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Improving antibiotic stewardship in COVID-19: Bacterial co-infection is less common than with influenza

      Keywords

      To the editor in chief
      In the recent systematic review and meta-analysis by Lansbury et al. only 7% of hospitalised patients with COVID-19 were reported as having evidence of bacterial co-infection, yet >90% received empirical antibiotics
      • Louise Lansbury
      • Benjamin Lim
      • Vadsala Baskaran
      • Shen Lim Wei
      Co-infections in people with COVID-19: a systematic review and meta-analysis.
      . This finding, which has been replicated elsewhere
      • Rawson Timothy M
      • Moore Luke S P
      • Zhu Nina
      • Ranganathan Nishanthy
      • Skolimowska Keira
      • Gilchrist Mark
      • Satta Giovanni
      • Holmes Graham Cooke Alison
      Bacterial and fungal co-infection in individuals with coronavirus: a rapid review to support COVID-19 antimicrobial prescribing.
      , is hardly surprising given the challenges associated with distinguishing bacterial from viral pneumonia and that bacterial coinfection is likely to worsen an already poor prognosis in these patients
      • Crotty Matthew P.
      • Ronda Akins
      • An Nguyen
      • Rania Slika
      • Kristen Rahmanzadeh
      • Marie H.
      • et al.
      Investigation of subsequent and co-infections associated with SARS-CoV-2 (COVID-19) in hospitalized patients.
      . Whilst the role of biomarkers such as procalcitonin is being explored, a desire to treat what is treatable is understandable but represents a threat to antibiotic stewardship

      NICE. COVID-19 rapid guideline: antibiotics for pneumonia in adults in hospital. NICE guideline [NG173] 2020;(May):1–17.

      ,
      • Huttner B.D.
      • Catho G.
      • Pano-Pardo J.R.
      • Pulcini C.
      • Schouten J
      COVID-19: don't neglect antimicrobial stewardship principles.
      . In their study, Lansbury et al. found that bacterial coinfection was more common for those in intensive care (ICU) (14%, 95% CI 5–26, vs 4%, 95% CI 1–9) but only one study provided data on the timing of infection in relation to admission. Distinguishing between bacterial co-infection acquired prior to or following ICU admission is essential when developing antibiotic prescribing policies.
      Some of the concern over bacterial co-infection in COVID-19 stems from experience with influenza where bacterial co-infection is well-recognised and often the factor precipitating admission to ICU.
      • England Public Health
      Seasonal influenza Guidance for adult critical care units.
      Experience is growing that the same is not true for COVID-19
      • Hugh Adler
      • Robert Ball
      • Michael Fisher
      • Kalani Mortimer
      • Vardhan Madhur S
      Correspondence: low rate of bacterial co-infection in patients with COVID-19.
      . Whilst any patient on ICU is vulnerable to nosocomial infection, we observe that- in contrast to influenza- bacterial co-infection at ICU admission is rare.
      Table 1 presents microbiologically-confirmed bacterial co-infection findings from a subset of patients enrolled into the ongoing AspiFlu study (www.isrctn.com/ISRCTN51287266). Ventilated adults with confirmed SARS-CoV-2 or influenza infection that had ≥1 respiratory tract sample sent for culture were included in this analysis. Bacterial co-infection was defined as either i) positive urinary antigen test; ii) culture of pathogen from blood/bronchoalveolar lavage (BAL) fluid; or iii) positive endotracheal aspirate culture with suggestive radiology (e.g. focal/ lobar consolidation), neutrophilia and clinician-instigated antibiotic treatment.
      Table 1Bacterial co-infection in mechanically ventilated adults with severe viral pneumonia.
      Influenza (n = 24)SARS-Cov-2 (n = 36)
      Patient characteristics
      Age, median (IQR)56 (47–63)59 (51–65)p = 0.29
      Male, n (%)15 (63%)25 (69%)p = 0.59
      Severe immunosuppression, n (%)2 (8%)2 (6%)P>0.99
      Systemic corticosteroids last 21 days, n (%)7 (29%)4 (11%)p = 0.097
      Chronic Lung Disease, n (%)7 (29%)4 (11%)p = 0.097
      Chronic Kidney Disease, n (%)1 (4%)3 (8%)p = 0.64
      Diabetes, n (%)4 (17%)12 (33%)p = 0.23
      Hypertension, n (%)5 (21%)13 (36%)p = 0.26
      Active / Past Smoker, n (%)11 (46%)14 (39%)p = 0.61
      Duration of symptoms (days), median (IQR)5 (2–7)9 (6–11)p = 0.0018
      Admission SOFA score, median (IQR)10 (9–13)6 (4–8)p<0.0001
      Admission APACHE 2 score, median (IQR)22 (17–27)14 (11–19)p<0.0001
      Lymphocyte: Neutrophil ratio, median (IQR)112 (7–20)13 (6–18)p = 0.85
      Diagnostic sampling, no of patients (%)
      Respiratory tract sampling24 (100%)36 (100%)p>0.99
      Bronchoalveolar lavage19 (79%)3 (8%)P<0.0001
      Urine legionella Antigen19 (79%)30 (83%)p = 0.74
      Urine pneumococcal Antigen20 (83%)27 (75%)p = 0.53
      Blood culture24 (100%)36 (100%)p>0.99
      Mycoplasma serology/PCR20 (83%)7 (19%)P<0.0001
      Interventions and Outcomes
      Renal replacement therapy, n (%)15 (63%)15 (42%)p = 0.19
      Extra Corporeal Membrane Oxygenation, n (%)11 (46%)0 (0%)P<0.0001
      Days ventilated, median (IQR)16 (9–28)18 (12–27)p = 0.62
      Days on ICU, median (IQR)22 (16–32)20 (16–31)p = 0.97
      90 day all-cause mortality, n (%)4 (17%)18 (50%)p = 0.013
      Bacterial coinfection
      Early (<48 h of ICU admission), n (%)14 (58%)3 (8%)P<0.0001
      Late (>48 h of ICU admission), n (%)12 (50%)13 (36%)p = 0.30
      Gram positiveEarlyLateEarlyLate
      Streptococcus pneumoniae2000
      Staphylococcus aureus2011
      Streptococcus pyogenes (Group A Strep)2000
      Enterococci0110
      Gram negativeEarlyLateEarlyLate
      Haemophilus influenzae1100
      Coliforms1509
      Pseudomonas1101
      Other5412
      Influenza; A not subtyped (n = 9), H1N1 (n = 10), H3N2 (n = 4), B (n = 1). Coliforms; Klebsiella, Escherichia coli, Citrobacter, Enterobacter, Serratia. Other; Proteus, Stenotrophomonas, polymicrobial. Respiratory tract sampling; sputum, bronchoalveolar lavage, non-directed lavage, endotracheal aspirate. p values calculated using Fisher's exact test for categorical and Mann-Whitney U test for continuous variables using GraphPad Prism 8.4.2. SOFA/Apache 2 scores calculated using www.mdcalc.com.
      In the influenza cohort, early (<48 h hours of ICU admission) bacterial co-infection was common, 14/24 (58%), and caused by community-acquired pathogens such as Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae and Streptococcus pyogenes (Group A strep) in 7/14. In contrast, early co-infection was uncommon in the COVID-19 cohort 3/36 (8%, P<0.0001). The incidence of late (>48 h of ICU admission) co-infection in COVID-19 did not significantly differ from influenza (36% vs. 50%, p = 0.3) and in 12/13 cases was caused by gram negative bacteria commonly associated with ventilator-associated pneumonia (VAP) and catheter-related bloodstream infection
      • Louise Lansbury
      • Benjamin Lim
      • Vadsala Baskaran
      • Shen Lim Wei
      Co-infections in people with COVID-19: a systematic review and meta-analysis.
      . Important differences between the groups were that the influenza cohort had a shorter duration of symptoms before ICU admission (5  vs 9 days, p = 0.002) and a higher proportion received Extra Corporeal Membrane Oxygenation (46% vs 0%, P<0.0001) and BAL sampling (79% v 8%, P<0.0001). Interestingly, the influenza cohort had better survival despite worse baseline SOFA/APACHE 2 scores.
      For the purposes of antibiotic stewardship, COVID-19 is not like influenza. Most patients with COVID-19 present to ICU with a viral pneumonitis rather than bacterial co-infection. More work is needed on strategies and biomarkers to help identify those most likely to benefit from antibiotics. Whilst clinicians must remain vigilant about nosocomial infection, we advocate against routine empiric antibiotic use in patients hospitalised with COVID-19 infection. Courses of empirical antibiotics initiated whilst SARS-CoV-2 test results are pending should be promptly reviewed upon having the diagnosis of COVID-19 confirmed. Antibiotics should only be continued for those with a presentation suggestive of bacterial coinfection (e.g. productive cough, focal consolidation, neutrophilia) or supportive positive microbiology

      NICE. COVID-19 rapid guideline: antibiotics for pneumonia in adults in hospital. NICE guideline [NG173] 2020;(May):1–17.

      . A narrow spectrum antibiotic should be used wherever possible, informed by local guidance and microbiology results. It can be especially difficult to withhold antibiotics from patients with COVID-19 cytokine release syndrome, which can mimic bacterial sepsis. In such patients, the ongoing need for antibiotics should be continuously reviewed in light of response to immunomodulatory therapy and limited to as short a duration as possible. The impact of immunomodulatory therapies such as corticosteroids (now standard of care for ventilated patients in light of RECOVERY trial findings
      • Peter Horby
      • Martin Landray
      Low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe respiratory complications of COVID-19.
      ), anti-cytokine antibodies and JAK inhibitors (currently being investigated

      Frances Hall, Cambridge University Hospitals NHS Foundation Trust. mulTi-Arm Therapeutic Study in Pre-ICu Patients Admitted With Covid-19 - Repurposed Drugs (TACTIC-R). ClinicalTrials.gov Identifier: NCT04390464. Available at https://clinicaltrials.gov/ct2/show/NCT043904642020.

      ,

      Hoffmann-La Roche. A Study to Evaluate the Safety and Efficacy of Tocilizumab in Patients With Severe COVID-19 Pneumonia (COVACTA). ClinicalTrials.gov Identifier: NCT04320615. Available athttps://clinicaltrials.gov/ct2/show/NCT043206152020.

      ) on bacterial coinfection warrants further study. Future research could also explore whether the rate of nosocomial infection in ICU patients with COVID-19 was artificially high at the peak of the pandemic when challenging working environments and shortages of PPE may have impeded optimal infection prevention and control practice.

      Conflict of Interest

      None.

      Acknowledgments

      We would like to thank the participants of the AspiFlu study and all those that made it possible as well as all the clinical staff who worked so tirelessly during the peak of the COVID-19 pandemic.

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        Bacterial and fungal co-infection in individuals with coronavirus: a rapid review to support COVID-19 antimicrobial prescribing.
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        COVID-19: don't neglect antimicrobial stewardship principles.
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