SARS-CoV-2 infection has arguably been one of the most significant challenges of health
care systems around the world in over a century. The coronavirus disease 2019 (COVID-19)
lead to a massive increase in demand for acute care beds in many countries [1]. Here,
we focus on one of the unintended side effects of the surge in COVID-19 patients in
the intensive care unit (ICU).
Under these circumstances, it became challenging to uphold basic principles in patient
management. During the pandemic, the goals of antimicrobial stewardship programs (ASP)
remain unchanged. First, limiting antimicrobial exposure to prevent antimicrobial
resistance in ventilated patients with prolonged ICU stay is highly relevant in the
patient admitted with COVID-19. Second, avoiding toxicity is a particular concern,
as many of the antivirals and antibiotics can have severe side effects and interactions.
Finally, given the high mortality, improving the outcome of the patient with COVID-19
is central.
Remarkably, as the pandemic spread, we have been ignoring many of the antimicrobial
stewardship (AMS) strategies that were developed and implemented in the past decade.
Although there was no evidence that bacterial superinfection was a major problem in
patients admitted to the ICU—there was compelling evidence that the inflammatory response
was the main driver of disease severity—empirical administration of antibiotics was
widespread [2]. This was also advocated by international guidelines [3], based on
extrapolation from other viral diseases e.g., influenza, while for coronavirus infections
in the past, superinfection occurred in only 14% of patients during the total ICU
stay [4]. When bacterial pneumonia develops, this is typically later in the clinical
course, presenting as late-onset ventilator-associated pneumonia [5]. A recent meta-analysis
found that only 3.5% of all COVID-19 patients present with co-infection, and 14% develop
infections at a later stage; in critically ill patients, an estimated 8% developed
infections (including co-infection and secondary infection) [6]. Most of the data
in this meta-analysis come from centers in China and it is not clear how this applies
to other patient populations and settings.
Admittedly the situation was challenging. Patients were in the ICU and ventilated
for much longer than usual, with an inherent risk of nosocomial infections. The diagnostic
approach for bacterial infection was difficult, with the inflammatory response in
COVID-19 mimicking the clinical construct of bacterial infection. Another factor was
the potential risk of transmitting the virus by performing invasive diagnostic procedures.
At the same time, it was more cumbersome to examine a patient as usual due to the
obstacles of donning and doffing each time. The reluctance to disconnect ventilator
circuits and sample the airways because of the aerosol generated in the procedure
made fewer microbiological samples available. Supplementary Table 1 lists challenges
encountered as well as solutions to improve antimicrobial use.
Furthermore, COVID-19 has led to a fundamental reorganization of hospitals and ICUs,
and this new situation also impacted AMS efforts. Also, the care for the patients
was changed in different ways, with non-ICU healthcare workers (HCW) taking care of
critically ill patients, capacity expanded to over 200% in many hospitals, and critically
ill patients admitted to areas of the hospital that were not designed for this purpose.
As a result, infection prevention was under duress, and there was even a risk of personal protective
equipment becoming a vector for horizontal transmission. Finally, the increased workload
for HCW also contributed to this.
So, what can we learn from this experience? Rational infection management remains
of utmost importance. We list some recommendations for this in Supplementary Table
2. More research will be needed to assist in developing evidence based guidance (Supplementary
Table 3). Surely new insights and treatments may continue to challenge ASPs. The use
of immunomodulatory and potentially immunosuppressive drug such as corticosteroids
or interleukin inhibitors may increase patient susceptibility for bacterial, viral
or fungal superinfection, but for now there is no evidence to prophylactically treat
patients with antimicrobials. For practical use, we propose a flow chart to guide
empirical antibiotic therapy (Fig. 1). Also other aspects of AMS should not be forgotten
e.g. appropriate dosing in situations such as acute kidney injury (AKI) or in case
of renal replacement therapy (RRT) or extracorporeal membrane oxygenation (ECMO) use.
Fig. 1
Clinical algorithm for initiating antibiotics in patients admitted with COVID-19 to
the ICU
In summary, the use of antimicrobial drugs in the COVID-19 pandemic highlights the
importance of upholding the AMS principles. Although it is challenging to apply the
concepts used outside of pandemics, we need to reflect on how antimicrobial agents
should be used. We have summarized a number of challenges in this respect, but for
each of them, potential solutions are available. Rational infection management remains
the goal.
Conflicts of interest
JDW: grant from the Flanders Research Foundation (Senior Clinical Investigator Grant);
consulted for Accelerate, Bayer Healthcare, Grifols, MSD, Pfizer (honoraria were paid
to his institution). LD: none. MB: outside the submitted work, MB has participated
in advisory boards and/or received speaker honoraria from Achaogen, Angelini, Astellas,
Bayer, Basilea, BioMérieux, Cidara, Gilead, Menarini, MSD, Nabriva, Paratek, Pfizer,
Roche, Melinta, Shionogi, Tetraphase, VenatoRx and Vifor and has received study grants
from Angelini, Basilea, Astellas, Shionogi, Cidara, Melinta, Gilead, Pfizer and MSD.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Supplementary file1 (DOCX 13 kb)
Supplementary file2 (DOCX 54 kb)
Supplementary file3 (DOCX 56 kb)