Examining pharmacological management in COVID-19 patients with ARDS requiring antifungal therapy during extracorporeal life support.
SARS-CoV-2 infection has led to a drastic increase in the utilization of extracorporeal membrane oxygenation (ECMO) for supportive care. Based on data reported in the Extracorporeal Life Support Organization (ELSO) data set—from the start of the pandemic in North America through April 2021—more than 4000 patients were initiated on ECMO, with a reported 50% in-hospital mortality rate.1 The median duration of ECMO support in the most recent ELSO publication was 13.9 days (interquartile range, 7.8-23.3).2 The longer duration of ECMO support begs the question: Are these patients at higher risk of nosocomial infections compared to other critically ill patients?
Potential reasons for increased nosocomial infections in critically ill patients with COVID-19 include3,4:
Per COVID-19 Real-Time Learning Network, the current data indicate less than 10% rates of bacterial coinfections in patients with the diagnosis of COVID-19 upon presentation. However, with prolonged duration of hospitalization or mechanical ventilation, patients are prone to acquiring nosocomial bacterial and fungal infections. Despite various case series, the epidemiology of COVID-19–associated pulmonary aspergillosis (CAPA) and other fungal coinfections in COVID-19 is not known. The primary focus of this article is to review the diagnosis of fungal infections in population of COVID-19 patients with ARDS requiring support from ECMO and comparing it to the previously published data on its incidence and diagnosis in other viral infections such as Influenza-related ARDS. The secondary focus of this article is to review the published data on pharmacokinetics and pharmacodynamics (PK/PD) of antifungal dosing in ECMO.
Data are lacking in studying the epidemiology of fungal infection in the subpopulation of critically ill patients on ECMO, including the type of ECMO support and variable criteria for clinical diagnosis of invasive fungal infections, which makes the application of these data to clinical practice difficult.
To study the prevalence of fungal infections in ECMO, we should first review its incidence in critically ill patients regardless of their ECMO status.
Candida and Aspergillus are 2 commonly isolated fungi among critically ill patients.5 Schauwvlieghe and colleagues6reported retrospective data on a cohort of mixed immunocompromised and nonimmunocompromised intensive care unit (ICU) patients to identify risk factors for invasive pulmonary aspergillosis (IPA) among polymerase chain reaction–positive influenza A/B patients (n=432) vs patients with severe community-acquired pneumonia as a comparator group (n=321). The diagnosis of IPA was made based on the presence of clinical, radiological, and mycological criteria (Table 1).6
In the subgroup analysis, 12% of patients in the influenza cohort were on ECMO. Within the ECMO subgroup, 19% were diagnosed with IPA. In this cohort, influenza was reported as an independent risk factor for IPA. The study reported a high prevalence of bronchoalveolar lavage (BAL) sampling in approximately half of the influenza cohort (n=233), in which only 60% of the BAL samples were tested for the presence of galactomannan (GM).
To study if prevalence IPA is also applicable to patients with the diagnosis of COVID-19, Lahmer and colleagues recently published the results of the first randomized, controlled trial to study the prevalence of IPA in patients with severe COVID-19 pneumonia (AspCOVID-19 study).7 Based on anecdotal reports on an increased rate of IPA in patients with a diagnosis of COVID-19 and prior reports during the hemagglutinin type 1 and neuraminidase type 1 influenza pandemic, the authors utilized a modified AspICU algorithm for identifying patients with IPA and risk factors associated with this diagnosis. Figure 1 reviews the standardized diagnostic algorithm the AspCOVID-19 investigators utilized for screening and diagnosis of IPA.
Patients were screened for CAPA until extubation. Patients with the diagnosis of CAPA (positive GM antigen from respiratory and/or serum blood) continued to be followed for 28 days.
A total of 32 patients were included in the final analysis of this study, which found no difference in IPA between COVID-19 and the severe influenza-pneumonia groups.
In a published ELSO registry data set from 2006 to 2016 (including both venoarterial ECMO and venovenous ECMO), solid organ transplant, mechanical ventilation, and influenza infection were found to be risk factors for aspergillosis, and renal replacement therapy and sepsis were independently associated with an increased risk of Candida bloodstream infection (C-BSI).8 In this cohort of patients, 10.8% were found to have fungal infection/colonization, 1.3% Aspergillus, and 1.2% C-BSI. This study reported its findings in a retrospective data set from cultures collected at the discretion of the clinicians rather than a protocolized approach (collecting cultures and conducting bronchoscopy or sending biomarkers when an infection is suspected). Although this study may underestimate the actual prevalence of IPA and/or Candida infections, the diagnostic algorithm for IPA proposed by Schauwvlieghe and colleagues6 may lead to inflating the number of actual patients with this diagnosis, secondary to overtesting and possible false-positive diagnoses.
The balance between overtesting and risk stratification based on the patient’s baseline risk factors for C-BSI and IPA needs to be better studied. Future prospective studies are needed to guide clinicians on empiric treatment without waiting for positive cultures versus conducting appropriate diagnostic imaging and microbiological studies first.
Drug pharmacokinetics (PK) may be altered in ECMO due to various factors such as drug sequestration in the ECMO circuit, increased volume of distribution, and altered clearance (organ dysfunction and/or need for continuous renal replacement therapy).9
If the diagnosis of CAPA/C-BSI is confirmed or highly suspected, timely initiation of antifungal therapy is prudent, as these infections have been associated with an increased rate of mortality and length of hospital stay.10
Per the 2020 European Excellence Center for Medical Mycology/International Society for Human and Animal Mycology consensus criteria for research and clinical guidance, voriconazole or isavuconazole is recommended as a first-line treatment option for CAPA.11 This guideline recommends initiating liposomal amphotericin B in cases of azole resistance in CAPA.
Per Infectious Diseases Society of America guidelines, an echinocandin is the recommended first-line therapy for C-BSI in critically ill patients, which can be later deescalated to an azole based on the isolate susceptibility.12 Liposomal amphotericin B is recommended in case of suspected/confirmed azole resistance.
Table 2. PK Studies in ECMO for Various Antifungal Agents13-22Table 2
Mehrnaz Sadrolashrafi, PharmD, BCCCP, is a critical care pharmacist in the medical intensive care unit at Beth Israel Deaconess Medical Center in Boston, Massachusetts. Her clinical interests include septic shock, antimicrobial stewardship in intensive care unit, and drug dosing in ECMO.