key: cord-0805073-ihtwxanu
authors: Schouten, Jeroen; De Waele, Jan; Lanckohr, Christian; Koulenti, Despoina; Haddad, Nisrine; Rizk, Nesrine; Sjövall, Fredrik; Kanj, Souha S.
title: Antimicrobial stewardship in the ICU in COVID times: the known unknowns
date: 2021-07-30
journal: Int J Antimicrob Agents
DOI: 10.1016/j.ijantimicag.2021.106409
sha: d77493682cb3339c77ae77d662cc3849b5ed6c3c
doc_id: 805073
cord_uid: ihtwxanu

Since the start of the COVID-19 pandemic, there has been concern about the concomitant rise of antimicrobial resistance (AMR). While bacterial co-infections seem rare in COVID-19 patients admitted to hospital wards and 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 Program (ASP) 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 ICU stay is difficult and the much-debated relevance of fungal and viral co-infections adds to the complexity of empirical antimicrobial prescribin. Biomarkers such as PCT for the decision to start antibacterial therapy for ICU nosocomial infections seem to be more promising in COVID-19 than in non-COVID-19 patients. In COVID-19 patients CMV reactivation is an important factor to consider when assessing patients infected with SARS-CoV-2 as it may have a role in modulating patient immune response. The diagnosis of COVID-19 associated Invasive Aspergillosis (CAPA) is challenging because of the lack of sensitivity and specificity of the available tests. Further, altered PK/PD 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.

Since the start of the COVID-19 pandemic, there has been concern about the concomitant rise of another -equally relevant but more chronic-pandemic: antimicrobial resistance (AMR) (1) . While bacterial co-infections seem rare in COVID-19 patients admitted to hospital wards and ICUs (2, 3) , an increase in empirical antibiotic use has been described in this group of patients (4) . In the ICU setting, where antibiotics are already abundantly -and often inappropriately-prescribed, the need for an ICU specific Antimicrobial Stewardship Program (ASP) has been widely advocated (5, 6) . This warning should be emphasized during the current pandemic (7) . Apart from essentially warning against the use of antibacterial drugs for the treatment of a viral infection, relevant aspects of ICU antimicrobial stewardship need to be reconsidered in view of the clinical course and characteristics of patients admitted with COVID-19. In this paper, we describe how some of the established principles of ICU antimicrobial stewardship (use of biomarkers, empirical treatment, Pk/Pd and treatment of ICUacquired infections) may need adaptation in COVID-19 infected patients. In this rapidly evolving pandemic, we are aware that the available knowledge is still limited. Therefore, in a field with lack of significant evidence for stewardship strategies, we point to the need for more studies and suggest the direction of such research.

In this review, we want to focus on key aspects of AMS that are impacted most by COVID19. This may relate to patients as well as organizational factors. These topics were not randomly selected but rather chosen by all authors based on the fact that they either lack definitive data and clear evidence or remain controversial . We identified the empirical use of antibacterials, PK changes in patients with COVID19, use of biomarkers and opportunistic infections as most relevant for the clinician at the bedside.

Empirical antibiotics are often administered in severely ill patients when a bacterial infection is suspected as the primary cause of thecritical illness. Viral pneumonia can predispose to bacterial superinfections by causing structural damage to the lung tissue and weakening of the host immunity.

In previous influenza pandemics, bacterial co-infections and superinfections were associated with excessive mortality (8) .

Severe COVID-19 infection presents with clinical, radiological and laboratory signs that mimic those of bacterial pneumonia and initiation of empirical antibiotic treatment has therefore been common practice. At the same time, different from our experience with influenza infections, it is clear that upon initial presentation to the hospital bacterial infection is rarely present. Recent studies have reported that 60 -98% of patients received empirical antibiotic treatment whereas the prevalence of documented bacterial co-infections ranges from 1 to 8% depending on the setting, with higher numbers reported in patients admitted to ICUs (2, 3, 9, 10) . Thus, this widespread empirical antibiotic use is not supported by contemporary data.

However, it is very challenging to diagnose bacterial superinfection in patients with COVID-19 for many reasons. The most prevalent radiological findings in these patients are ground-glass opacities, consolidation and a mix of these two features in a predominantly peripheral distribution (11) . There are no specific radiographic features that distinguish between viral and bacterial pneumonia, particularly the atypical bacterial pneumonias. As the viral infection progresses so do the radiological findings and the distinction between that and a superimposed infection is often difficult (12) .

Furthermore, severe COVID-19 is accompanied by a profound systemic inflammatory reaction, reflected by elevated inflammatory markers such as C-reactive protein (CRP), ferritin, and interleukin-6 (IL-6). Procalcitonin (PCT) is an inflammatory marker considered to rise more in bacterial compared to viral infections. However, in a recent systematic review and meta-analysis on the ability of PCT to distinguish bacterial from nonbacterial causes of community acquired pneumonia (CAP), the pooled sensitivity and specificity was only 0.55 when using a cut off value of 0.5 µg/L concluding that this is too low to be of real clinical value (13) . In COVID-19, PCT levels have been shown to correspond to disease severity with the highest values seen in patients needing ICU-care and elevated values also associated with poor outcome (14, 15) . Even though the cut-off value of 0.5 µg/L does not seem useful, the specificity of PCT increases with increasing levels. Thus, in a patient presenting with double-digit PCT levels, a bacterial infection should be highly considered and managed accordingly. Further details on the utility of PCT are discussed below.

Therefore, based on the available evidence, we recommend not to initiate antimicrobials routinely in patients admitted to the emergency departments (ED) or ICU with proven COVID-19. When superimposed infection is suspected, appropriate microbiological sampling is highly recommended whenever possible advised. Whereas one may be reluctant to sample intubated COVID-19 patients invasively, taking appropriate precautions during endotracheal aspirate sampling will minimize the risk of viral transmission.

For patients developing septic shock however, empirical antibiotics are indicated and should be used according to standard antibiotic guidelines with the aim of providing as optimal antibiotic coverage as possible. The choice of antibiotic should be influenced by local susceptibility patterns and patient related factors and immune status. In view of the emerging literature on the predominance of Gram negative pathogens in ventilated associated pneumonia (VAP) in ICU COVID patients including multidrug resistant pathogens (Clancy CG CID, Chen X Appl Microbiol Biotechnol, Li J, Antimicrob Resi Infect Control) ) empiric coverage shall include adequate therapy for such pathogens. Also since centers have reported increased incidence of Gram positive bacteremias with coagulase negative staphylococci and Enterococcus fecalis (Giacobbe Dr, Eur J Clin Invest) empiric coverage is recommended in the right clinical scenario. Once culture and susceptibility results are available, directed therapy with prompt de-escalation to a narrow spectrum antibiotic, whenever possible, is recommended to complete the remaining duration of treatment. Covid-19 infection often presents with a prolonged state of pro-inflammatory response, and it can therefore be challenging to assess treatment response based on the normalization of laboratory and clinical markers such as leukocytes count, CRP, fever, need for vasopressors etc. This may be even more difficult when patients are treated with immunomodulatory agents such as corticosteroids or tocilizumab. A fixed duration of therapy is therefore recommended depending on the site of infection and should be guided by available evidence indicating that shorter duration of 5-8 days for hospital acquired pneumonia (HAP) for example is without disadvantages compared to older recommendations of 10 -14 days (17) .

COVID-19 is characterized by inflammatory damage to endothelial tissues, particularly in the lung. It is thus logical to expect that a wide range of inflammatory markers are elevated in COVID-19 and that these parameters correlate with disease severity and outcomes (18) . This observation also holds true for procalcitonin (PCT) (14, 19) . Recent evidence has questioned the traditional "dogma" that PCT is able to distinguish bacterial and viral infections (20, 21) and suggests that it may more likely be a "host-response-marker", rather than a specific determinant of the etiology of infections. Still, as bacterial superinfections have the potential to complicate viral pneumonias and thus increase inflammatory activation, PCT might have a discriminatory potential.

Originally, the value of PCT in COVID-19 is three-fold. First, as discussed above, PCT may have a decisive role in the identification of patients in whom antibiotics may be safely withheld, particularly in an ED settings with non-critically-ill patients. This is an established use of PCT that can be "applied" from its use in the management of other respiratory infections (22) . Second, serial measurements of PCT offers insight into the "inflammatory dynamics" of patients, where secondary increases should trigger a work-up for bacterial superinfections (7) . Third, PCT-guidance may be used once antibiotic therapy has been initiated to shorten the duration of treatment (23, 24, 25) . This is also an established use of PCT, and may be part of an institutional AMS program.

All these aspects of PCT-guidance of antibiotic therapy have been successfully applied in patients with COVID-19. A study looking at the effects of an AMS-intervention comprising institutional treatment guidelines in combination with frequent "audit and feedback" (called the "COVID-19 huddle") incorporated PCT-guidance for both initiation and discontinuation of antibiotics (26) . The intervention was able to reduce antibiotic prescription significantly. In three other studies with similar PCT-thresholds to withhold therapy, antibiotic use was safely reduced in patients with "low" PCT values (27-29). The incorporation of PCT into clinical decision-making might thus help to withhold or rapidly discontinue antibiotics when bacterial infections appear unlikely in the setting of low PCT values. Evidence for such a strategy was also provided by a retrospective multicenteranalysis from the Netherlands, where the effect of clinical guidelines including a PCT-algorithm were examined (2) . Despite abundant antibiotic prescriptions on admission to the hospital, the duration of treatment was kept relatively short with a median of 2 days.

In the ICU, the value of PCT to identify secondary infections was demonstrated in an analysis of 66 critically ill patients (30) . While both CRP and PCT were variably elevated in many patients on initial presentation, secondary increases were clearly associated with super-infections complicating COVID- 19 . This effect was particularly distinctive for PCT.

Taken together, the measurement of PCT on diagnosis of COVID-19 may influence the decision to initiate or withhold antibiotics. If PCT is low (<0,5 µg/L), it appears safe to not give antibiotics in the absence of overt organ failure. In the uncommon situation where this is unclear and antibiotics are started, a repeated measurement after 24-48 hours is recommended. If PCT remains low, stopping antibiotics should be highly considered. If a bacterial co-infection is likely or proven and antibiotic therapy is started, repeated measurements every 48-72 hours make sense to guide the duration of therapy. If PCT decreases by >80% from the initial value or falls below 0,5 µg/L, stopping antibiotics is reasonable.

Secondary increases of PCT during ICU admission should trigger a careful evaluation for infectious complications, including extrapulmonary sources (urinary tract, soft-tissue, and bloodstream infections).

It is unclear what effect immunomodulatory therapies (e.g. dexamethasone but also IL-1 and IL-6 blocking agents) have on biomarkers. Such interventions are increasingly advocated for patients admitted to the ICU with severe COVID pneumonia (31) . Earlier studies showed that while induction of CRP may be attenuated by corticosteroids, PCT appears to be unaltered (32) . In one study on the use of anakinra, an IL-1 blocking agents in COVID-19, a decrease of PCT (p = 0.001), was more pronounced in the anakinra group (33) . Another study showed that tocilizumab treatment is associated with reduction of CRP and PCT in COVID-19 infection (34) . Whether this reduction reflects the intended attenuation of a dysregulated immune reaction ("cytokine storm") or is a hallmark of serious immunosuppression is uncertain at this moment. It is also not clear if the dynamics of CRP and PCT are suppressed in bacterial superinfection, jeopardizing the indicative value of these parameters.

Since early in the course of the COVID-19 pandemic there was a concern about the emergence of invasive pulmonary aspergillosis (IPA) as viral pneumonias are known to increase patients' susceptibility to fungal co-infections (35) . Invasive fungal infections including aspergillosis were reported during the SARS-Co-V1 outbreak in 2002 (36, 37) . Similarly, aspergillosis is known to complicate the course of severe influenza pneumonia and to increase morbidity and mortality in this population (38, 39) . Following the onset of the COVID-19 pandemic, several reports emerged on IPA complicating severe COVID-19 disease and increasing mortality (40 -45) including reports on azole resistant aspergillus pneumonia (46, 47) . In addition, reports on emerging Candida auris in the times of COVID-19 have emerged in countries where this fungus had not been previously reported (Allaw F et al, Pathogens 2021). Overuse and abuse of antifungal agents might be partly responsible.

Coronavirus associated pulmonary aspergillosis (CAPA) was coined to refer to invasive aspergillosis that complicates acute respiratory distress syndrome (ARDS) in patients with severe COVID-19

pneumonia. While bacterial pneumonia may be over-diagnosed in critically ill COVID-19 patients, CAPA poses diagnostic challenges in clinical practice. Therefore, one year after the onset of the pandemic, it is necessary to address these two questions: how to differentiate colonization from invasive disease in critically ill COVID-19 patients and what is the true incidence of CAPA?

The diagnosis of IPA is particularly problematic in COVID-19 as evidenced by a wide range of reported incidences among ICU patients: 3.3% to 30% in different case series (48, 49) . IPA is well defined in patients with neutropenia, immunosuppression and organ transplant using radiologic diagnostic criteria (EORTC/MSG criteria as either proven, probable or possible) (50, 51) . Likewise, the AspICU group proposed and validated an algorithm (52) for diagnosing IPA in non-neutropenic ICU patients, and introduced the term Putative Invasive Pulmonary Aspergillosis (PIPA) (53) . Applying these diagnostic criteria to COVID-19 ARDS may not be valid for a number of reasons (54) In a prospective Italian cohort (48), 30-day mortality was higher in patients with suspected CAPA.

Another prospective study from the UK (49) revealed a trend towards lower mortality with antifungal therapy. Hence, it is essential to establish diagnosis and expedite treatment to reduce mortality. An expert panel proposed consensus criteria for a case definition of CAPA and provided up-to-date management recommendations for the diagnosis and treatment (57) . They recommend to consider investigations for CAPA with any of the clinical findings in COVID-19 patients with refractory respiratory failure for more than 5-14 days who are critically ill: refractory fever for more than 3 days or a new fever after a period of defervescence of longer than 48 h while on appropriate antibiotic therapy, in the absence of any other obvious causes; worsening respiratory status (ex. tachypnea or increasing oxygen requirements); hemoptysis; and pleural friction rub or chest pain. Imaging will not differentiate CAPA from ARDS complicating COVID-19, However, IPA should be highly considered when nodularities or lung cavitations are noted on lung CT. The panel recommended to collect lower respiratory tract samples for microbiologic cultures in addition to the use of (serum and/or BAL) galactomannan and PCR as well as 1-3 beta-D-Glucan if available. The latter tests have a low sensitivity but high specificity in non-neutropenic patients. We suggest a diagnostic and treatment algorithm as depicted in figure 2.

As mentioned earlier, the literature abounds with reports of case series and cohorts of patients with CAPA. Two prospective cohorts (56, 58) found the incidence of CAPA to be 14.1% and 27.7% respectively after a median of 4 (2-8) days from ICU admission. A systematic review summarized 85 published cases (59) and found that the mean age at the time of presentation was 67 years, and that the majority of patients were male (75.4%), the vast majority had no pre-existing immunocompromising conditions. However, comorbidities such as type 2 diabetes mellitus, obesity, hypertension, and COPD were fairly common. Leukopenia is another risk factor. White et al. (58) found that the use of corticosteroids and COPD were important for development of CAPA in addition to mechanical ventilation. One study found an increased risk with the use of azithromycin prior to ICU admission (60) . This needs to be verified in future studies. In a cohort from France (61) where the AspICU algorithm was used, there were fewer cases of putative aspergillosis in COVID-19 ARDS patients compared to non-COVID-19 ARDS but there was no difference in aspergillus colonization between the two groups.

Therefore, it may be legitimate to ask whether CAPA really exists. How does CAPA differ from the IPA generally described in ICU patients? How does it differ from Influenza Associated Invasive Aspergillosis? After all, all share similar risk factors, contribute alike to mortality and morbidity and deserve the same treatment. The difference lies in the diagnosis and the difficulty applying those criteria to CAPA. While more research is needed to define the real incidence of CAPA, understand the risk factors in order to mitigate them, and study treatment and outcomes, it is essential to further develop diagnostic criteria specific to COVID-19 associated invasive aspergillosis.

Severe COVID-19 manifests as viral pneumonia causing acute respiratory distress syndrome (ARDS) and as a heightened immune activation resulting in a "cytokine storm" potentially leading to multiorgan failure. Elderly patients appear to be significantly more susceptible to complications of COVID-19 (62) . According to some observations, mortality from COVID-19 was greatest in cities and regions with a large proportion of elders among their populations. Immuno-senescence, which is a gradual decline in innate and acquired immunity seen in the elderly, could be contributing to the inability to control initial infection with SARS-CoV-2, resulting in severe disease and death (63, 79) .

There may be an association between latent CMV infection and immune-senescence. The prevalence of latent CMV infection increases with age and in itself could be a major driver of immunesenescence and inflammation (63, 79, 80) 

differentiated T-cells accompanied by a decrease in naïve T-cells, potentially leading to immune modulation and immune deficiency seen with older age (81) (82) (83) . This may result in a decreased ability to fight other viruses, such as SARS-CoV-2 (63). On another hand, CMV infection and reactivation is also accompanied by a rise in inflammatory markers, which may predict an increased vulnerability of the elderly population to the cytokine storm associated with COVID-19 (63) .

CMV reactivation in COVID-19 may result from the stress and from the use of IL-1 inhibitors, IL-6 inhibitors, glucocorticoids, and other immunobiological therapies (64) (65) (66) . We reviewed the potential roles and interactions between CMV infection and/or reactivation and SARS-CoV-2 in critically ill nonneutropenic patients. CMV reactivation is common in critically ill ICU patients; it is usually associated with poor outcomes and increased morbidity and mortality (67) (68) (69) (70) (71) (72) . CMV reactivation can present as viremia and could include end-organ damage such as colitis and pneumonitis. CMV seropositive at the time of hospitalization, but none had CMV reactivation. However, the incidence of EBV reactivation in this study was significant with an incidence of 95.2% in ICU patients, and 83.6% in sub-ICU patients (74) . We found only one report of SARS-CoV-2 and CMV co-infection in a 93 year-old woman who had bilateral pneumonia and lymphocytopenia. The patient had CMV viremia with elevated CMV IgG (>180 U/ml) and IgM (38.7 U/ml) levels. She received lopinavirritonavir and hydroxychloroquine but passed away 6 days after her admission, secondary to acute respiratory distress syndrome. A few reports described CMV end-organ damage in critically ill COVID-19 patients, specifically colitis and other GI involvement (65, 75, 76) . All three case reports describe patients who were treated with ganciclovir. Two of the patients were successfully treated and fully recovered from the infection while one patient had partial resolution of symptoms with residual gastrointestinal inflammation after treatment (65, 75, 76) . CMV reactivation might be an important factor to consider in COVID patients as it may have a role in modulating patient immune response and therefore increasing the risk of other opportunistic pathogens, as well as a potential effect on COVID-19 viral elimination and response to the cytokine storm. Data is currently scarce and further research is needed to assess the incidence and outcomes of CMV reactivation on morbidity and mortality in the context of COVID-19 to help guiding recommendations for therapy and follow-u.

Just like other patients in the ICU, the PK of multiple drugs maybe severely affected in patients with COVID-19. The most important contributors to pk changes in critically ill patients are changes in the volume of distribution (Vd), changes in protein binding, and changes in drug clearance (figure 1) (78) (79) (80) (81) (82) (83) (84) (85) (86) (87) (88) (89) (90) (91) (92) .

Increases in the Vd have been described in small patient series reporting on PK of antivirals and other drugs, and it can be expected that this is also the case for many antibiotics. The use of extracorporeal techniques may add to this risk, as well as obesity, which is a common feature of patients with severe COVID-19 disease (82) . On the other hand, fluid administration in patients with COVID-19 may be less aggressive compared to sepsis and septic shock, resulting in smaller changes in Vd.

Protein binding of antimicrobials is also affected. Hypoalbuminemia is a common finding in patients with COVID-19.;In a large series of ICU patients, hypoalbuminemia was very common in patients who did not survive (83) and has been identified as a risk factor for mortality in a study from China (80) . Renal clearance is the main route of elimination for many antibiotics used in the ICU. In COVID-19 patients, kidney function may be altered for many reasons. Patients with COVID-19 often have comorbidities; a large study from Italy found that hypertension and cardiovascular disease are most common, with chronic kidney disease (CKD) only present in 3 percent of patients. On the other hand, a Spanish study reported CKD in 6.7% of patients (9.7% in > 65 years cohort), while another study from the United Kingdom reported end-stage renal failure in 13% of the COVID-19 ICU admissions (81, 84) . Acute kidney injury (AKI) has been widely reported in hospitalized patients with COVID-19, seems to be multifactorial, but its pathophysiology is not fully elucidated [refs] .. It typically develops throughout hospital stay and is most frequently reported in patients with severe disease and in those with lower eGFR at presentation (85) . Reported incidences are variable (86), but AKI incidence up to 76% in ICU patients has been reported (ref), ), as well as need for renal replacement therapy (RRT) as high as for more than a quarter of ICU patients (84, 87) .

Augmented renal clearance (ARC) on the other hand, has been identified as a cause of increased elimination of antibiotics, leading to subtherapeutic concentrations (88) . Patients presenting with COVID-19 have some clinical features that could be linked to ARC, such as fever and hyperinflammation. Published data on the incidence of ARC in COVID-19 patients at this moment are scarce. A recent study from Tomasa-Irriguible et al. documented ARC in nearly 40% of a small group of COVID-19 patients admitted to the ICU (89); unfortunately, no details on the clinical characteristics related to ARC are reported. ARC was an uncommon finding in a small series of 20 patients in whom TDM of beta lactam antibiotics was reported (90) ; the median measured creatinine clearance was 98 milliliters per minute. It should be taken into consideration that ARC might not be that prominent in COVID-19 cohorts, as a high percentage of the patients are elderly and, apart from the effect of possible comorbidities, the aging process itself may cause a decline in renal function (91, 92) . Finally, the use of extracorporeal techniques is often required, with CRRT and ECMO as primary techniques (82) , both of which are known to impact PK of antibiotics. ECMO poses particular challenges as drug sequestration and hypoalbuminemia all resulting in increased Vd for many antibiotics.

A few studies have reported on antibiotic concentrations in patients with COVID-19. One small study from France describes a high inter-individual variability of beta lactam antibiotic concentrations despite similarities in clinical features (90) . The authors also reported a high risk of toxicity and recommend using TDM for monitoring. Toxicity was a particular concern in patients at the later stages of antimicrobial therapy.

The question then is how can we improve dosing? Basic principles of antimicrobial dosing remain the same in patients with infections complicating COVID19, and both the pathogen and the host should be considered important when selecting the appropriate dose. As explained above, the Vd may be higher, and drug clearance variable, putting the patients at risk for both underdosing and overdosing, and strategies should be aligned to this risk profile.

In order to increase target attainment, a variety of strategies including extended and continuous infusion of selected antibacterials, and use of a loading dose is mandatory when using these infusion strategies. Renal function should be closely monitored to early identify impairment. Monitoring should not only include creatinine levels/clearance or urine volume, but also other factors, such as the presence of hematuria and proteinuria; in a very recent meta-analysis, although two-thirds of the patients with severe COVID-19 had laboratory finding of renal damage (increased creatinine, hematuria, proteinuria), the majority did not fulfil AKI criteria [ref] . Also, where available, TDM is recommended to optimize dosing, both to monitor toxicity and efficacy of the drugs. As reduced kidney function and AKI may be more prevalent in patients with COVID19 compared to sepsis from other causes, TDM is of particular relevance for antibiotics with potential toxicity such as vancomycin or aminoglycosides.

Considering that COVID-19 patients might typically develop severe nosocomial infections such as VAP and bacteremia, the importance of antimicrobial dosing cannot be overestimated. Moreover, involved pathogens may have limited susceptibility for commonly used antimicrobials. Several reports have pointed towards an increased risk of multidrug resistance infections (7); This is partly due to an increased antibiotic use as well as compromised infection prevention strategies during the COVID-19 pandemic.

In summary, COVID19 patients are at high risk for PK changes, and while inadequate concentrations may be encountered, some have a risk for higher concentrations and associated toxicity. Also considering that nosocomial pathogens with higher MICs may be more often encountered with VAP as a typical complicating infection, leniency towards higher concentrations for many antimicrobials is justified. When RRT is required, antibiotic dosing strategies should be adopted to the RRT modality, duration and membrane used. This often poses challenges, particularly when intermittent or SLEDD techniques are used, as PK varies considerably during episodes of on and off RRT. Finally, TDM is of particular importance, while development of population PK and PK-PD models specifically dedicated to COVID-19 patients, might be useful ref].

During the current COVID-19 pandemic, AMS in the ICU setting is challenging. Distinction between infectious and non-infectious (inflammatory) causes of respiratory deterioration during ICU stay is difficult and the much-debated relevance of fungal and viral co-infections adds to the complexity.

Apart from the general recommendations to withhold antibacterial therapy for COVID-19 patients on admission unless patients are hemodynamically unstable, general stewardship principles regarding starting, adapting and stopping antimicrobial treatment remain relevant. However, circumstances specific to COVID-19 patients need to be taken into account, especially related to altered PK/PD properties in these patients. Finally, the value of biomarkers such as PCT for the decision to start antibacterial therapy for nosocomial infections later on in the course of ICU stay seems to be more promising in COVID-19 than in non-COVID-19 patients. Co-infections with fungi and re-activation of other viruses warrant attention although implications for therapy are not clear at this stage. Overuse of antifungal agents is discouraged in an era of emerging antifungal resistance except in scenarios where invasive infections are likely. Future research should now further explore these "known unknowns", ideally with robust prospective study designs. Figure 2 . A flowchart depicting a diagnostic and therapeutic algorithm (deducted from: Dutch SWAB Guideline addendum, unpublished data, reprinted with permission) (@) This does not mean that a 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.

(*) Standard of care. The SOC of COVID-19 is likely to change in the future but for now it includes thromboembolic prophylaxis, therapy with dexamethasone, exclusion of pulmonary embolism with 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 on site or at a mycology reference laboratory. In culture negative but GM positive BAL samples, the CYP51A Aspergillus PCR can be used to exclude the presence of the 2 most frequent resistance mutations that confer azole resistance (TR34/TR46 pattern).

(#) Formally, only when septate hyphae size 2.5 to 4.5 µm in diameter are seen AND the presence of Aspergillus DNA is documented as well, 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. 

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Epidemiology of Invasive Pulmonary Aspergillosis Among Intubated Patients With COVID-19: A Prospective Study

Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance

A National Strategy to Diagnose Coronavirus Disease 2019-Associated Invasive Fungal Disease in the Intensive Care Unit

Invasive Pulmonary Aspergillosis in Patients with SARS-CoV-2 Infection: A Systematic Review of the Literature

Risk factors associated with COVID-19-associated pulmonary aspergillosis in ICU patients: a French multicentric retrospective cohort

Risks of ventilator-associated pneumonia and invasive pulmonary aspergillosis in patients with viral acute respiratory distress syndrome related or not to Coronavirus 19 disease

Why the elderly appear to be more severely affected by COVID-19: The potential role of immunosenescence and CMV

The Ancient and the New":Is there an Interaction between Cytomegalovirus and SARS-CoV-2 Infection?

A Case of Coinfection with SARS-COV-2 and Cytomegalovirus in the Era of COVID-19

COVID-19 and Cytomegalovirus Co-infection: A Challenging Case of a Critically Ill Patient with Gastrointestinal Symptoms

Cytomegalovirus viremia, pneumonitis, and tocilizumab therapy

Cytomegalovirus infection in immunocompetent critically ill adults: literature review. Ann Intensive Care

Cytomegalovirus infection in critically ill patients: associated factors and consequences

Cytomegalovirus reactivation in critically ill immunocompetent patients

Active cytomegalovirus infection is common in mechanically ventilated medical intensive care unit patients

A contributive result of open-lung biopsy improves survival in acute respiratory distress syndrome patients

Cytomegalovirus infection and outcome in immunocompetent patients in the intensive care unit: a systematic review and meta-analysis

Herpes simplex virus and cytomegalovirus reactivations among severe COVID-19 patients

COVID-19 Task Force

EBV DNA increase in COVID-19 patients with impaired Lymphocyte subpopulation count

Cytomegalovirus haemorrhagic enterocolitis associated with severe infection with COVID-19

Cytomegalovirus-Induced Gastrointestinal Bleeding and Pancreatitis Complicating Severe Covid-19 Pneumonia: A Paradigmatic Case

Safety and Efficacy of Antiviral Therapy for Prevention of Cytomegalovirus Reactivation in Immunocompetent Critically Ill Patients: A Randomized Clinical Trial

International Society of Anti-Infective Pharmacology and the Pharmacokinetics and Pharmacodynamics Study Group of the European Society of Clinical Microbiology and Infectious Diseases

Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions

The effect of pathophysiology on pharmacokinetics in the critically ill patient--concepts appraised by the example of antimicrobial agents

Clinical characteristics and outcomes of critically ill patients with novel coronavirus infectious disease (COVID-19) in China: a retrospective multicenter study

Characteristics, complications and outcomes among 1549 patients hospitalised with COVID-19 in a secondary hospital in Madrid, Spain: a retrospective case series study

Clinical characteristics and day-90 outcomes of 4244 critically ill adults with COVID-19: a prospective cohort study

Clinical characteristics of a group of deaths with COVID-19 pneumonia in Wuhan, China: a retrospective case series

Characteristics and outcomes of hospitalised patients with acute kidney injury and COVID-19

Acute Kidney Injury in COVID-19 Patients: An Inner City Hospital Experience and Policy Implications

Acute kidney injury in critically ill patients with COVID-19

Clinical characteristics and outcomes of critically ill patients with COVID-19 admitted to an intensive care unit in London: A prospective observational cohort study

Epidemiology of augmented renal clearance in mixed ICU patients

Low molecular weight heparins in COVID-19 patients: beware of augmented renal clearance! Crit Care

Preliminary therapeutic drug monitoring data of βlactams in critically ill patients with SARS-CoV-2 infection

ESCMID Study Group for Infections in the Elderly (ESGIE). Considerations for the optimal management of antibiotic therapy in elderly patients

Pharmacokinetic and pharmacodynamic alterations in the geriatric patient

Erratum in: Consult Pharm

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