key: cord-0711662-5t3rem98 authors: Son, Hyo-Ju; Kim, Tark; Lee, Eunjung; Park, Se Yoon; Yu, Shinae; Hong, Hyo-Lim; Kim, Min-Chul; Hong, Sun In; Bae, Seongman; Kim, Min Jae; Kim, Sung-Han; Yun, Ji Hyun; Jo, Kyeong Min; Lee, Yu-Mi; Lee, Seungjae; Park, Jung Wan; Jeon, Min Hyok; Kim, Tae Hyong; Choo, Eun Ju title: Risk factors for isolation of multi-drug resistant organisms in coronavirus disease 2019 pneumonia: a multicenter study date: 2021-06-17 journal: Am J Infect Control DOI: 10.1016/j.ajic.2021.06.005 sha: 88ffc8f9ceb4db0bd0cb5ddd94759ed6c56cf89e doc_id: 711662 cord_uid: 5t3rem98 OBJECTIVES: Superimposed multi-drug resistant organisms (MDROs) co-infection can be associated with worse outcomes in patients with severe coronavirus disease 2019 (COVID-19), even if these patients were managed with strict airborne and contact precautions. Identifying risk factors for isolation of MDROs is critical to COVID-19 treatment. METHODS: All eligible adult patients with confirmed COVID-19 pneumonia from 10 hospitals in the Republic of Korea between February 2020 and May 2020 were retrospectively enrolled. Using this cohort, epidemiology and risk factors for isolation of MDROs were evaluated. RESULTS: Of 152 patients, 47 with microbial culture results were included. Twenty isolates of MDROs from 13 (28%) patients were cultured. Stenotrophomonas maltophilia (five isolates) was the most common MDRO, followed by methicillin-resistant staphylococcus aureus (four isolates). MDROs were mostly isolated from sputum samples (80%, 16/20). The median time from hospitalization to MDRO isolation was 28 days (interquartile range, 18–38 days). In-hospital mortality was higher in patients with MDRO isolation (62% versus 15%; p = 0.001). Use of systemic corticosteroids after diagnosis of COVID-19 (adjusted odds ratio [aOR]: 15.07; 95% confidence interval [CI]: 2.34–97.01; p = 0.004) and long-term care facility (LTCF) stay before diagnosis of COVID-19 (aOR: 6.09; 95% CI: 1.02–36.49; p = 0.048) were associated with MDRO isolation. CONCLUSIONS: MDROs were isolated from 28% of COVID-19 pneumonia patients with culture data and 8.6% of the entire cohort. Previous LTCF stay and adjunctive corticosteroid use were risk factors for the isolation of MDROs. Strict infection prevention strategies may be needed in these COVID-19 patients with risk factors. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID- 19) , first appeared in China at the end of 2019. It is constantly spreading over the world 1 . Clinical presentation of COVID-19 ranges from asymptomatic to severe cases requiring mechanical ventilation 2 . The fatality rate of COVID-19 is approximately 1.4% 3 . Remdesivir and dexamethasone might be helpful for certain patients. However, because drugs with proven therapeutic effects are limited, supportive treatment and prevention of secondary infections are important as well It is well-known that respiratory viral diseases will make patients vulnerable to bacterial infections. Bacterial infections of S. aureus and S. pneumonia following influenza infection have been reported 4 . There is also a concern of superimposed bacterial infection after SARS-CoV-2 infection. Patients with severe COVID-19 are often indistinguishable from bacterial co-infection based on signs, symptoms, physical findings, and radiographic findings 5 . Bacterial co-infections occur more often in patients requiring intensive care unit and mechanical ventilation with increased disease severity [5] [6] [7] [8] [9] [10] . They are known to be associated with worse outcomes of patients with COVID-19 pneumonia 11 . Understanding the epidemiology and risk factors of MDROs in COVID-19 patients is very important for establishing strategies to treat COVID-19 and prevent infection by MDROs. Although, several studies reported MDRO isolation and antimicrobial stewardship challenges in patients in COVID-19 [12] [13] [14] , only few studies have dealt with risk factors of MDRO isolation in patients with COVID-19 15 . Therefore, the aim of this study was to evaluate incidences of and risk factors for isolation of MDROs in COVID-19 patients. All eligible adult patients with confirmed COVID-19 pneumonia at 10 hospitals in the Republic of Korea between February 2020 and May 2020 were retrospectively evaluated. Figure 1 ). Cases were defined as patients with culture-confirmed MDRO and controls were defined as patients who underwent culture tests, but with negative results or isolated non-MDRO. Data about age, gender, underlying diseases, history of medical institution visit, antibiotics use, isolation of MDROs before admission due to SARS-COV2 infection, types of rooms during hospitalization after admission due to SARS-CoV2 infection, intensive care unit stay, use of systemic corticosteroids, antibacterial agents, and in-hospital mortality were collected. Risk factors for isolation of MDROs were then evaluated. COVID-19 pneumonia was defined when patients with COVID-19 had radiologically relevant findings of SARS-CoV2 infection on chest radiograph or computed tomography 16 . MDROs were defined as seven antibiotic-resistant organisms, including methicillin-resistant Categorical variables were compared using χ2 test or Fisher's exact test as appropriate. Continuous variables were compared using Student's t-test or Mann-Whitney U-test as appropriate. All tests of significance were two-tailed and P values < 0.05 were considered statistically significant. A univariate analysis was performed using a logistic regression to determine independent risk factors associated with isolation of MDROs. Subsequently, multiple logistic regression analysis was performed for variables with a P value < 0.1 in the univariate analysis based on the backward stepwise selection method. Two variables, the use of urinary tract catheter and the use of antibacterial agent after diagnosis of COVID-19, were excluded from the logistic regression analysis as their occurrence was 100%. Results are reported as odds ratio (OR) with 95% confidence interval (CI). All statistical analyses were performed with SPSS for Windows, version 26 (SPSS Inc., Chicago, IL, USA). This study was approved by the Institutional Review Board (IRB) of Soonchunhyang University Seoul Hospital (IRB No. 2020-06-012). Informed consent was waived by the IRB because no intervention was involved and no patient-identifying information was included. A total of 152 patients with COVID-19 pneumonia were identified during the study period. Patients without a culture study (n = 105) were excluded. Clinical characteristics of the entire cohort including patients without a culture study is described in Supplementary Table 1 Table 1 . The median age of these patients was 68 years (interquartile range [IQR]: 62-77 years). Of these patients, 26 (55%) were males. Diabetes mellitus (23%, 11/47) was the most common underlying disease, followed by neurologic disease (19%, 9/47) and chronic lung disease (17%, 8/47). Twelve (26%) patients stayed in LTCF within 90 days before admission due to COVID-19. A total of 34 (72%) patients stayed in negative pressured single room after admission due to COVID-19. Two (4%) patients developed bacteremia and two (4%) developed candidemia and all these patients were included in MDRO group. Twenty-two (47%) patients received antibacterial agents and 36 (77%) received systemic corticosteroids. In-hospital mortality was 28% (13/47). MDROs were detected from 28% (13/47) among patients with culture data and 8.6% (13/152) of the entire cohort. A total of 20 isolates of MDROs were cultured from 13 patients. The median time from COVID-19 diagnosis to MDRO isolation was 28 days (IQR: 18-38 days) (Table 2, Figure 2 ). Characteristics of these 13 patients with MDRO isolation are summarized in Table 2 . Eleven (85%) patients had visited or stayed at any type of healthcare facilities within 90 days before hospitalization. All patients with isolation of MDROs received antibacterial agents and 85% (11/13) used systemic corticosteroids. The number of identified MDRO was as follows: five Stenotrophomonas maltophilia, four MRSA, three CRAB, three CRPA, two ESBL enterobacteriaceae, two VRE, and one CRE. Most bacteria were isolated from sputum (16 isolates). Two MDRO isolates were identified from blood and urine, respectively. In-hospital mortality of patients with MDRO isolation was 62% (8/13). Candida was isolated from four patients with MDRO and polymicrobial non-MDRO was isolated from one patient. Of six patients with monomicrobial non-MDRO isolates, three had non-MDRO isolation from sputum, two had non-MDRO isolation from urine, and one had non-MDRO isolation from sputum and urine. Types of non-MDRO were as follows: two candida species, one klebsiella pneumonia, one Escherichia coli, one Enterococcus faecalis, one Rahnella aquatilis, and one nontuberculous mycobacteria. The median time from COVID-19 diagnosis to non-MDRO isolation was 17 days (IQR: 6-34 days). In-hospital mortality in the non-MDRO group 33% (2/6) (Supplementary Table 2 ). Significant variables in univariate analysis were LTCF admission before diagnosis of (Table 3) . Risk factors for MDRO isolation from the entire cohort including patients without culture data were also evaluated. Not only LTCF stay and receipt of corticosteroids but also mechanical ventilation revealed to be a risk factor of MDRO isolation (Supplementary Table 3 ). The COVID-19 pandemic has highlighted the need for monitoring the use of excess antibiotics and multi-drug resistance 19 In our study, more MDRO tended to be isolated from patients who stayed at the LTCF before COVID-19 diagnosis. Clusters of COVID-19 in LTCF have been widely reported 25, 26 . Patients in LTCF are usually the elderly who have many underlying diseases 26 . They are also at higher risk of antibiotic resistance and more likely to have MDRO colonizations 27 SARS-CoV-2 can cause immune dysregulation due to increased production and circulation of cytokines, leading to hyper-inflammation and defects of lymphoid function 28, 29 . Dexamethasone, a corticosteroid, is strongly recommended as it has been shown to improve survival outcomes for inpatients who require oxygen supplementation 30, 31 . However, the use of corticosteroids for treating COVID-19 might have unintended consequences. The use of corticosteroids is known to be associated with secondary bacterial infection, invasive pulmonary aspergillosis, osteonecrosis of femoral head, and delayed viral clearance in other viral infections. High-dose corticosteroids potentially delayed viral shedding of patients with COVID-19 32 . Our finding that steroid use may promote MDRO infection has great implications. Even during therapeutic use of corticosteroids, it is necessary for clinicians to proceed with caution and steroids should only be given for the shortest recommended duration. Previous studies have found that fewer than 10% of patients with COVID-19 experience coinfections and over 70% receive antibiotics 7, 11, 19, [33] [34] [35] . In the present study, the rate of antibiotic use was 113/152 (74%). Despite a low rate of bacterial co-infection reported in patients with COVID-19, high rates of antimicrobial prescribing have been reported 5, 34, 35 . It is not unreasonable to treat bacterial pneumonia in unwell patients empirically with antimicrobials. However, frequent use of broad-spectrum antibiotics in a hospital setting is a risk factor for hospital-acquired infections by MDROs because these antibiotics will alter microbiota and select naturally resistant bacteria 6, 17 . Previous studies have reported an increase in MRSA after SARS in 2003 and the gaining of antimicrobial-resistance in Gramnegative bacilli after COVID-19 pandemics 19, 36 . One study reported that 100% of COVID-19 patients with MDRO infections received preceding antibiotics 19 . This was also observed in our study. Since administration of antibiotics to COVID-19 patients is heavily dependent on the judgement and experience of frontline clinicians 37 , caution is needed when using empirical antibiotics in patients with COVID-19. Stewardship will play a crucial role in limiting unnecessary antimicrobial use and antimicrobial-resistance. Our study has several limitations. First, this study does not give information on MDRO infection, because positive cultures of MDRO may represent disease or colonization. Although it would be more useful to discriminate MDRO infections from colonization, we assume that understanding the MDRO co-detection in COVID-19 patients is also worthwhile. Second, this study was from the early months of the COVID-19 pandemic, and incidence, microbiology and resistance patterns may differ as the pandemic unfolded and patient management evolved. Third, culture samples were not available for all patients and information about previous bacterial colonization was not known for many patients. Culture implementation was limited due to safety and biosafety of medical staff in a laboratory. Fourth, a retrospective study with a low number of patients included in our analysis might limit the generalizability of our findings. Thus, results of this study should be interpreted cautiously owing to potential bias and confounding factors from an observational study. Furthermore, it would be helpful to perform risk-score stratification with more data and successive internal and external validation for further understanding of MDRO isolation and secondary infection prevention. In conclusion, MDROs were isolated in the significant number of patients with COVID-19. Previous LTCF stay and therapeutic use of corticosteroids were important risk factors for the isolation of MDROs. In-hospital mortality was higher in patients with MDRO isolation. Thus, infection control management, antibiotic stewardship, and surveillance culture to monitor secondary MDRO infection are necessary, especially for patients with COVID-19 outbreak in a long term care facility. Owing to the risk of MDRO infection, corticosteroid usage should be carefully considered only for patients with indication. There are no potential conflicts of interest to declare. All patients with MDRO isolation received antibiotics during hospitalization before MDRO isolation. The model fitted data well in terms of discrimination (C-statistic = 0.83) and calibration (Hosmer-Lemeshow goodness of fit statistic = 2.18, P = 0.34). 26 Figure 2 A Novel Coronavirus from Patients with Pneumonia in China Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention World Health Organization. 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