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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">COVID-19: don’t neglect antimicrobial stewardship principles!</title>
<author><name sortKey="Huttner, Benedikt" sort="Huttner, Benedikt" uniqKey="Huttner B" first="Benedikt" last="Huttner">Benedikt Huttner</name>
<affiliation><nlm:aff id="aff1">Division of Infectious Diseases, Geneva University Hospitals, Geneva, Switzerland</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff2">Faculty of Medicine, University of Geneva, Geneva, Switzerland</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff6">Université de Lorraine, CHRU-Nancy, Infectious Diseases Department, F-54000, Nancy, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Catho, Gaud" sort="Catho, Gaud" uniqKey="Catho G" first="Gaud" last="Catho">Gaud Catho</name>
<affiliation><nlm:aff id="aff1">Division of Infectious Diseases, Geneva University Hospitals, Geneva, Switzerland</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pano Pardo, Jose Ram N" sort="Pano Pardo, Jose Ram N" uniqKey="Pano Pardo J" first="José Ram N" last="Pano-Pardo">José Ram N Pano-Pardo</name>
<affiliation><nlm:aff id="aff4">Division of Infectious Diseases, Hospital Clínico Universitario, IIS Aragón, Zaragoza, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pulcini, Celine" sort="Pulcini, Celine" uniqKey="Pulcini C" first="Céline" last="Pulcini">Céline Pulcini</name>
<affiliation><nlm:aff id="aff5">Université de Lorraine, APEMAC, équipe MICS, F-54000, Nancy, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff6">Université de Lorraine, CHRU-Nancy, Infectious Diseases Department, F-54000, Nancy, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Schouten, Jeroen" sort="Schouten, Jeroen" uniqKey="Schouten J" first="Jeroen" last="Schouten">Jeroen Schouten</name>
<affiliation><nlm:aff id="aff3">Radboud Center for Infectious Diseases; Intensive care department, Nijmegen, The Netherlands</nlm:aff>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmc">7190532</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190532</idno>
<idno type="RBID">PMC:7190532</idno>
<idno type="doi">10.1016/j.cmi.2020.04.024</idno>
<idno type="pmid">NONE</idno>
<date when="2020">2020</date>
<idno type="wicri:Area/Pmc/Corpus">000292</idno>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">COVID-19: don’t neglect antimicrobial stewardship principles!</title>
<author><name sortKey="Huttner, Benedikt" sort="Huttner, Benedikt" uniqKey="Huttner B" first="Benedikt" last="Huttner">Benedikt Huttner</name>
<affiliation><nlm:aff id="aff1">Division of Infectious Diseases, Geneva University Hospitals, Geneva, Switzerland</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff2">Faculty of Medicine, University of Geneva, Geneva, Switzerland</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff6">Université de Lorraine, CHRU-Nancy, Infectious Diseases Department, F-54000, Nancy, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Catho, Gaud" sort="Catho, Gaud" uniqKey="Catho G" first="Gaud" last="Catho">Gaud Catho</name>
<affiliation><nlm:aff id="aff1">Division of Infectious Diseases, Geneva University Hospitals, Geneva, Switzerland</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pano Pardo, Jose Ram N" sort="Pano Pardo, Jose Ram N" uniqKey="Pano Pardo J" first="José Ram N" last="Pano-Pardo">José Ram N Pano-Pardo</name>
<affiliation><nlm:aff id="aff4">Division of Infectious Diseases, Hospital Clínico Universitario, IIS Aragón, Zaragoza, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pulcini, Celine" sort="Pulcini, Celine" uniqKey="Pulcini C" first="Céline" last="Pulcini">Céline Pulcini</name>
<affiliation><nlm:aff id="aff5">Université de Lorraine, APEMAC, équipe MICS, F-54000, Nancy, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff6">Université de Lorraine, CHRU-Nancy, Infectious Diseases Department, F-54000, Nancy, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Schouten, Jeroen" sort="Schouten, Jeroen" uniqKey="Schouten J" first="Jeroen" last="Schouten">Jeroen Schouten</name>
<affiliation><nlm:aff id="aff3">Radboud Center for Infectious Diseases; Intensive care department, Nijmegen, The Netherlands</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">Clinical Microbiology and Infection</title>
<idno type="ISSN">1198-743X</idno>
<idno type="eISSN">1469-0691</idno>
<imprint><date when="2020">2020</date>
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</back>
</TEI>
<pmc article-type="discussion"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Clin Microbiol Infect</journal-id>
<journal-id journal-id-type="iso-abbrev">Clin. Microbiol. Infect</journal-id>
<journal-title-group><journal-title>Clinical Microbiology and Infection</journal-title>
</journal-title-group>
<issn pub-type="ppub">1198-743X</issn>
<issn pub-type="epub">1469-0691</issn>
<publisher><publisher-name>Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases.</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmc">7190532</article-id>
<article-id pub-id-type="publisher-id">S1198-743X(20)30232-9</article-id>
<article-id pub-id-type="doi">10.1016/j.cmi.2020.04.024</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>COVID-19: don’t neglect antimicrobial stewardship principles!</article-title>
</title-group>
<contrib-group><contrib contrib-type="author" id="au1"><name><surname>Huttner</surname>
<given-names>Benedikt</given-names>
</name>
<degrees>MD, MS</degrees>
<email>benedikt.huttner@hcuge.ch</email>
<xref rid="aff1" ref-type="aff">1</xref>
<xref rid="aff2" ref-type="aff">2</xref>
<xref rid="aff6" ref-type="aff">6</xref>
<xref rid="cor1" ref-type="corresp">∗</xref>
</contrib>
<contrib contrib-type="author" id="au2"><name><surname>Catho</surname>
<given-names>Gaud</given-names>
</name>
<degrees>MD</degrees>
<xref rid="aff1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author" id="au3"><name><surname>Pano-Pardo</surname>
<given-names>José Ramón</given-names>
</name>
<degrees>MD</degrees>
<xref rid="aff4" ref-type="aff">4</xref>
</contrib>
<contrib contrib-type="author" id="au4"><name><surname>Pulcini</surname>
<given-names>Céline</given-names>
</name>
<degrees>MD, PhD</degrees>
<xref rid="aff5" ref-type="aff">5</xref>
<xref rid="aff6" ref-type="aff">6</xref>
</contrib>
<contrib contrib-type="author" id="au5"><name><surname>Schouten</surname>
<given-names>Jeroen</given-names>
</name>
<degrees>MD, PhD</degrees>
<xref rid="aff3" ref-type="aff">3</xref>
</contrib>
<aff id="aff1"><label>1</label>
Division of Infectious Diseases, Geneva University Hospitals, Geneva, Switzerland</aff>
<aff id="aff2"><label>2</label>
Faculty of Medicine, University of Geneva, Geneva, Switzerland</aff>
<aff id="aff3"><label>3</label>
Radboud Center for Infectious Diseases; Intensive care department, Nijmegen, The Netherlands</aff>
<aff id="aff4"><label>4</label>
Division of Infectious Diseases, Hospital Clínico Universitario, IIS Aragón, Zaragoza, Spain</aff>
<aff id="aff5"><label>5</label>
Université de Lorraine, APEMAC, équipe MICS, F-54000, Nancy, France</aff>
<aff id="aff6"><label>6</label>
Université de Lorraine, CHRU-Nancy, Infectious Diseases Department, F-54000, Nancy, France</aff>
</contrib-group>
<author-notes><corresp id="cor1"><label>∗</label>
Corresponding author. Division of Infectious Diseases, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1205, Genève, Switzerland Faculty of Medicine, University of Geneva, Geneva, Switzerland, Tel.: +41 22 372 92 42. <email>benedikt.huttner@hcuge.ch</email>
</corresp>
</author-notes>
<pub-date pub-type="pmc-release"><day>30</day>
<month>4</month>
<year>2020</year>
</pub-date>
<pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="epub"><day>30</day>
<month>4</month>
<year>2020</year>
</pub-date>
<history><date date-type="received"><day>4</day>
<month>4</month>
<year>2020</year>
</date>
<date date-type="rev-recd"><day>17</day>
<month>4</month>
<year>2020</year>
</date>
<date date-type="accepted"><day>21</day>
<month>4</month>
<year>2020</year>
</date>
</history>
<permissions><copyright-statement>© 2020 Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases.</copyright-statement>
<copyright-year>2020</copyright-year>
<copyright-holder></copyright-holder>
<license><license-p>Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.</license-p>
</license>
</permissions>
</article-meta>
<notes><p id="misc0010">Editor: Professor L Leibovici</p>
</notes>
</front>
<body><p id="p0010">The SARS-CoV-2 pandemic is currently dominating every aspect of health care across the globe putting other longer-term public health issues, including the steady rise of antimicrobial resistance, in the shadow. Yet, there will be a time after COVID-19 and we should not lose sight of problems that will persist and may potentially be exacerbated by this pandemic.</p>
<p id="p0015">An important proportion of patients with COVID-19 present with fever and cough. Those requiring hospitalization because of dyspnea usually present bilateral radiologic infiltrates.[<xref rid="bib1" ref-type="bibr">1</xref>
, <xref rid="bib2" ref-type="bibr">2</xref>
] Despite the viral origin of COVID-19, a standard reflex by physicians is to start treatment with antibiotics since cough, fever and radiologic infiltrates are hallmarks of bacterial community-acquired pneumonia which requires antibiotic treatment. The anxiety and uncertainty surrounding the pandemic and the absence of antiviral treatments with proven efficacy are probably other contributors to the widespread and excessive prescription of antibiotics.</p>
<p id="p0020">The rationale for antibiotic treatment in patients with COVID-19 seems to be based on the experience with bacterial superinfection in influenza, where most studies report initial co-infection or secondary bacterial pneumonia between 11% and 35% of cases, mostly by <italic>Streptococcus pneumoniae</italic>
and <italic>Staphylococcus aureus</italic>
.[<xref rid="bib3" ref-type="bibr">3</xref>
] The exact incidence of bacterial superinfection in COVID-19 is unknown and while there are anecdotal reports of documented bacterial superinfections the incidence seems to be much lower than in severe influenza.[<xref rid="bib4" ref-type="bibr">4</xref>
] Among 16’654 patients in Italy deceased of COVID-19 (and as such the subpopulation with most severe diseases) “superinfections” were reported in 11% of cases (data as of April 09, 2020)(<ext-link ext-link-type="uri" xlink:href="https://www.epicentro.iss.it/coronavirus/bollettino/Report-COVID-2019_9_aprile.pdf" id="intref0010">https://www.epicentro.iss.it/coronavirus/bollettino/Report-COVID-2019_9_aprile.pdf</ext-link>
). In Wuhan, where the pandemic started, most patients with COVID-19 seem to have received antibiotics, mostly respiratory quinolones, although Chinese guidelines state “inappropriate use of antibacterial drugs should be avoided, especially the broad-spectrum antibacterial drugs” <ext-link ext-link-type="uri" xlink:href="http://kjfy.meetingchina.org/msite/news/show/cn/3337.html" id="intref0015">http://kjfy.meetingchina.org/msite/news/show/cn/3337.html</ext-link>
. [<xref rid="bib5" ref-type="bibr">5</xref>
] Recommendations regarding the use of antibiotics in patients with suspected or confirmed COVID-19 vary by country, with some recommendations likely to encourage antibiotic use in a large proportion of patients (see <xref rid="appsec1" ref-type="sec">supplementary table 1</xref>
), particularly because it is unclear what “pneumonia” means in the context of a viral infection that may cause radiologic alterations even in asymptomatic patients (many guidance documents recommend antibiotic treatment for patients with COVID-19 and “pneumonia”).[<xref rid="bib6" ref-type="bibr">6</xref>
] This scenario is worsened by the fact that health professionals involved in treating patients with COVID-19 have a high workload and show high level of stress and might therefore not be in the position to modulate clinical practice recommendations.[<xref rid="bib7" ref-type="bibr">7</xref>
]</p>
<p id="p0025">We acknowledge that given the difficulty to differentiate COVID-19 from bacterial pneumonia, the uncertainty regarding bacterial superinfections, the lack of specific antiviral agents with proven efficacy, and the high mortality, antibiotics should be considered as part of the empirical treatment strategy for the most severe suspected or confirmed COVID-19 cases (e.g. patients with hypoxic respiratory failure requiring mechanical ventilation), provided their use is regularly reevaluated. We believe, however, that even during a pandemic antibiotics should be used responsibly and sparingly, given concerns about the global supply chain of these valuable medicines potentially leading to antibiotics not being available for those who need them, the increased nursing workload associated with parenteral administration of antibiotics and the many unintended negative long-term consequences associated with antibiotic overuse potentially leading to increased morbidity and mortality in the future.</p>
<p id="p0030">In order to base antibiotic stewardship in the times of COVID-19 on a more evidence-based approach, several unmet research needs that could improve management of COVID-19 patients should be addressed as outlined in <xref rid="tbl1" ref-type="table">table 1</xref>
.<table-wrap position="float" id="tbl1"><label>Table 1</label>
<caption><p>The most urgent need for data concerns patients with requiring hospitalization because of respiratory failure (with or without the need for mechanical ventilation). Given the large scale of the pandemic, ultimately data will be needed for all types of patients except maybe those with the least severe presentations. To increase external validity studies should be conducted in several centers whenever possible.</p>
</caption>
<alt-text id="alttext0010">Table 1</alt-text>
<table frame="hsides" rules="groups"><thead><tr><th>Research need</th>
<th>Study design</th>
<th>Challenges</th>
<th>Comment</th>
</tr>
</thead>
<tbody><tr><td>(1) Establish the exact incidence of bacterial co-infection and superinfection at the different phases of the disease</td>
<td>Observational cohort study or in the context of randomized controlled trials assessing other interventions</td>
<td>Adequate diagnostics of lower respiratory tract infections require bronchoalveolar lavage (BAL) which may be difficult to perform (risk of respiratory deterioration, risk of exposure for healthcare personnel, resource constraints)<break></break>
Limited availability of bacteriologic tests in the context of the pandemic)</td>
<td><list list-type="simple" id="ulist0010"><list-item id="u0010"><label>•</label>
<p id="p0145">Ideally combined with (2)</p>
</list-item>
</list>
</td>
</tr>
<tr><td>(2) Assess the diagnostic performance of biomarkers to rule out/rule in bacterial superinfection</td>
<td>Observational cohort study or in the context of randomized controlled trials assessing other interventions</td>
<td>The reference standard (presence or absence of bacterial super/co-infection) may be difficult to ascertain and have suboptimal accuracy by itself (see (1))</td>
<td><list list-type="simple" id="ulist0015"><list-item id="u0015"><label>•</label>
<p id="p0150">Ideally combined with (1)</p>
</list-item>
<list-item id="u0020"><label>•</label>
<p id="p0155">Ideally studies should assess more than 1 biomarker</p>
</list-item>
</list>
</td>
</tr>
<tr><td>(3) Better understand the contribution of infection versus immune response in the different phases of COVID (first days after start of symptoms versus second week)</td>
<td>Observational cohort study or in the context of randomized controlled trials (e.g. of immune-modulating interventions such as steroids or IL-6 or IL-1 inhibitors)</td>
<td>See (1). Obtaining BAL samples may be challenging</td>
<td></td>
</tr>
<tr><td>(4) Assess the impact of the COVID pandemic on antibiotic use and resistance in all settings (community, nursing homes, hospitals)</td>
<td>National, regional, local surveillance of antibiotic use and resistance based on established networks</td>
<td>Many confounding factors need to be taken into account (e.g. overcrowding of hospitals)</td>
<td></td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
<p id="p0035">Until better evidence is available, we propose the following approach:<list list-type="simple" id="olist0010"><list-item id="o0010"><label>(1)</label>
<p id="p0040">Antibiotics should be reserved for the patients with the most severe presentations (e.g those with high oxygen demands and rapidly progressing respiratory failure). Biomarkers [C-reactive protein, procalcitonin] may play a role in deciding for which patients antibiotics can be withheld, but this needs further investigation. Patients without severe respiratory compromise should be managed without antibiotics. As in hospitals the diagnostic work-up often includes a CT thorax, this allows for a more exact determination of the typical infiltrate associated with bacterial LRTI as opposed to the typical glass ground opacities seen in COVID-19. This extra diagnostic (CT scan for conventional pneumonia patients is not common) should empower physician to withhold empirical antibiotics in patients with characteristic images for COVID-19 on CT.[<xref rid="bib8" ref-type="bibr">8</xref>
]</p>
</list-item>
<list-item id="o0015"><label>(2)</label>
<p id="p0045">If antibiotics are started, microbiological tests should ideally be obtained beforehand (e.g. urinary antigen test for <italic>Legionella</italic>
, blood cultures) although this has to be balanced with the potentially limited availability of these tests due to supply problems during the pandemic.</p>
</list-item>
<list-item id="o0020"><label>(3)</label>
<p id="p0050">Antibiotic treatment should be rapidly reevaluated and stopped as soon as possible if the probability of bacterial superinfection is considered low (e.g. persistently low inflammatory biomarkers, negative bacteriologic tests, CT scan non-compatible with COVID).</p>
</list-item>
<list-item id="o0025"><label>(4)</label>
<p id="p0055">If antibiotic treatment is continued, an oral switch should be performed rapidly if the patient is able to take oral medication and the absence of fever should not be required as a criterion since patients with COVID-19 often show persistent fever over several days.</p>
</list-item>
<list-item id="o0030"><label>(5)</label>
<p id="p0060">Antibiotic treatment duration should not exceed 5 days in most cases as generally recommended in most guidelines for community acquired pneumonia.[<xref rid="bib9" ref-type="bibr">9</xref>
]</p>
</list-item>
<list-item id="o0035"><label>(6)</label>
<p id="p0065">If antibiotics are considered a beta-lactam providing coverage for <italic>S. pneumoniae</italic>
+/- methicillin-susceptible <italic>S. aureus</italic>
should be the first option (e.g. amoxicillin + clavulanic acid or 3<sup>rd</sup>
generation cephalosporins). Once-a-day administration (where applicable) or continuous administration of beta-lactam antibiotics should be considered to decrease the use of personal protective equipment which may be in short supply in many places. Macrolides and quinolones should be avoided because of their cardiac side effects (considering that other agents associated with cardiac side effects such as (hydroxy)chloroquine, lopinavir/ritonavir are used in many places notwithstanding the limited evidence for their efficacy) and impact on antimicrobial resistance. If atypical coverage is considered necessary (e.g. COVID-19 not yet confirmed and suspicion of <italic>Legionella</italic>
infection) consideration should be given to doxycycline. Routine atypical coverage does, however, not seem warranted given the low a priori probability of superinfection with atypical pathogens.[<xref rid="bib10" ref-type="bibr">10</xref>
]</p>
</list-item>
<list-item id="o0040"><label>(7)</label>
<p id="p0070">For patients in intensive care units requiring mechanical ventilation standard measures to prevent ventilator-associated pneumonia (VAP) and other healthcare associated infections should be applied. Empiric treatment of VAP in these patients should be based on local and individual patient-level resistance data and treatment should be adapted according to microbiologic results (ideally from the lower respiratory tract).</p>
</list-item>
<list-item id="o0045"><label>(8)</label>
<p id="p0075">Anecdotal data about the impact of azithromycin on SARS-CoV-2 viral load does not justify the routine administration of this antibiotic before confirmatory trials are completed.</p>
</list-item>
<list-item id="o0050"><label>(9)</label>
<p id="p0080">Antibiotics should not be given “prophylactically” to prevent bacterial pneumonia (use of selective digestive decontamination [SDD] may be an exception in intensive care units where this is established practice).</p>
</list-item>
<list-item id="o0055"><label>(10)</label>
<p id="p0085">If during COVID-19 treatment a secondary respiratory worsening occurs one should re-consider the use of antibiotics after taking adequate respiratory samples and performing radiologic diagnostics. It is, however, important to realize that secondary worsening commonly seen at day 7-9 is in most cases probably attributable to the hyperinflammatory phase (adaptive immune reaction) rather than a bacterial superinfection.[<xref rid="bib11" ref-type="bibr">11</xref>
] Other causes of respiratory worsening should be ruled out, such as cardiogenic failure (myocarditis is common), pulmonary embolism (thrombotic events are commonly reported) or fluid overload</p>
</list-item>
<list-item id="o0060"><label>(11)</label>
<p id="p0090">Finally, it should be kept in mind that even during the COVID pandemic patients will present with other infections such as urinary tract infections, skin and soft tissue infections, intraabdominal infections etc. which should be considered in the differential diagnosis (especially in the elderly) and be managed according to established guidelines. Importantly, the suspicion of COVID-19 should not delay the adequate management of these patients.</p>
</list-item>
<list-item id="o0065"><label>(12)</label>
<p id="p0095">National recommendations taking into account this stewardship perspective should be promoted, as well as sharing of best practices</p>
</list-item>
</list>
</p>
<p id="p0100">The COVID-19 pandemic puts a tremendous pressure on all healthcare professionals, not the least on infectious disease and infection control specialists. We advocate that antibiotic stewardship principles will continue to be applied and promoted even in these challenging times.</p>
<sec id="sec1"><title>Conflicts of interest</title>
<p id="p0105">BH, GC, CP, JS, JP none to declare.</p>
</sec>
<sec id="sec2"><title>Funding</title>
<p id="p0110">No external funding.</p>
</sec>
<sec id="sec3"><title>Authors' contributions</title>
<p id="p0115">Conceptualization: BH and J.</p>
<p id="p0120">Writing – Original Draft: BH.</p>
<p id="p0125">Writing – Review & Editing: all authors.</p>
</sec>
</body>
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<sec id="appsec1" sec-type="supplementary-material"><label>Appendix A</label>
<title>Supplementary data</title>
<p id="p0135">The following is the Supplementary data to this article:<supplementary-material content-type="local-data" id="ec1"><media xlink:href="mmc1.docx"></media>
</supplementary-material>
</p>
</sec>
<ack id="ack0010"><title>Acknowledgments</title>
<p>We would like to thank Lorenzo Moja for his useful comments. This manuscript has been endorsed by the ESGAP (ESCMID Study Group Antimicrobial Stewardship) executive committee.</p>
</ack>
<fn-group><fn id="appsec2" fn-type="supplementary-material"><label>Appendix A</label>
<p id="p0140">Supplementary data to this article can be found online at <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1016/j.cmi.2020.04.024" id="intref0020">https://doi.org/10.1016/j.cmi.2020.04.024</ext-link>
.</p>
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</pmc>
</record>
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