The impact of immunosuppressive therapy on secondary infections and antimicrobial use in COVID-19 inpatients: a retrospective cohort study.

BACKGROUND: Immunosuppressive therapies have become a cornerstone of the management of severe COVID-19. The impact of these therapies on secondary infections and antimicrobial prescribing remains unclear. We sought to assess antimicrobial use and the incidence of bacterial and fungal infections in patients with severe COVID-19, and to explore their associations with receipt of immunosuppressive therapies. METHODS: Our retrospective cohort study included 715 hospitalised, adult patients with severe COVID-19 admitted to St George's Hospital, London, UK, during the first UK pandemic wave (1st March-10th June 2020). Co-infections (occurring within 48 h of admission) and secondary infections (≥ 48 h) were defined as a positive microbiological culture with supporting clinical, radiological or laboratory data to suggest true infection. Cox regression models with time-dependent covariates were used to explore the association between immunosuppressant use and secondary infection. RESULTS: Microbiologically confirmed co-infection occurred in 4.2% (n = 30) and secondary infection in 9.3% (n = 66) of the cohort (n = 715) and were associated with in-hospital mortality (48% vs 35%, OR 1.8, 95%CI 1.1-2.7, p = 0.01). Respiratory (n = 41, 39%) and bloodstream infections (n = 38, 36%) predominated, with primarily Gram-negative pathogens. 606 (84.7%) patients received an antimicrobial, amounting to 742 days of therapy per 1000 patient-days (DOTs). In multivariable models, receipt of high-dose steroids (≥ 30 mg prednisolone or equivalent) or tocilizumab was significantly associated with increased antimicrobial consumption (+ 5.5 DOTs, 95%CI 3.4-7.7 days) but not secondary infection (HR 0.56, 95%CI 0.26-1.18). CONCLUSIONS: Bacterial and fungal infections in severe COVID-19 were uncommon. Receipt of steroids or tocilizumab was independently associated with antimicrobial consumption despite its lack of association with secondary infection. These findings should galvanise efforts to promote antimicrobial stewardship in patients with COVID-19.

National action plans for antimicrobial resistance and variations in surveillance data platforms.

Objective: To assess how national antimicrobial susceptibility data used to inform national action plans vary across surveillance platforms. Methods: We identified available open-access, supranational, interactive surveillance platforms and cross-checked their data in accordance with the World Health Organization's (WHO's) Data Quality Assurance: module 1. We compared platform usability and completeness of time-matched data on the antimicrobial susceptibilities of four blood isolate species: Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus and Streptococcus pneumoniae from WHO's Global Antimicrobial Resistance and Use Surveillance System, European Centre for Disease Control's (ECDC's) network and Pfizer's Antimicrobial Testing Leadership and Surveillance database. Using Bland-Altman analysis, paired t-tests, and Wilcoxon signed-rank tests, we assessed susceptibility data and number of isolate concordances between platforms. Findings: Of 71 countries actively submitting data to WHO, 28 also submit to Pfizer's database; 19 to ECDC; and 16 to all three platforms. Limits of agreement between WHO's and Pfizer's platforms for organism-country susceptibility data ranged from -26% to 35%. While mean susceptibilities of WHO's and ECDC's platforms did not differ (bias: 0%, 95% confidence interval: -2 to 2), concordance between organism-country susceptibility was low (limits of agreement -18% to 18%). Significant differences exist in isolate numbers reported between WHO-Pfizer (mean of difference: 674, P-value: < 0.001, and WHO-ECDC (mean of difference: 192, P-value: 0.04) platforms. Conclusion: The considerable heterogeneity of nationally submitted data to commonly used antimicrobial resistance surveillance platforms compromises their validity, thus undermining local and global antimicrobial resistance strategies. Hence, we need to understand and address surveillance platform variability and its underlying mechanisms.

Population Pharmacokinetic Study of Benzylpenicillin in Critically Unwell Adults.

Pharmacokinetics are highly variable in critical illness, and suboptimal antibiotic exposure is associated with treatment failure. Benzylpenicillin is a commonly used beta-lactam antibiotic, and pharmacokinetic data of its use in critically ill adults are lacking. We performed a pharmacokinetic study of critically unwell patients receiving benzylpenicillin, using data from the ABDose study. Population pharmacokinetic modelling was undertaken using NONMEM version 7.5, and simulations using the final model were undertaken to optimize the pharmacokinetic profile. We included 77 samples from 12 participants. A two-compartment structural model provided the best fit, with allometric weight scaling for all parameters and a creatinine covariate effect on clearance. Simulations (n = 10,000) demonstrated that 25% of simulated patients receiving 2.4 g 4-hourly failed to achieve a conservative target of 50% of the dosing interval with free drug above the clinical breakpoint MIC (2 mg/L). Simulations demonstrated that target attainment was improved with continuous or extended dosing. To our knowledge, this study represents the first full population PK analysis of benzylpenicillin in critically ill adults.

Treatment of Capnocytophaga sputigena meningitis in a neurosurgical patient.

A woman in her 50s developed meningitis following an endoscopic, endonasal resection of a clival meningioma which was complicated by a cerebrospinal fluid (CSF) leak through the nose. CSF analysis showed a raised white cell count, and Capnocytophaga sputigena was isolated. This organism is an oral commensal and is implicated in periodontal disease; the CSF leak explains the portal of entry. C. sputigena is rarely isolated, and this is the first report of a central nervous system (CNS) infection caused by this organism. A worsening of our patient's dermatological condition, urticaria pigmentosa, coincided with empiric treatment with vancomycin and meropenem, which were therefore discontinued. Treatment was continued with chloramphenicol for 3 weeks, and the patient made a full recovery. Systemic chloramphenicol is uncommonly used in contemporary UK practice, but remains an excellent antibiotic for CNS penetration and it has excellent bioavailability. We anticipate increased chloramphenicol use as the number of multiresistant Gram-negative infection increases.

Antibiotic usage and stewardship in patients with COVID-19: too much antibiotic in uncharted waters?

BACKGROUND: Antimicrobial usage and stewardship programmes during COVID-19 have been poorly studied. Prescribing practice varies despite national guidelines, and there is concern that stewardship principles have suffered. AIM: To analyse antibiotic prescriptions during the COVID-19 pandemic at a teaching hospital and to propose improved approaches to stewardship. METHODS: We reviewed COVID-19 admissions to medical wards and intensive care units (ICUs) in a London teaching hospital to assess initial antibiotic usage and evidence of bacterial co-infection, and to determine if our current antibiotic guidelines were adhered to. FINDINGS: Data from 130 inpatients (76% medical and 24% ICU) were obtained. On admission, 90% were treated with antibiotics. No microbiological samples taken on admission provided definitive evidence of respiratory co-infection. In 13% of cases, antibiotics were escalated, usually without supporting clinical, radiological or laboratory evidence. In 16% of cases, antibiotics were stopped or de-escalated within 72 h. Blood results and chest radiographs were characteristic of COVID-19 in 20% of ward patients and 42% of ICU patients. Overall mortality was 25% at 14 days - similar to rates described for the UK as a whole. CONCLUSION: The majority of patients received antibiotics despite limited evidence of co-infection. Most patients received narrower spectrum antibiotics than recommended by NICE. As understanding of the natural history of COVID-19 infections progresses, stewardship programmes will need to evolve; however, at this point, we feel that a more restrictive antibiotic prescribing approach is warranted. We propose strategies for effective stewardship and estimate the effect this may have on antibiotic consumption.

What can we learn from supermarkets? An application of the Poisson distribution (order-up-to) model to improve blood culture bottle supplies.

BACKGROUND: The order-up-to inventory model is a method for identifying and maintaining the optimal product level for items that that hold value over time and have recurring demand. Typically, supermarkets utilise it to manage stock-levels of non-perishable goods. LOCAL PROBLEM: This project aimed to improve blood culture bottle supplies following reports by junior doctors of shortages when dealing with septic/unwell patients. METHODS: Data regarding blood culture bottle use was acquired from four hospitals within one trust in London (245 wards). The mathematical 'order-up-to' inventory model (an iterative Poisson distribution) was applied to the 6 months' data. INTERVENTIONS: The model found three predictable levels of demand to stock wards with no shortages in 99.3% of circumstances (based on historical data). Wards were stocked with blood culture bottles as per their required demand. RESULTS: A collection method and infrastructure was designed to implement the new policy and was applied to a London tertiary centre. A review of doctors, nurses and ward-managers found significant improvements in supply with no shortages since the model was applied. Issues with the dataset were identified for intensive therapy unit / high dependency unit. CONCLUSIONS: The 'order-up-to' inventory model provides a useful tool within hospitals for improving stock levels of blood cultures bottles and with that the satisfaction of trainees and patient safety.

Consensus-based antimicrobial resistance and stewardship competencies for UK undergraduate medical students.

BACKGROUND: In the UK there is limited coverage of antimicrobial stewardship across postgraduate curricula and evidence that final year medical students have insufficient and inconsistent antimicrobial stewardship teaching. A national undergraduate curriculum for antimicrobial resistance and stewardship is required to standardize an adequate level of understanding for all future doctors. OBJECTIVES: To provide a UK national consensus on competencies for antimicrobial resistance and stewardship for undergraduate medical education. METHODS: Using the modified Delphi method over two online survey rounds, an expert panel comprising leads for infection teaching from 25 UK medical schools reviewed competency descriptors for antimicrobial resistance and stewardship education. RESULTS: There was a response rate of 100% with all 28 experts who agreed to take part completing both survey rounds. Following the first-round survey, of the initial 55 descriptors, 43 reached consensus (78%). The second-round survey included the 12 descriptors from the first round in which agreement had not been reached, four amended descriptors and 12 new descriptors following qualitative feedback from the panel members. Following the second-round survey, a total of 58 consensus-based competency descriptors within six overarching domains were identified. CONCLUSIONS: The consensus-based competency descriptors defined here can be used to inform standards, design curricula, develop assessment tools and direct UK undergraduate medical education.

Atypical pneumonia.

PURPOSE OF REVIEW: We present the key advances in the infections that clinicians conventionally associate with atypical pneumonia: legionellosis, Mycoplasma pneumonia, Chlamydophila species pneumonia and Q fever. RECENT FINDINGS: There have been significant developments in molecular diagnosis to include Mycoplasma pneumoniae and Chlamydophila pneumoniae in multiplex PCR of respiratory specimens. There are diagnostic challenges in distinguishing carriage from infection, which is recognized in C. pneumoniae and now also evident in M. pneumoniae. Macrolide-resistant M. pneumoniae has emerged in Asia. There are new antimicrobials on the horizon in the ketolide class with activity against typical and atypical pathogens and useful empirical agents. SUMMARY: There are few advances in our knowledge of the epidemiology of atypical pathogens or the effectiveness of antimicrobial therapy--empirical or pathogen specific. However, if molecular testing becomes widely implemented, there will be an increased understanding of the epidemiology and presentation of atypical pneumonia and a shift to more targeted antimicrobial therapy.

Management of hepatitis B in pregnant women and infants: a multicentre audit from four London hospitals.

BACKGROUND: Pregnant women with hepatitis B virus (HBV) infection can transmit the infection to their infants, screening of patients and appropriate interventions reduce vertical transmission. This audit was conducted to assess adherence to the national guidelines for management of HBV infection in pregnancy. METHODS: A retrospective audit was conducted on pregnant women diagnosed with hepatitis B on screening in antenatal clinics, across four hospitals in London over 2 years (2009-2010). Data was collected from antenatal records and discharge summaries using a standard audit form. The outcomes measured included HBV serological markers, HBV DNA, detection of other blood borne viruses and referral to hepatology services, administration of active and passive prophylaxis to infants at birth. Descriptive statistics are presented. Proportions were compared using the χ2 test and 95% confidence intervals (CI) were calculated for prevalence estimates. Analyses were conducted using STATA 12. RESULTS: HBsAg was detected in 1.05% (n = 401, 95% CI 0.95-1.16) of women attending an antenatal appointment, 12% (n = 48) of the women were at a high risk of vertical transmission (HBe Ag positive or antiHBe and HBeAg negative or HBV DNA >106 IU/ml). Only 62% (n = 248) women were referred to hepatology or specialist clinics and 29% (n = 13) of women of high infectivity were on antiviral agents. Testing for hepatitis C and delta virus was suboptimal. 75% (n = 36) of the infants at a high risk of acquisition of HBV received both active and passive prophylaxis. CONCLUSION: In certain sectors of London, implementation of the pathway for management of women with hepatitis B and their infants is suboptimal. National guidelines should be followed and improved intersectorial sharing of information is needed to reduce the risk of women of high infectivity being lost to follow up.

Effective management in clusters of pneumococcal disease: a systematic review.

Outbreaks of serious pneumococcal disease can occur with high attack rates in certain settings. We systematically reviewed studies of interventions implemented in pneumococcal clusters and those reporting the effect of antibiotics on carriage reduction to assess the effectiveness of interventions. Evidence was graded according to the Scottish Intercollegiate Guidelines Network system. Of 28 identified cluster reports, one showed that administration of antibiotics to close contacts reduced risk of pneumococcal disease. In three of four clusters where rifampicin chemoprophylaxis was used and in four of five clusters where penicillin was used no further cases were seen after intervention. In clusters where pneumococcal polysaccharide vaccine was used, subsequent cases occurred, all within around 2 weeks of vaccination, which suggests delayed benefit with this approach (evidence grade D). Use of infection control measures alone was reported in eight clusters, with no further cases being reported in seven (grade D). From 21 selected carriage studies, large carriage reductions were observed consistently with use of penicillin and azithromycin, with median values being 90% and 73%, respectively (grade C). The findings were presented to a working group for pneumococcal cluster guidelines and used to develop key recommendations on the management of clusters that supported prompt use of amoxicillin or azithromycin chemoprophylaxis, pneumococcal vaccination for close contacts, and implementation of infection control measures.

Outbreaks of serious pneumococcal disease in closed settings in the post-antibiotic era: a systematic review.

SUMMARY OBJECTIVES: Since the introduction of antibiotics, pneumococcal disease is predominantly sporadic, with occasional outbreaks. Our objective was to review the epidemiology of reported outbreaks of serious pneumococcal disease in closed settings to inform the development of guidelines to manage such outbreaks. METHODS: We systematically reviewed the literature for reported outbreaks of serious pneumococcal disease in closed settings to inform the development of guidelines in managing such outbreaks. RESULTS: We identified 42 outbreaks reported in 39 papers---14 in hospitals, 12 in long term care facilities, five outbreaks in households, four in military settings, three in child care settings and two each in homeless shelters and jails. The serotype/group most frequently associated with outbreaks was 14 (seven outbreaks) followed by 4 (five outbreaks) then serotypes/groups 1, 9 and 9V each causing four outbreaks. The median outbreak size was four cases (2 - 46). The median duration was eight days, with 84% of cases occurring within 14 days of the first case. CONCLUSION: Outbreaks of serious pneumococcal disease are likely to continue happening requiring early recognition and implementation of public health measures in order to interrupt transmission. This study facilitated the development of the first UK interim guidelines for managing such outbreaks.