Antimicrobial stewardship in the ICU in COVID-19 times: the known unknowns

Abstract

Since the start of the COVID-19 pandemic, there has been concern about the concomitant rise of antimicrobial resistance. While bacterial co-infections seem rare in COVID-19 patients admitted to hospital wards and intensive care units (ICUs), an increase in empirical antibiotic use has been described. In the ICU setting, where antibiotics are already abundantly-and often inappropriately-prescribed, the need for an ICU-specific antimicrobial stewardship programme is widely advocated. Apart from essentially warning against the use of antibacterial drugs for the treatment of a viral infection, other aspects of ICU antimicrobial stewardship need to be considered in view of the clinical course and characteristics of COVID-19. First, the distinction between infectious and non-infectious (inflammatory) causes of respiratory deterioration during an ICU stay is difficult, and the much-debated relevance of fungal and viral co-infections adds to the complexity of empirical antimicrobial prescribing. Biomarkers such as procalcitonin for the decision to start antibacterial therapy for ICU nosocomial infections seem to be more promising in COVID-19 than non-COVID-19 patients. In COVID-19 patients, cytomegalovirus reactivation is an important factor to consider when assessing patients infected with SARS-CoV-2 as it may have a role in modulating the patient immune response. The diagnosis of COVID-19-associated invasive aspergillosis is challenging because of the lack of sensitivity and specificity of the available tests. Furthermore, altered pharmacokinetic/pharmacodynamic properties need to be taken into account when prescribing antimicrobial therapy. Future research should now further explore the 'known unknowns', ideally with robust prospective study designs.

Keywords: Antimicrobial stewardship; COVID-19; ICU; Recommendations.

Fig. 1

Flowchart depicting a diagnostic and therapeutic algorithm (taken from Dutch SWAB Guideline addendum, unpublished data, reprinted with permission). ^@ This does not mean that lung CT should be standard of care for all ICU patients with COVID-19. Instead, the flow diagram is meant to be used when a CT is done during routine patient care and shows cavitating or well-described nodular lung lesions. * The standard of care of COVID-19 is likely to change in the future but for now it includes thromboembolic prophylaxis, therapy with dexamethasone and exclusion of pulmonary embolism by CT. Other causes of clinical respiratory deterioration may also need to be have been excluded (pneumothorax, atelectasis, progressive pulmonary fibrosis). ^$ If there is growth of Aspergillus, phenotypic resistance testing can be used, e.g. with VIPcheck^TM on site or at a mycology reference laboratory. In culture-negative but GM-positive BAL samples, CYP51A Aspergillus PCR can be used to exclude the presence of the two most frequent resistance mutations conferring azole resistance (TR₃₄/TR₄₆ pattern). ^# Formally, only when septate hyphae of 2.5–4.5 μm in diameter are seen AND the presence of Aspergillus DNA is also documented, the infection is classified as proven CAPA. However, the presence of hyphae compatible with Aspergillus suffices to start antifungal therapy. ^† Serum GM is generally negative but increases the probability of CAPA if positive in combination with positive BAL GM. ^& It is recommended to start antifungal therapy as early as possible. If BAL test results are available the same day, these can be awaited before antifungal therapy is started. If not immediately available, it is recommended to consider starting antifungal therapy pre-emptively while awaiting test results. CT, computed tomography, ICU, intensive care unit; COVID-19, coronavirus disease 2019; GM, galactomannan; BAL, bronchoalveolar lavage; CAPA, coronavirus-associated pulmonary aspergillosis.

Fig. 2

Pharmacokinetics/pharmacodynamic (PK/PD) alterations in COVID-19 patients. AKI, acute kidney injury; ARDS, acute respiratory distress syndrome; DM, diabetes mellitus; ECMO, extracorporeal membrane oxygenation; eGFR, estimated glomerular filtration rate; HT, hypertension; RRT, renal replacement therapy; Vd, volume of distribution.