key: cord-0762961-j87gwco9 authors: Goldstein, Ellie J C; Tillotson, Glenn; Redell, Mark title: Antimicrobial management of respiratory infections in SARS-CoV-2 patients: Clinical and ASP conundrums date: 2020-10-26 journal: Open Forum Infect Dis DOI: 10.1093/ofid/ofaa517 sha: 313f1c29dccfab2523c3615225748e2dd77de8c6 doc_id: 762961 cord_uid: j87gwco9 The role of empirical and even directed antimicrobial management of patients hospitalized with SARS- CoV-2 infection is problematic; antibiotics are used frequently among these patients whether to treat confirmed or suspected co-infection or simply symptoms. In the rapidly changing clinical landscape of SARS- CoV-2 there is minimal guidance for selecting appropriate treatment versus non-antimicrobial treatment, and clinicians are pressed to make daily decisions under the stress of absence of data while watching patients deteriorate. We review current data and patterns of antimicrobial use and the potential approach for antimicrobial stewardship in the context of SARS- CoV-2. The role of empirical and even directed antimicrobial management of patients hospitalized with SARS-CoV-2 infection is problematic. The number of published research papers on 'coronavirus pneumonia' has exceeded 10,000 references on PubMed (as of August 3 2020) and on 'COVID 19 SARS 2' exceeds 79,200 on Google Scholar (as of August 3,2020) . A variety of experimental regimens are being investigated including some agents which may have the dual purpose of providing antiinflammatory and antimicrobial activities. There is scant guidance for selecting appropriate treatment and clinicians are forced to make daily decisions under the stress of absence of data and watching patients deteriorate. Based on diagnostic criteria used in community-acquired bacterial pneumonia (CABP) guidelines [1] it is difficult to distinguish bacterial infection from SARS-CoV-2 infection. A recent publication [2] supported the supposition that bacterial pathogens isolated from the respiratory tract in patients with COVID-19 pneumonia were the same as in CABP. An early surge in the empirical use of the macrolide azithromycin serves as a singular example of an agent with both antibacterial and antiinflammatory effects that failed to provide a clear role in therapy [3, 4] . Of concern was the frequent use of antibiotics despite the lack of isolating a bacterial or fungal pathogen. A review of 806 patients hospitalized with COVID-19 showed 8% had a bacterial or fungal co-infection, although 72% received antimicrobial therapy, compared to 11% of non-COVID-19 cases [5] . The concern for antibiotic stewardship efforts is clear: increases in unnecessary antimicrobial use poses direct risks to the patient including the potential collateral damage such as side effects and adverse drug reactions, in addition to potentiating the risk of antimicrobial resistance through selective pressure Most antibiotic use in patients with confirmed SAR-CoV-2 pneumonia has been empirical while the lung damage may be a result of severe immune dysfunction linked to tissue invasion by the virus. A recent review of 16 publications by Clancy and Nguyen [15] reported that of 3,302 hospitalized patients' invasive mechanical ventilation (IMV) ranged from 1% in Zhejiang province to > 40% in 2 Wuhan hospital sites while in three US reports, IMV ranged from 20-75%. Antibiotic use was very common (~90%) while antifungals were prescribed in approximately 15%. Up to 17% developed superinfections but this varied considerably with some sites not reporting any superinfections. Gram-negative bacilli were frequently reported, including Acinetobacter species, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The wide discrepancies in reporting super-infections may have been due to different definitions and variable ability to differentiate infection from colonization at the different sites. In a retrospective, observational study at a Bronx, NY hospital center, Nori et al [16] noted a 71% mismatch between empirical antimicrobial therapy and a 3.6% co-infection rate. These investigators noted the top five respiratory isolates to be Staphylococcus aureus (equally dispersed between methicillin-susceptible and methicillin-resistant strains), P. aeruginosa, K. pneumoniae, Enterobacter spp. and Escherichia coli. Multidrug-resistant organisms were observed in 9% and 19% of BSI and respiratory infections, respectively. The investigators noted that 79% of COVID-19 patients received antibiotics in the previous 30 days and 98% during hospitalization. Moreover >70% received three or more classes of antibiotics despite a 17% incidence of multidrug resistant Gram-negative organisms. The median duration of antibiotic therapy was 8.5 days. The physician's decision to select an empirical antibiotic that covers CABP pathogens or to escalate to one that covers nosocomial pathogens is equally problematic. In the previously cited studies, the selection of antibiotics in the current pandemic environment lacked clear criteria. Most viral respiratory infections originate in the community, e.g. influenza, COVID-19, adenovirus. It seems reasonable to assume that early associated bacterial pneumonias are due to conventional It may be appropriate for ASP to consider other antibiotics that provide both antibacterial activity and anti-inflammatory properties. Two such classes include the fluoroquinolones and tetracyclines. Over thirty years ago the fluoroquinolones were shown to modulate the host-response interaction Enterobacterales of various phenotypes, including ESBL-and metallo-beta-lactamase-producing isolates and Gram-negative non-pseudomonal non-fermenters such as A. baumannii and S. maltophilia, should be also considered as empirical agents. We may never identify the actual contribution of bacterial co-pathogens and therefore will not understand how critical antibiotics will be or have been successful in the current pandemic. Likely, the incidence will vary according to the institutions' MDRO profiles and infection control policies. In the meantime, many resources have been dedicated to development of anti-viral therapies, vaccines, and immune modulators. Complicating the empiric use of broad-spectrum antibiotics is the danger of emergence of antibiotic resistance. A c c e p t e d M a n u s c r i p t 9 Despite the current lack of early microbiological data in pneumonia patients suffering from COVID-19 infection, empirical use of antibiotics is common. Without further guidance when to initiate antibiotic therapy and which regimens, and in light of the rapidly destructive nature of pulmonary pathogenesis, ASP efforts should focus on the selection of antibiotics with combined in vitro potency and an appropriate spectrum of activity (against early pneumonia or later hospital-acquired pneumonia), anti-inflammatory effects and immune modulation, and overall patient safety. Concomitantly, all empiric antibiotic therapies used to treat co-infections associated with SARS-CoV-2 infections must be assessed for risk of adverse drug reactions, development of Clostridioides difficile infection, disturbance of the protective microbiome, and emergence of resistance. These considerations are important in patients who may be more prone to adverse effects of antibiotics given any multi-organ dysfunction attributable to the primary viral infection. A c c e p t e d M a n u s c r i p t 10 Authorship statement: All authors had a role in study design, conceiving and writing the manuscript. According to the guidelines of the International Committee of Medical Journal Editors (ICMJE, www.icmje.org) all authors met the criteria for authorship and no deserving authors have been omitted. EG is on the apeakers bereau for Allergan and Merck, and the advisory board for Acrux Pharmaceuticals LLC, Bio K+, Merck, Shionogi, Inc., Isnsmed, and Kindred Hospital System. MR is an employee of Melinta Therapeutics Inc. GT has received consulting fees from Shionogi Inc., Melinta Therapeutics, Ferring, Inc., and Summit plc. This manuscript does not include factors necessitating patient consent. 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