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.
An important proportion of patients with COVID-19 present with fever and cough. Those requiring hospitalization because of dyspnea usually present bilateral radiologic infiltrates. [1, 2] 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.
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 coinfection or secondary bacterial pneumonia between 11% and 35% of cases, mostly by Streptococcus pneumoniae and Staphylococcus aureus. [3] 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. [ show high level of stress and might therefore not be in the position to modulate clinical practice recommendations. [7] 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 CLM-20-17325 consequences associated with antibiotic overuse potentially leading to increased morbidity and mortality in the future.
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 table 1.
Until better evidence is available, we propose the following approach:
(1) 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 . [8] (2) If antibiotics are started, microbiological tests should ideally be obtained beforehand (e.g. urinary antigen test for Legionella, blood cultures) although this has to be balanced with the potentially limited availability of these tests due to supply problems during the pandemic.
CLM-20-17325
(3) 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).
(4) 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. 
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. [11] 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 (11) 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 CLM-20-17325 established guidelines. Importantly, the suspicion of COVID-19 should not delay the adequate management of these patients.
(12) National recommendations taking into account this stewardship perspective should be promoted, as well as sharing of best practices
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. Table 1 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.
(1) Establish the exact incidence of bacterial co-infection and superinfection at the different phases of the disease Observational cohort study or in the context of randomized controlled trials assessing other interventions 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) Limited availability of bacteriologic tests in the context of the pandemic)
• Ideally combined with (2) (2) Assess the diagnostic performance of biomarkers to rule out / rule in bacterial superinfection Observational cohort study or in the context of randomized controlled trials assessing other interventions
The reference standard (presence or absence of bacterial super / co-infection) may be difficult to ascertain and have suboptimal accuracy by itself (see (1)) • Ideally combined with (1) • Ideally studies should assess more than 1 biomarker 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) See (1). Obtaining BAL samples may be challenging (4) Assess the impact of the COVID National, regional, local surveillance Many confounding factors need pandemic on antibiotic use and resistance in all settings (community, nursing homes, hospitals) of antibiotic use and resistance based on established networks to be taken into account (e.g. overcrowding of hospitals)