antibiotics Review Potential Roles for Probiotics in the Treatment of COVID-19 Patients and Prevention of Complications Associated with Increased Antibiotic Use Ravina Kullar 1,*, Stuart Johnson 2, Lynne V. McFarland 3 and Ellie J. C. Goldstein 4 1 Expert Stewardship, Inc., 320 Superior Avenue, Newport Beach, CA 92663, USA 2 Hines VA Hospital and Loyola University Medical Center, Chicago, IL 60141, USA; [email protected] 3 Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA; [email protected] 4 RM Alden Research Laboratory and the David Geffen School of Medicine at UCLA, Los Angeles, CA 90230, USA; [email protected] * Correspondence: [email protected] Abstract: Medical care for patients hospitalized with COVID-19 is an evolving process. Most COVID-19 inpatients (58–95%) received empiric antibiotics to prevent the increased mortality due to ventilator-associated pneumonia and other secondary infections observed in COVID-19 patients. The expected consequences of increased antibiotic use include antibiotic-associated diarrhea (AAD) and Clostridioides difficile infections (CDI). We reviewed the literature (January 2020–March 2021) to explore strategies to reduce these consequences. Antimicrobial stewardship programs were effective in controlling antibiotic use during past influenza epidemics and have also been shown to reduce healthcare-associated rates of CDI. Another potential strategy is the use of specific strains of Citation: Kullar, R.; Johnson, S.; probiotics shown to be effective for the prevention of AAD and CDI prior to the pandemic. During McFarland, L.V.; Goldstein, E.J.C. Potential Roles for Probiotics in the 2020, there was a paucity of published trials using these two strategies in COVID-19 patients, but Treatment of COVID-19 Patients and trials are currently ongoing. A multi-strain probiotic mixture was found to be effective in reducing Prevention of Complications COVID-19-associated diarrhea in one trial. These strategies are promising but need further evidence Associated with Increased Antibiotic from trials in COVID-19 patients. Use. Antibiotics 2021, 10, 408. https://doi.org/10.3390/ Keywords: COVID-19; SARSCoV2; Clostridioides difficile; antibiotics; AAD; probiotics; antibiotic antibiotics10040408 stewardship Academic Editor: Nicholas Dixon Received: 23 March 2021 1. Introduction Accepted: 7 April 2021 Published: 9 April 2021 In the year since the first case of coronavirus disease (COVID-19) was reported in Wuhan, China, the pandemic has exploded worldwide, with over 111 million COVID-19 Publisher’s Note: MDPI stays neutral cases and over 2.5 million deaths reported as of February 2021 [1]. The pandemic has with regard to jurisdictional claims in impacted the world on an unprecedented scale, burdening social, economic and healthcare published maps and institutional affil- systems. Lockdown measures instituted in countries during the early stages of the COVID- iations. 19 pandemic prevented an estimated 3.1 million deaths in Europe and 61 million deaths in six selected countries around the world, but the pandemic has continued despite these measures [2,3]. Relaxing control measures in many countries has led to increases in new COVID-19 cases [4]. Globally, 20% of COVID-19 patients have been hospitalized with severe acute respiratory distress, fever or sepsis, and 2–50% also have diarrhea at Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. admission [5,6]. High rates of mortality (16–46%) due to sepsis, respiratory failure, or This article is an open access article ventilator-associated pneumonia (VAP) have been observed in COVID-19 inpatients [7–9]. distributed under the terms and Most (58–95%) COVID-19 inpatients have been placed on empiric antibiotics to prevent conditions of the Creative Commons ventilator-associated pneumonia (VAP) and secondary infections, creating an inherent Attribution (CC BY) license (https:// challenge for antimicrobial stewardship programs (ASP) [7,10]. The justification for the creativecommons.org/licenses/by/ high use of empiric antibiotics has been questioned based on the low rate of co-infections 4.0/). at admission (3–6%), the low rate of secondary bacterial and fungal infections developing Antibiotics 2021, 10, 408. https://doi.org/10.3390/antibiotics10040408 https://www.mdpi.com/journal/antibiotics Antibiotics 2021, 10, 408 2 of 12 during hospitalization (4–14%), and concerns about the complications of the overuse of antibiotics [7,10–16]. Patients admitted with COVID-19 continue to receive empiric antibiotics (58–95%), despite concerns of antibiotic overuse [10]. This increased use of antibiotics has led to concerns relating to complications associ- ated with antibiotic use, including antibiotic-associated diarrhea (AAD) and Clostridioides difficile infections (CDI), the development of allergies or chronic inflammatory bowel dis- ease and the potential for the development of antibiotic resistant bacterial strains [15,17]. Altered intestinal microbiomes have been detected in COVID-19 patients, which may make them more susceptible to AAD or opportunistic pathogens such as C. difficile [18,19]. Two potential strategies suggested to reduce antibiotic complications in COVID-19 patients have included antibiotic stewardship programs to reduce the overuse of empiric antibiotics and the use of specific probiotics to prevent AAD or CDI [10,20]. Probiotics have been previously shown to effectively reduce AAD and CDI among other types of diseases, due to multiple mechanisms of action found in some probiotic strains, including destruction of pathogenic toxins, inference with pathogen attachment to host cells, and the ability to act as an immune regulator among other mechanisms [21–24]. Our paper raises awareness of these issues, and reviews the potential strategies for the following: (1) antimicrobial stewardship programs (ASP) for COVID-19 patients; (2) potential for C. difficile infections or AAD in subsequent waves of COVID-19; (3) use of probiotics to avert collateral damage associated with increased antibiotic use; (4) challenges involved in probiotic use including shifts in taxonomy and Lactobacillus susceptibilities to antibiotics; (5) use of probiotics to treat COVID-19-associated diarrhea. 2. Antimicrobial Stewardship Programs (ASP) and COVID-19 Patients The initial rationale for antibiotic use in COVID-19 patients was based on experiences with bacterial superinfections in influenza patients, which was often the factor precipitating admission to intensive care units (ICU). Various studies reported initial co-infection or sec- ondary bacterial pneumonia in 11–35% of hospitalized patients with influenza, with most of the superinfections caused by Streptococcus pneumoniae or Staphylococcus aureus [25]. However, the literature demonstrates that the same does not hold true for COVID-19, as most COVID-19 patients are admitted to an ICU due to viral respiratory distress and not bacterial pneumonia [16]. The rates of co-infections at admission are also lower in COVID- 19 patients. A recent systematic review and meta-analysis of 31 studies showed that only 7% of hospitalized patients with COVID-19 had evidence of bacterial co-infections, yet >90% received empirical antibiotics [26]. In another study of 989 hospitalized COVID-19 patients in Spain, only 3% had a co-infection at admission and only 4.4% developed a secondary infection while admitted (most due to Staphylococci or Pseudomonas aerugi- nosa) [12]. In addition, antibiotic use in COVID-19 patients has included multiple types of antibiotics and anti-fungal medications. In one study of 99 COVID-19 patients in China, 71% received antibiotics for 3–17 days, 45% received combination antibiotics and 15% were also given anti-fungal medications, but only one patient had a culture-confirmed bacterial co-infection [27]. ASPs have been effective in reducing the overuse of antibiotics in studies done before the COVID-19 pandemic and most have reduced the incidence of healthcare-associated infections [28]. A component in these programs has been to evaluate the rationale behind the use of antibiotics. Buetti et al. retrospectively reviewed 48 intubated ICU patients with COVID-19 over one month to determine if early antibiotic administration decreased mortality [29]. There was no difference in mortality in those who received antibiotics compared to those who did not (26% died with antibiotics vs. 24% died without antibiotics, p = 0.86). Staub et al. reported increased antibiotic use at their medical center in Tennessee USA, after COVID-19 patients began to be admitted and, in response, implemented an ASP for their COVID-19 patients [30]. A significant reduction in antibiotic use was observed after the ASP was implemented. During the spring of 2020, a hospital in New York City experienced an upsurge in admitted COVID-19 patients, which resulted in an increase in Antibiotics 2021, 10, 408 3 of 12 the number of patients on mechanical ventilation and a significant increase in the use of empiric antibiotics [31]. Although their staff adapted their ASP for COVID-19 patients and a reduction in antibiotic use was noted, there were many challenges ranging from increased workflow, staff shortages, limited time to review cases and lack of supplies [31]. ASP for COVID-19 patients should incorporate recent guidelines on which patients should receive empiric antibiotics. The World Health Organization (WHO) released an updated interim guidance for the clinical management of COVID-19 patients, stating