genes may be responsible for these changing AMR profiles. Our study highlights the value of exploring existing routine surveillance data to determine underlying mechanisms of AMR. These insights may substantially improve our understanding of the importance of antibiotic exposure variation, and the success of single S. aureus clones.

Antibiotic spectrum index as an antimicrobial stewardship tool in paediatric intensive care settings.

OBJECTIVES: Antibiotic spectrum index (ASI) is a recently developed antimicrobial stewardship (AMS) tool that aims to classify antibiotics based on activity against clinically relevant bacterial pathogens. METHODS: We utilised ASI in a 2-year retrospective study between April 2019 and April 2021 in four paediatric intensive care units of a specialist UK children's hospital to quantify antibiotic use based on age, presence of immunosuppression and AMS input. We then compared ASI to days of therapy (DOT) to determine the utility of this AMS metric. We have made changes to Gerber's original ASI list and score of antibiotics to align with prescribing and resistance patterns in the UK. RESULTS: Median ASI/antibiotic days increased with age: for infants under 1 year of age 4.1 (IQR 4.0-4.3), for children 1-5 years 4.4 (IQR 4.0-4.6) and for children over 5 years 4.5 (IQR 4.1-4.6). Immunocompromised patients received much broader-spectrum antibiotics than immunocompetent patients throughout the whole study period. Patients who had AMS input had a higher ASI compared with those who did not throughout the whole period, likely due to more complex patients being discussed on such rounds. CONCLUSIONS: Our results show a complex picture of changing antibiotic consumption and prescribing in a large specialist paediatric hospital in the UK with a long-standing AMS programme before and throughout the COVID-19 pandemic. ASI shows less variability than DOT and can potentially be used to identify patient groups and time periods where broader-spectrum antibiotics are used to help guide further AMS efforts.

The influence of time on the sensitivity of SARS-CoV-2 serological testing.

Sensitive serological testing is essential to estimate the proportion of the population exposed or infected with SARS-CoV-2, to guide booster vaccination and to select patients for treatment with anti-SARS-CoV-2 antibodies. The performance of serological tests is usually evaluated at 14-21 days post infection. This approach fails to take account of the important effect of time on test performance after infection or exposure has occurred. We performed parallel serological testing using 4 widely used assays (a multiplexed SARS-CoV-2 Nucleoprotein (N), Spike (S) and Receptor Binding Domain assay from Meso Scale Discovery (MSD), the Roche Elecsys-Nucleoprotein (Roche-N) and Spike (Roche-S) assays and the Abbott Nucleoprotein assay (Abbott-N) on serial positive monthly samples collected as part of the Co-STARs study ( www.clinicaltrials.gov , NCT04380896) up to 200 days following infection. Our findings demonstrate the considerable effect of time since symptom onset on the diagnostic sensitivity of different assays. Using a time-to-event analysis, we demonstrated that 50% of the Abbott nucleoprotein assays will give a negative result after 175 days (median survival time 95% CI 168-185 days), compared to the better performance over time of the Roche Elecsys nucleoprotein assay (93% survival probability at 200 days, 95% CI 88-97%). Assays targeting the spike protein showed a lower decline over the follow-up period, both for the MSD spike assay (97% survival probability at 200 days, 95% CI 95-99%) and the Roche Elecsys spike assay (95% survival probability at 200 days, 95% CI 93-97%). The best performing quantitative Roche Elecsys Spike assay showed no evidence of waning Spike antibody titers over the 200-day time course of the study. We have shown that compared to other assays evaluated, the Abbott-N assay fails to detect SARS-CoV-2 antibodies as time passes since infection. In contrast the Roche Elecsys Spike Assay and the MSD assay maintained a high sensitivity for the 200-day duration of the study. These limitations of the Abbott assay should be considered when quantifying the immune correlates of protection or the need for SARS-CoV-2 antibody therapy. The high levels of maintained detectable neutralizing spike antibody titers identified by the quantitative Roche Elecsys assay is encouraging and provides further evidence in support of long-lasting SARS-CoV-2 protection following natural infection.

Within-host diversity improves phylogenetic and transmission reconstruction of SARS-CoV-2 outbreaks.

Accurate inference of who infected whom in an infectious disease outbreak is critical for the delivery of effective infection prevention and control. The increased resolution of pathogen whole-genome sequencing has significantly improved our ability to infer transmission events. Despite this, transmission inference often remains limited by the lack of genomic variation between the source case and infected contacts. Although within-host genetic diversity is common among a wide variety of pathogens, conventional whole-genome sequencing phylogenetic approaches to reconstruct outbreaks exclusively use consensus sequences, which consider only the most prevalent nucleotide at each position and therefore fail to capture low frequency variation within samples. We hypothesized that including within-sample variation in a phylogenetic model would help to identify who infected whom in instances in which this was previously impossible. Using whole-genome sequences from SARS-CoV-2 multi-institutional outbreaks as an example, we show how within-sample diversity is stable among repeated serial samples from the same host, is transmitted between those cases with known epidemiological links, and how this improves phylogenetic inference and our understanding of who infected whom. Our technique is applicable to other infectious diseases and has immediate clinical utility in infection prevention and control.

The Influence of Time on the Sensitivity of SARS-CoV-2 Serological Testing.

Background: Serological testing is used to quantify SARS-CoV-2 seroprevalence, guide booster vaccination and select patients for anti-SARS-CoV-2 antibodies therapy. However, our understanding of how serological tests perform as time passes after infection is limited. Methods: Four assays were compared in parallel: 1) the multiplexed spike, nucleoprotein and receptor binding domain Meso Scale Discovery (MSD) assay 2) the Roche Elecsys-Nucleoprotein assay (Roche-N) 3) the Roche Spike assay (Roche-S) and 4) the Abbott Nucleoprotein assay (Abbott-N) on serial positive monthly samples from hospital staff up to 200 days following infection as part of the Co-Stars study. Results: We demonstrate that 50% of the Abbott-N assays give a negative result after 175 days (median survival time 95% CI 168-185 days) while the Roche-N assay (93% survival probability at 200 days, 95% CI 88-97%) maintained seropositivity. The MSD spike (97% survival probability at 200 days, 95% CI 95-99%) and the Roche-S assay (95% survival probability at 200 days, 95% CI 93-97%) also remained seropositive. The best performing quantitative Roche-S assay showed no evidence of waning Spike antibody titres over 200-days. Conclusions: The Abbott-N assay fails to detect SARS-CoV-2 antibodies as time passes since infection. In contrast the Roche and the MSD assays maintained high sensitivity. The limitations of the Abbott assay must be considered in clinical decision making. The long duration of detectable neutralizing spike antibody titres by the quantitative Roche-S assay provides further evidence in support of long-lasting SARS-CoV-2 protection to pre-existing strains of SARS-CoV-2 following natural infection. Trial registration : Co-STARs study was registered with ClinicalTrials.gov on May 8th, 2020, with trial number NCT04380896 (www.clinicaltrials.gov, NCT04380896).

The impact of the COVID-19 pandemic on antimicrobial prescribing at a specialist paediatric hospital: an observational study.

BACKGROUND: The COVID-19 pandemic has severely impacted healthcare delivery and there are growing concerns that the pandemic will accelerate antimicrobial resistance. OBJECTIVES: To evaluate the impact of the COVID-19 pandemic on antibiotic prescribing in a tertiary paediatric hospital in London, UK. METHODS: Data on patient characteristics and antimicrobial administration for inpatients treated between 29 April 2019 and Sunday 28 March 2021 were extracted from the electronic health record (EHR). Interrupted time series analysis was used to evaluate antibiotic days of therapy (DOT) and the proportion of prescribed antibiotics from the WHO 'Access' class. RESULTS: A total of 23 292 inpatient admissions were included. Prior to the pandemic there were an average 262 admissions per week compared with 212 during the pandemic period. Patient demographics were similar in the two periods but there was a shift in the specialities that patients had been admitted to. During the pandemic, there was a crude increase in antibiotic DOTs, from 801 weekly DOT before the pandemic to 846. The proportion of Access antibiotics decreased from 44% to 42%. However, after controlling for changes in patient characteristics, there was no evidence for the pandemic having an impact on antibiotic prescribing. CONCLUSIONS: The patient population in a specialist children's hospital was affected by the COVID-19 pandemic, but after adjusting for these changes there was no evidence that antibiotic prescribing was significantly affected by the pandemic. This highlights both the value of routine, high-quality EHR data and importance of appropriate statistical methods that can adjust for underlying changes to populations when evaluating impacts of the pandemic on healthcare.

Evolution of viral variants in remdesivir-treated and untreated SARS-CoV-2-infected pediatrics patients.

Detailed information on intrahost viral evolution in SARS-CoV-2 with and without treatment is limited. Sequential viral loads and deep sequencing of SARS-CoV-2 from the upper respiratory tract of nine hospitalized children, three of whom were treated with remdesivir, revealed that remdesivir treatment suppressed viral load in one patient but not in a second infected with an identical strain without any evidence of drug resistance found. Reduced levels of subgenomic RNA during treatment of the second patient, suggest an additional effect of remdesivir on viral replication. Haplotype reconstruction uncovered persistent SARS-CoV-2 variant genotypes in four patients. These likely arose from within-host evolution, although superinfection cannot be excluded in one case. Although our dataset is small, observed sample-to-sample heterogeneity in variant frequencies across four of nine patients suggests the presence of discrete viral populations in the lung with incomplete population sampling in diagnostic swabs. Such compartmentalization could compromise the penetration of remdesivir into the lung, limiting the drugs in vivo efficacy, as has been observed in other lung infections.

Long-Term Persistence of Spike Protein Antibody and Predictive Modeling of Antibody Dynamics After Infection With Severe Acute Respiratory Syndrome Coronavirus 2.

BACKGROUND: Antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been shown to neutralize the virus in vitro and prevent disease in animal challenge models on reexposure. However, the current understanding of SARS-CoV-2 humoral dynamics and longevity is conflicting. METHODS: The COVID-19 Staff Testing of Antibody Responses Study (Co-Stars) prospectively enrolled 3679 healthcare workers to comprehensively characterize the kinetics of SARS-CoV-2 spike protein (S), receptor-binding domain, and nucleoprotein (N) antibodies in parallel. Participants screening seropositive had serial monthly serological testing for a maximum of 7 months with the Meso Scale Discovery Assay. Survival analysis determined the proportion of seroreversion, while 2 hierarchical gamma models predicted the upper and lower bounds of long-term antibody trajectory. RESULTS: A total of 1163 monthly samples were provided from 349 seropositive participants. At 200 days after symptoms, >95% of participants had detectable S antibodies, compared with 75% with detectable N antibodies. S antibody was predicted to remain detectable in 95% of participants until 465 days (95% confidence interval, 370-575 days) using a "continuous-decay" model and indefinitely using a "decay-to-plateau" model to account for antibody secretion by long-lived plasma cells. S-antibody titers were correlated strongly with surrogate neutralization in vitro (R2 = 0.72). N antibodies, however, decayed rapidly with a half-life of 60 days (95% confidence interval, 52-68 days). CONCLUSIONS: The Co-Stars data presented here provide evidence for long-term persistence of neutralizing S antibodies. This has important implications for the duration of functional immunity after SARS-CoV-2 infection. In contrast, the rapid decay of N antibodies must be considered in future seroprevalence studies and public health decision-making. This is the first study to establish a mathematical framework capable of predicting long-term humoral dynamics after SARS-CoV-2 infection. CLINICAL TRIALS REGISTRATION: NCT04380896.

The Case for Early Antibiotic Commencement and Source Control in Paediatric Subdural Empyema: A Single-Centre Retrospective Case Series.

BACKGROUND: Subdural empyema is a neurosurgical emergency requiring prompt diagnosis and treatment. There is a debate between the benefits and risks of starting early antibiotics prior to surgical drainage as this is purported to reduce the rate of microbiological diagnosis. Here, we describe our experience of treating this potentially life-threatening condition, advocating for the early commencement of antibiotics and importance of source control in its treatment. METHODS: Retrospective review of a prospectively collected electronic departmental database included all patients who were admitted to our unit with a diagnosis of subdural empyema over an 11-year period (2008-2018). Basic demographic data were collected. Further data pertaining to mode of presentation, surgical approach, causative organism, post-operative antibiotic regime, anti-seizure medications, length of hospital stay, further surgery, and neurological outcomes were extracted. RESULTS: Thirty-six children underwent 44 operations for subdural empyema at our institution during the study period. Median age was 11.0 (range 0.2-15.8); 47.2% (17/36) were female. Over time, there was decreasing use of burr holes and increasing use of craniectomy as the index surgery. Using a combination of extended culture and polymerase chain reaction, a microbiological diagnosis was achieved in all 36 cases; the commonest causative microorganism was of the Streptococcus anginosus group of bacteria. Seven patients underwent repeat surgery, and 4 patients underwent a concurrent ENT procedure. No risk factors were significant in predicting the likelihood of re-operation (location of subdural empyema, age, index surgery type, inflammatory markers, concurrent ENT procedure, and microorganism) although it was notable that none of the patients undergoing a concurrent ENT procedure underwent repeat surgery (p = 0.29). Median length of stay was 12 days (range 3-74), and there were no inpatient or procedure-related mortalities. Clinical outcomes were good with 94.4% (34/36) categorized as modified Rankin Scale 0-3 at discharge and there were 2 cranioplasty-related complications. CONCLUSIONS: We observed an evolution of practice from limited surgical approaches towards more extensive index surgery over the study period. Given that a microorganism was isolated in all cases using a comprehensive approach, initiation of antibiotic therapy should not be delayed on presentation. Concurrent ENT surgery may be an important factor in providing aggressive source control thereby reducing the need for repeat surgery.