Complicated Milieu of Issues During COVID-19 Affected Stewardship

BY JAMES S. LEWIS II, PHARMD

Antibiotic stewardship is a core tenet in hospital and public health as a tool to minimize the emergence of antibacterial resistance.1 Great strides have been made during the past decade to increase awareness of the overuse of antibiotics in medicine. Randomized trials have facilitated a “shorter is better” mindset in medical practice that has allowed for improved antibiotic use in many commonly encountered infections.2 In addition, a variety of other tools and data reporting structures now exist to improve the use of this critical class of medicines.3

Since its arrival in 2020, COVID-19 has created a complicated milieu of issues resulting in a step backward for many antibiotic stewardship programs: Diagnostic uncertainty while managing critically ill patients, the recognition that many moderately ill patients with COVID-19 would need ICU care, and the reemergence of the long-held perception that antibiotics can only help have coalesced around COVID19 patients in the ICU. These issues combined with a new and unknown infectious entity have led clinicians to an uncomfortable space where a patient’s clinical syndrome could be COVID-19; however, it could be a bacterial infection, and providers are very aware of the deleterious effects of delayed effective antibacterial therapy on bacterial infection–related mortality.4

This scenario affected antibiotic stewardship programs in many clinical settings, as clinicians often were reassigned to assist in the implementation of COVID-19 therapeutic plans and strategies.5 These efforts, while certainly important and worthy of the dedicated resources, have resulted in marked reductions in the time dedicated to antibiotic stewardship rounds and responsibilities. Furthermore, early in the pandemic, there was considerable concern about bacterial superinfections that have historically

been associated with influenza infections.6-8 This concern combined with the recognition that many hospitalized patients with COVID-19 rapidly decompensate to ICU care led to worries that bacterial superinfections similar to that reported with influenza would be a real clinical challenge.

However, similar rates of bacterial superinfection were not observed early in the pandemic, and many early reports did not identify bacterial superinfections until late in the ICU stay of COVID-19 patients.9,10 Many of these data identified nosocomial gram-negative bacteria such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter species as common pathogens in late-onset infections in the ICU. Whether these isolates were infections or colonization of upper and lower airways with common ICU pathogens highlighted the clinical challenge presented by diagnostic uncertainty in critically ill patients. With the margin of error sometimes razor thin for critically ill patients, providers justifiably prescribed just-in-case antibiotics.

In the early months of the pandemic, emerging literature described high rates of ventilator-associated pneumonia in patients who required ICU care.6,8 These studies were limited by small numbers but widely cited and discussed, as they arrived at a time when the medical community was desperate for information surrounding the management and implications of this new virus. These and other data instilled in providers a concern that COVID-19 patients could often develop bacterial superinfections, so antibacterial treatment would likely be needed. An editorial published several months later discussed this belief and sounded a word of caution that an “appreciable minority of critically ill” patients would develop superinfections, and that as risk factors such as age, comorbidities, and length of stay accumulated, this problem would become more prevalent and recognized.11

Reports from early in the pandemic quickly resulted in the realization that influenza pneumonia and post–COVID-19 pneumonia were markedly different in their epidemiology. Likely causative pathogens associated with influenza superinfections, such as Staphylococcus aureus and Streptococcus pneumoniae of community origin, were infrequently identified in COVID-19 patients in whom superinfections often occurred late in the hospital course and associated with gram-negative nosocomial pathogens.6,10,11 Recent data also have suggested a markedly different cytokine profile in COVID-19 patients compared with those with influenza, which may contribute to these differences.12 Also, the onset for post–COVID-19 bacterial pneumonia appeared to be approximately 17 days after symptom onset or 8 days after intubation.11 In hospitalized patients, this immediately raises the question of colonization versus true infection, a discussion that was largely overlooked in many early data sets. This lack of discussion was understandable, given the novelty of COVID-19 and the high mortality rates observed early in the pandemic. However, it set a precedent that these infections were not uncommon and that mortality was high—the ideal scenario to create excessive antibiotic use.

Discussions regarding the importance and apparent lack of antibiotic stewardship in COVID-19 patients began early in the pandemic with the recognition that this viral infection was leading to frequent antibiotic use, particularly in hospitalized patients.9 Cultures obtained on day 1 or 2 of hospitalization in COVID19 patients frequently remained negative or only occasionally grew community-associated organisms. However, in COVID-19 patients requiring ICU care, P. aeruginosa appeared after the first week and quickly became the predominant pathogen along with a rapid shift to nosocomial pathogens.9

Ominously, reports of invasive fungal infections began to appear in COVID-19 patients. Early reports of invasive aspergillosis in COVID-19 patients drove early empiric antifungal therapy in critically ill COVID-19 patients.13 The recurring theme in bacterial and fungal infections in this space was the difficulty in distinguishing between true infections and colonization. However, the high mortality rates reported in these series created a situation in which providers were often justifiably unwilling or unable to remove antibacterial/ antifungal coverage.

Once again, as often seen in the critical care/sepsis literature, the difficulty facing clinicians in distinguishing between viral and bacterial infections in critically ill patients leads to antibiotic use. The lack of a widely available diagnostic test that clearly and reliably differentiates between the 2 creates uncertainty and leads to the use of just-in-case antibiotics. Procalcitonin (PCT), while initially promising in the outpatient respiratory infection arena, has proven to be

of limited value during the pandemic. The test had already begun to fall out of favor in some institutions after international guidelines for nosocomial pneumonia were unable to firmly recommend its use and recent US data suggesting that the test was of limited benefit in stewardship.14,15 These diagnostic limitations combined with the uncertainties of a new clinical entity with a high mortality rate created a situation in which clinicians would be slow to stop antibiotics, even when presented additional data such as a negative PCT result.

This lack of clarity coupled with a new clinical entity at a time when antibiotic stewardship teams were redirected to COVID-19 responsibilities highlights the need for improved diagnostic capabilities in this space. A recent publication evaluating host–gene expression as a way to distinguish between bacterial and viral infections is encouraging, but previous diagnostic platforms promised to improve the situation and were overshadowed by the clinical realities.16,17

Similar challenges have arisen in the arena of antifungal stewardship in COVID-19 patients, particularly in the realm of invasive Aspergillus infections and the diagnosis of COVID-19–associated pulmonary aspergillosis. Reports of invasive aspergillosis in patients with COVID-19 appeared early in the pandemic; rates of the dreaded condition varied markedly across institutions.13 Similar to trends observed for bacterial infections, considerable difficulty exists in determining between colonization and infection. Standard radiographic findings typically identified in invasive aspergillosis patients with hematologic malignancies often are not present, and other diagnostic tests such as galactomannan and 1,3-beta-D-glucan are of questionable value and have not been evaluated in COVID19 patients.18 Again, this placed stewardship programs in a difficult position: Faced with critically ill patients with positive cultures, radiological results complicated by the presence of COVID-19–induced lung damage and acute respiratory distress syndrome, and the increasing use of immunosuppressive regimens for COVID-19 management, antifungals were often initiated based on the literature from other disease states suggesting high mortality rates and the importance of early effective antifungal therapy.

Candidemia also has been increasingly recognized in critically ill COVID-19 patients; recent data have painted a bleak picture of the clinical outcomes in these patients.19 One-fourth of patients with candidemia in the CDC’s Emerging Infections Program were COVID-19–positive between April and August 2020. In-hospital mortality was 2 times higher in COVID-19 patients with candidemia compared with controls (62.5%), and the fact that these patients were candidemic left no doubt as to the question of colonization or infection. However, many of these patients lacked the usual risk factors associated with the development of candidemia. Instead, it was reported by the authors that the use of factors associated with COVID-19 care, such as immunosuppressive medications, appeared to play a larger role. In an accompanying editorial, it was noted that almost all of these patients had received antibiotics in the 2 weeks prior to their candidemia diagnosis, despite bacterial coinfections with COVID-19 at presentation being rare. The author noted the importance of understanding that viral sepsis is a real entity and that antibiotic stewardship was largely lacking in these patients, underscoring the important role of diagnostic uncertainty and the challenges this has created for stewardship programs.20

COVID-19 has presented numerous hurdles for antibiotic stewardship programs during the last 2 years of the pandemic. Hopefully the peak of the pandemic has passed, and more routine activities and duties for antibiotic stewardship personnel can resume. COVID-19 has reminded us that we have a long way to go in optimizing the use of antibiotics in critically ill patients, and diagnostic uncertainty often results in unnecessary and potentially harmful antibiotic use.

1. CDC. Antibiotic Use in the United States, 2021 Update: Progress and Opportunities. Accessed April 25, 2022. https://www.cdc. gov/antibiotic-use/pdfs/stewardship-report-2021-H.pdf 2. Spellberg B, Rice LB. The shorter is better movement: past, present, future. Clin Microbiol Infect. 2022 Apr 15. doi:10.1016/ j.cmi.2022.04.00 3. Jenkins TC, Tamma PD. Thinking beyond the “core” antibiotic stewardship interventions: shifting the onus for appropriate antibiotic use from stewardship teams to prescribing clinicians.

Clin Infect Dis. 2021;72(8):1457-1462.

4. Ferrer R, Martin-Loeches I, Phillips G, et al. Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: results from a guideline-based performance improvement program. Crit Care Med. 2014;42(8):1749-1755.

5. Wimmer MR. The impact of coronavirus disease 2019 (COVID-19) on the antimicrobial stewardship pharmacist workforce: a multicenter survey. Antimicrobial Stewardship Healthcare Epidemiol. 2022;2(1):e56.

6. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-1062. 7. Sharifipour E, Shams S, Esmkhani M, et al. Evaluation of bacterial co-infections of the respiratory tract in COVID-19 patients admitted to ICU. BMC Infect Dis. 2020;20(1):646.

8. Quartuccio L, Sonaglia A, McGonagle D, et al. Profiling COVID-19 pneumonia progressing into the cytokine storm syndrome: results from a single Italian centre study on tocilizumab versus standard of care. J Clin Virol. 2020;129:104444.

9. Stevenson DR, Sahemey M, Cevallos Morales J, et al. Improving antimicrobial stewardship in critically-ill patients with COVID-19.

Clin Infect Dis. 2021;72(11):e926.

10. Hughes S, Troise O, Donaldson H, et al. Bacterial and fungal coinfection among hospitalized patients with COVID-19: a retrospective cohort study in a UK secondary-care setting.

Clin Microbiol Infect. 2020;26(10):1395-1399.

11. Clancy CJ, Nguyen MH. Coronavirus disease 2019, superinfections, and antimicrobial development: what can we expect?

Clin Infect Dis. 2020;71(10):2736-2743.

12. Karaba AH, Zhou W, Hsieh LL, et al. Differential cytokine signatures of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza infection highlight key differences in pathobiology. Clin Infect Dis. 2022;74(2):254-262. 13. Thompson III GR, Cornely OA, Pappas PG, et al. Invasive aspergillosis as an under-recognized superinfection in COVID-19.

Open Forum Infect Dis. 2020;7(7):ofaa242. 14. Kalil AC, Metersky ML, Klompas M, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases

Society of America and the American Thoracic Society.

Clin Infect Dis. 2016;63(5):e61-e111. 15. Huang DT, Yealy DM, Filbin MR, et al. Procalcitonin-guided use of antibiotics for lower respiratory tract infection. N Engl J Med. 2018;379(3):236-249. 16. Ko ER, Henao R, Frankey K, et al. Prospective validation of a rapid host gene expression test to discriminate bacterial from viral respiratory infection. JAMA Netw Open. 2022;5(4):e227299. 17. Wils J, Saegeman V, Schuermans A. Impact of multiplexed respiratory viral panels on infection control measures and antimicrobial stewardship: a review of the literature. Eur J Clin

Microbiol Infect Dis. 2022;41(2):187-202. 18. Koehler P, Bassetti M, Chakrabarti A, et al. Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020

ECMM/ISHAM consensus criteria for research and clinical guidance. Lancet Infect Dis. 2021;21(6):e149-e162. 19. Seagle EE, Jackson BR, Lockhart SR, et al. The landscape of candidemia during the coronavirus disease 2019 (COVID-19) pandemic. Clin Infect Dis. 2022;74(5):802-811. 20. McCarty T. Candidemia and severe coronavirus disease 2019: which risk factors are modifiable? Clin Infect Dis. 2022;74(5):812-813.

James S. Lewis II, PharmD, FIDSA, is the ID pharmacy supervisor and an associate professor in the departments of Pharmacy and Infectious Diseases, at Oregon Health & Science University, in Portland, Oregon.

*Thank you for rating IDSE above average compared with other publications. 2021 Kantar Media Study, Med/Surg, Tables 102, 103 and 104.