Introduction. During previous viral pandemics, reported co-infection rates and implicated pathogens have varied. In the 1918 influenza pandemic, a large proportion of severe illness and death was complicated by bacterial co-infection, predominantly Streptococcus pneumoniae and Staphylococcus aureus . Gap statement. A better understanding of the incidence of co-infection in patients with COVID-19 infection and the pathogens involved is necessary for effective antimicrobial stewardship. Aim. To describe the incidence and nature of co-infection in critically ill adults with COVID-19 infection in England. Methodology. A retrospective cohort study of adults with COVID-19 admitted to seven intensive care units (ICUs) in England up to 18 May 2020, was performed. Patients with completed ICU stays were included. The proportion and type of organisms were determined at <48 and >48 h following hospital admission, corresponding to community and hospital-acquired co-infections. Results. Of 254 patients studied (median age 59 years (IQR 49–69); 64.6 % male), 139 clinically significant organisms were identified from 83 (32.7 %) patients. Bacterial co-infections/ co-colonisation were identified within 48 h of admission in 14 (5.5 %) patients; the commonest pathogens were Staphylococcus aureus (four patients) and Streptococcus pneumoniae (two patients). The proportion of pathogens detected increased with duration of ICU stay, consisting largely of Gram-negative bacteria, particularly Klebsiella pneumoniae and Escherichia coli . The co-infection/ co-colonisation rate >48 h after admission was 27/1000 person-days (95 % CI 21.3–34.1). Patients with co-infections/ co-colonisation were more likely to die in ICU (crude OR 1.78,95 % CI 1.03–3.08, P=0.04) compared to those without co-infections/ co-colonisation. Conclusion. We found limited evidence for community-acquired bacterial co-infection in hospitalised adults with COVID-19, but a high rate of Gram-negative infection acquired during ICU stay.

SummaryBackgroundStaphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection.MethodsIn this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants.FindingsBetween Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18–45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference −1·4%, 95% CI −7·0 to 4·3; hazard ratio 0·96, 0·68–1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3–4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005).InterpretationAdjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia.FundingUK National Institute for Health Research Health Technology Assessment.

Purpose: The microbiological aetiology of pneumonia complicating stroke is poorly characterised. In this second Pneumonia in Stroke ConsEnsuS statement, we propose a standardised approach to empirical antibiotic therapy in pneumonia complicating stroke, based on likely microbiological aetiology, to improve antibiotic stewardship. Methods: Systematic literature searches of multiple databases were undertaken. An evidence review and a round of consensus consultation were completed prior to a final multi-disciplinary consensus meeting in September 2017, held in Barcelona, Spain. Consensus was approached using a modified Delphi technique and defined a priori as 75% agreement between the consensus group members. Findings: No randomised trials to guide antibiotic treatment of pneumonia complicating stroke were identified. Consensus was reached for the following: (1) Stroke-associated pneumonia may be caused by organisms associated with either community-acquired or hospital-acquired pneumonia; (2) Treatment for early stroke-associated pneumonia (<72 h of stroke onset) should cover community-acquired pneumonia organisms; (3) Treatment for late strokeassociated pneumonia (!72 h and within seven days of stroke onset) should cover community-acquired pneumonia organisms plus coliforms þ/À Pseudomonas spp. if risk factors; (4) No additional antimicrobial cover is required for patients with dysphagia or aspiration; (5) Pneumonia occurring after seven days from stroke onset should be treated as for hospital-acquired pneumonia; (6) Treatment should continue for at least seven days for each of these scenarios.Discussion: Consensus recommendations for antibiotic treatment of the spectrum of pneumonia complicating stroke are proposed. However, there was limited evidence available to formulate consensus on choice of specific antibiotic class for pneumonia complicating stroke. Conclusion: Further studies are required to inform evidence-based treatment of stroke-associated pneumonia including randomised trials of antibiotics and validation of candidate biomarkers.

This dynamic model of IPA is a useful tool to address many remaining questions related to antifungal treatment of Aspergillus spp.

Although the analysis was limited by small and heterogeneous study populations, limiting determination of microbiological causality, this review suggests aerobic Gram-negative bacilli and Gram-positive cocci are frequently associated with pneumonia complicating stroke. This supports the need for appropriately designed studies to determine microbial cause and a consensus-based approach in antibiotic usage and further targeted antibiotic treatment trials for enhanced antibiotic stewardship.

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Introduction: Antibiotics used to treat post-stroke infections have differing antimicrobial and anti-inflammatory effects. Our aim was to investigate whether antibiotic class was associated with outcome after post-stroke infection. Methods: We analyzed pooled individual participant data from the Virtual International Stroke Trials Archive (VISTA)-Acute. Patients with ischemic stroke and with an infection treated with systemic antibiotic therapy during the first 2 weeks after stroke onset were eligible. Antibiotics were grouped into eight classes, according to antimicrobial mechanism and prevalence. The primary analysis investigated whether antibiotic class for any infection, or for pneumonia, was independently associated with a shift in 90 day modified Rankin Scale (mRS) using ordinal logistic regression. Results: 2,708 patients were eligible (median age [IQR] = 74 [65 to 80] y; 51% female; median [IQR] NIHSS score = 15 [11 to 19]). Pneumonia occurred in 35%. Treatment with macrolides (5% of any infections; 9% of pneumonias) was independently associated with more favorable mRS distribution for any infection [OR (95% CI) = 0.59 (0.42 to 0.83), p = 0.004] and for pneumonia [OR (95% CI) = 0.46 (0.29 to 0.73), p = 0.001]. Unfavorable mRS distribution was independently associated with treatment of any infection either with carbapenems, cephalosporins or monobactams [OR (95% CI) = 1.62 (1.33 to 1.97), p < 0.001], penicillin plus β-lactamase inhibitors [OR (95% CI) = 1.26 (1.03 to 1.54), p = 0.025] or with aminoglycosides [OR (95% CI) = 1.73 (1.22 to 2.46), p = 0.002]. Conclusion: This retrospective study has several limitations including effect modification and confounding by indication. Macrolides may have favorable immune-modulatory effects in stroke-associated infections. Prospective evaluation of the impact of antibiotic class on treatment of post-stroke infections is warranted.

Voriconazole is a first-line agent for the treatment of invasive pulmonary aspergillosis. Isolates with elevated voriconazole MICs are increasingly being seen, and the optimal treatment regimen is not defined. We investigated whether the combination of voriconazole with anidulafungin may be beneficial for the treatment of A. fumigatus strains with elevated voriconazole MICs. We used an in vitro model of the human alveolus to define the exposure-response relationships for a wild-type strain (voriconazole MIC, 0.5 mg/liter) and strains with defined molecular mechanisms of triazole resistance (MICs, 4 to 16 mg/liter). All strains had anidulafungin minimum effective concentrations (MECs) of 0.0078 mg/liter. Exposure-response relationships were estimated using galactomannan as a biomarker. Concentrations of voriconazole and anidulafungin were measured using high-performance liquid chromatography (HPLC). The interaction of voriconazole and anidulafungin was described using the Greco model. Fungal growth was progressively inhibited with higher drug exposures of voriconazole. Strains with elevated voriconazole MICs required proportionally greater voriconazole exposures to achieve a comparable antifungal effect. Galactomannan concentrations were only marginally reduced by anidulafungin monotherapy. An additive effect between voriconazole and anidulafungin was apparent. In conclusion, the addition of anidulafungin does not markedly alter the exposure-response relationship of voriconazole. A rise in serum galactomannan during combination therapy with voriconazole and anidulafungin should be interpreted as treatment failure and not attributed to a paradoxical reaction related to echinocandin treatment.