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Risk factors for isolation of multi-drug resistant organisms in coronavirus disease 2019 pneumonia: A multicenter study

      Highlights

      • Multi-drug resistant organisms (MDRO) were isolated from 8.6% of COVID-19 pneumonia.
      • MDROs were detected from 28% (13/47) among patients with culture data.
      • Long-term care facility stay was a risk factor for isolation of resistant organisms.
      • Corticosteroids use in COVID-19 may increase the risk of bacterial co-infection.
      • Strict infection prevention strategies may be needed in patients with risk factors.

      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 (5 isolates) was the most common MDRO, followed by methicillin-resistant staphylococcus aureus (4 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% vs 15%; P = .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 = .004) and long-term care facility (LTCF) stay before diagnosis of COVID-19 (aOR: 6.09; 95% CI: 1.02-36.49; P = .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.

      Keywords

      Introduction

      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.
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      The fatality rate of COVID-19 is approximately 1.4%.
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      WHO Coronavirus Disease (COVID-19) Dashboard.
      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
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      Bacterial co-infections occur more often in patients requiring intensive care unit and mechanical ventilation with increased disease severity.
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      COVID-19, superinfections and antimicrobial development: what can we expect?.
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      They are known to be associated with worse outcomes of patients with COVID-19 pneumonia.
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      Incidence of co-infections and superinfections in hospitalised patients with COVID-19: a retrospective cohort study.
      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,
      • Rawson TM
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      Therefore, the aim of this study was to evaluate incidences of and risk factors for isolation of MDROs in COVID-19 patients.

      Materials and methods

      Patients and study design

      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. COVID-19 was diagnosed by real-time reverse transcriptase polymerase chain reaction (RT-PCR) for SARS-CoV-2 using a PowerChekTM 2019-nCoV Real-time PCR Kit (Kogenebiotech, Seoul, Korea) and an Allplex 2019-nCoV Assay (Seegene, Seoul, Korea) to determine virus using envelope (E) gene and RNA-dependent RNA polymerase (RdRp) gene as two genetic markers. Patients were excluded if cultures for bacteria and fungi were not done (Fig 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.
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      Definition of MDRO and microbiological methods

      MDROs were defined as seven antibiotic-resistant organisms, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), extended-spectrum beta-lactamase (ESBL) producing enterobacteriaceae, carbapenem-resistant enterobacteriaceae (CRE), carbapenem-resistant Acinetobacter baumannii (CRAB), carbapenem-resistant Pseudomonas aeruginosa (CRPA), and Stenotrophomonas maltophilia.
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      Management of multidrug-resistant organisms in health care settings, 2006.
      Microbiological test was performed at the judgment of the attending clinician. Microorganism identification was performed using standard methods at each hospital in which quality control of microbiological tests had passed the evaluation of accredited institutions. Susceptibility testing was done using microdilution method and results were interpreted according to the National Committee for Clinical Laboratory Standards guidelines.
      Clinical and Laboratory Standards Institute
      Performance standards for antimicrobial susceptibility testing; twenty-first informational supplement.

      Statistical analysis

      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 < .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 < .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).

      Ethical approval

      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.

      Results

      Patient characteristics

      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. A total of 47 patients with microbial culture data according to the doctor's judgement were included in the final analysis (Fig 1). Clinical characteristics of enrolled patients with COVID-19 pneumonia are described in 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).
      Table 1Clinical characteristics of patients with coronavirus disease 2019 pneumonia
      Characteristic of patientsMDRO (n=13)Control (n =34)Total (n = 47)P value
      Age (IQR)73 (65-77)64 (50-76)68 (62-77).18
      Male gender8 (62)18 (53)26 (55).60
      Underlying disease/condition
       Diabetes5 (39)6 (18)11 (23).13
       Neurologic disease3 (23)6 (18)9 (19).69
       Chronic lung disease3 (23)5 (15)8 (17).67
       Chronic kidney disease2 (15)4 (12)6 (13).99
       Cardiovascular disease3 (23)3 (9)6 (13).33
       Chronic liver disease2 (15)0 (0)2 (4).07
       Malignancy2 (15)1 (3)3 (6).18
       Corticosteroid use0 (0)1 (3)1 (2).99
       Human immunodeficiency virus infection0 (0)1 (3)1 (2).99
      Before admission due to SARS-CoV2 infection
       Medical institution visit within 90 d
        None (community acquired)2 (15)9 (27)11 (23).70
        LTCF6 (46)6 (17)12 (26).045
        Hospital4 (31)16 (47)20 (43).35
        Outpatient clinic visit4 (33)19 (56)23 (50).31
        Hemodialysis clinic1 (8)0 (0)1 (2).26
       Antibiotic use within 90 d2/6 (33)1/18 (6)3/24 (13).14
       MDRO isolation within 180 d1/3 (33)0/14 (0)1/17 (6).18
      After admission due to SARS-CoV2 infection
       Types of rooms during hospitalization
        General single room1 (8)0 (0)1 (2).28
        Negative pressured single room6 (46)28 (82)34 (72).01
        Negative pressured shared room6 (46)6 (18)12 (26).045
       Have been out of the hospital room for CT scan6 (46)14 (41)20 (43).76
       Intensive care unit10 (77)16 (47)26 (55).10
       Quick SOFA score ≥ 2 points3 (23)4 (12)7 (15).38
       Medical devices
        Urinary tract catheter13 (100)16 (47)29 (62).001
        Central venous catheter11 (85)12 (35)23 (49).003
        Mechanical ventilation9 (69)9 (27)18 (38).02
       Bacteremia2 (14)0 (0)2 (4).08
       Candidemia2 (14)0 (0)2 (4).08
       Use of systemic corticosteroids11 (85)11 (32)22 (47).002
       Use of antibacterial agent13 (100)23 (68)36 (77).02
       In hospital mortality8 (62)5 (15)13 (28).001
      NOTE. Data are presented as number of patients (with the corresponding percentage shown in parentheses) unless otherwise specified.
      CT, computed tomography; IQR, interquartile range; LTCF, long-term care facility; MDRO, multi-drug resistant organism; SOFA; sequential organ failure assessment

      Description of patients with isolation of multi-drug resistant microorganisms

      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, Fig 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, 4 MRSA, 3CRAB, 3 CRPA, 2 ESBL enterobacteriaceae, 2 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).
      Table 2Description of patients whose clinical specimens had multi-drug resistant microorganism
      Patient numberAge/genderSettingPrevious colonizationTypes of specimenMicroorganismDays from diagnosis to pathogen isolationIn hospital mortality
      Patient 173/FOutpatientNoSputumCRE (E. coli)18Died
      clinic visitUrineC. glabrata39
      Patient 272/FCommunityUnknownSputumCRAB7Alive
      SputumESBL K. pneumoniae22
      UrineCRPA49
      Patient 375/MHospitalUnknownSputumCRAB30Died
      Patient 492/MLTCFUnknownSputumCRAB12Died
      BloodVRE43
      SputumMRSA43
      Patient 565/MDialysis clinicUnknownBloodVRE19Alive
      SputumMRSA25
      SputumC. albicans19
      Patient 675/FLTCFNoSputumS. maltophilia0Died
      Patient 783/FHospitalUnknownSputumMRSA38Died
      Patient 864/MCommunityUnknownBloodC. parapsilosis38Died
      SputumS. maltophilia45
      Patient 958/MLTCFUnknownSputumS. maltophilia56Alive
      SputumCRPA80
      Patient 1065/FHospitalESBL E. coliUrineESBL E. coli19Alive
      Patient 1177/MHospitalUnknownBloodC. albicans44Died
      SputumMRSA28
      SputumS. maltophilia55
      Patient 1271/MLTCFUnknownSputumS. maltophilia46Died
      Patient 1381/MHospitalUnknownSputumCRPA53Alive
      StoolC. difficile24
      CRAB, carbapenem-resistant Acinetobacter baumannii; CRE, carbapenem-resistant enterobactericeae; CRPA, carbapenem-resistant Pseudomonas aeruginosa; ESBL, extended-spectrum beta-lactamase; LTCF, long-term care facility;
      MRSA, methicillin-resistant Staphylococcus aureus; VRE, vancomycin-resistant enterococci.
      Fig 2
      Fig. 2Timelines of 13 patients with coronavirus disease 2019 and isolation of multi-drug resistant microorganism.
      The median time from COVID-19 diagnosis to MDRO isolation was 28 days (IQR: 18-38 days) (red dash line). All patients except patients 10 and 13 received adjunctive corticosteroid. Patient 6 received only 2 days of corticosteroid because she died two days after admission. All patients with MDRO isolation received antibiotics during hospitalization before MDRO isolation.
      Candida was isolated from four patients with MDRO and polymicrobial non-MDRO was isolated from one patient. A total of 6 patients with monomicrobial non-MDRO isolates, 3 had non-MDRO isolation from sputum, 2 had non-MDRO isolation from urine, and 1 had non-MDRO isolation from sputum and urine. Types of non-MDRO were as follows: two candida species, 1 klebsiella pneumonia, 1 Escherichia coli, 1 Enterococcus faecalis, 1 Rahnella aquatilis, and 1 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).

      Risk factors for isolation of multi-drug resistant organisms

      Significant variables in univariate analysis were LTCF admission before diagnosis of COVID-19 (OR: 4.00, 95% CI: 0.98 - 16.26, P = .05), single room stay after diagnosis of COVID-19 (OR: 0.25, 95% CI: 0.06 -1.02, P = .05), having central venous catheter (OR: 10.08, 95% CI: 1.91 - 53.18, P = .01), mechanical ventilation (OR: 6.25, 95% CI: 1.54 - 25.42, P = .01), and use of systemic corticosteroids after diagnosis of COVID-19 (OR: 11.50, 95% CI: 2.17 - 61.04, P = .004). All significant variables in univariate analysis and age were included in the multivariate analysis. Multivariate analysis indicated that the use of systemic corticosteroids after COVID-19 diagnosis (aOR: 15.07, 95% CI: 2.34-97.01, P = .004) and LTCF stay before diagnosis of COVID-19 (aOR: 6.09, 95% CI: 1.02-36.49, P = 0.048) were independent risk factors for MDRO isolation (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).
      Table 3Risk factors for multi-drug resistant organism isolation in patients with coronavirus disease 2019 pneumonia
      Risk factorUnivariate analysisMultivariate analysis
      OR (95% CI)P valueAdjusted OR (95% CI)P value
      Age1.05 (0.99 - 1.11).10
      LTCF stay before diagnosis of COVID-194.00 (0.98 - 16.26).056.09 (1.02 - 36.49).048
      Single room stay after diagnosis of COVID-19 vs. shared room0.25 (0.06 - 1.02).05
      Central venous catheter10.08 (1.91 - 53.18).01
      Mechanical ventilation6.25 (1.54 - 25.42).01
      Use of systemic corticosteroids11.50 (2.17 - 61.04).00415.07 (2.34 - 97.01).004
      NOTE. The model fitted data well in terms of discrimination (C-statistic = 0.83) and calibration (Hosmer-Lemeshow goodness of fit statistic = 2.18, P = .34).
      CI, confidence interval; LTCF, long-term care facility; OR, odds ratio.

      Discussion

      The COVID-19 pandemic has highlighted the need for monitoring the use of excess antibiotics and multi-drug resistance.
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      Antimicrobial resistance in bacterial pathogens has become one of the most important threats to public health around the world. The Republic of Korea is also experiencing challenges with antimicrobial resistance. The recent nationwide surveillance system report by the Korea Centers for Disease Control and Prevention stated that MRSA is common (66% of S. aureus), and among tested Acinetobacter baumannii and Pseudomonas aeruginosa isolates collected from 16 general hospitals, 85% and 35% were imipenem-resistant.
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      Bacterial and fungal coinfections in COVID-19 patients hospitalized during the New York City pandemic surge.
      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,
      • Chang CY
      • Chan KG.
      Underestimation of co-infections in COVID-19 due to non-discriminatory use of antibiotics.
      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.

      Appendix. SUPPLEMENTARY MATERIALS

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