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Increase of multidrug-resistant bacteria after the COVID-19 pandemic in South Korea: Time-series analyses of a long-term multicenter cohort

  • Author Footnotes
    1 These authors contributed equally to this work (Co-first authorship).
    Yeonju La
    Footnotes
    1 These authors contributed equally to this work (Co-first authorship).
    Affiliations
    Division of Infectious Disease, Department of Internal Medicine, Kangwon National University Hospital, Chuncheon, Gangwon-do, Republic of Korea
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  • Author Footnotes
    1 These authors contributed equally to this work (Co-first authorship).
    Ji Young Hong
    Footnotes
    1 These authors contributed equally to this work (Co-first authorship).
    Affiliations
    Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Chuncheon Sacred Heart Hospital, Hallym University Medical Center, Republic of Korea
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  • Hye Sun Lee
    Affiliations
    Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, Republic of Korea
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  • Eun Hwa Lee
    Affiliations
    Division of Infectious Disease, Department of Internal Medicine, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul 06273, Republic of Korea
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  • Kyoung Hwa Lee
    Affiliations
    Division of Infectious Disease, Department of Internal Medicine, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul 06273, Republic of Korea
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  • Young Goo Song
    Affiliations
    Division of Infectious Disease, Department of Internal Medicine, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul 06273, Republic of Korea
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  • Sun Bean Kim
    Correspondence
    Corresponding authors.
    Affiliations
    Division of Infectious Diseases, Department of Internal Medicine, Korea University College of Medicine, 73 Goryeodae-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
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  • Sang Hoon Han
    Correspondence
    Corresponding authors.
    Affiliations
    Division of Infectious Disease, Department of Internal Medicine, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul 06273, Republic of Korea
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  • Author Footnotes
    1 These authors contributed equally to this work (Co-first authorship).
Published:September 29, 2022DOI:https://doi.org/10.1016/j.jinf.2022.09.026

      Highlights

      • Case and bacteremia of VRE considerably increased after the COVID-19.
      • New case of XDR-ABA and DTR-PAE was increased after pandemic.
      • Bacteremia of XDR-ABA, DTR-PAE on the decline was increased after pandemic.
      • Concerning finding because reduction of MDROs is difficult and time-consuming.
      • Need to continuously monitor the growth of MDROs.

      Keywords

      Dear editor,
      Concerns are being raised about whether the long-standing coronavirus disease 2019 (COVID-19) pandemic will increase the burden of multidrug-resistant organisms (MDROs).
      • Pelfrene E.
      • Botgros R.
      • Cavaleri M.
      Antimicrobial multidrug resistance in the era of COVID-19: a forgotten plight?.
      The healthcare practices may have been disrupted and overloaded owing to the lack and exhaustion of frontline healthcare workers (HCWs), particularly during the COVID-19 crisis.
      • Karan A.
      • Wadhera R.K.
      Healthcare system stress due to COVID-19: evading an evolving crisis.
      This situation could cause the overuse of antibiotics and inappropriate environmental management, given the move away from priorities of antimicrobial stewardship programs (ASP) and contact precautions.
      • Bork J.T.
      • Leekha S.
      • Claeys K.
      • Seung H.
      • Tripoli M.
      • Amoroso A.
      • et al.
      Change in hospital antibiotic use and acquisition of multidrug-resistant gram-negative organisms after the onset of coronavirus disease 2019.
      On the contrary, unprecedentedly strict implementation of non-pharmacological interventions (NPIs) may help reduce the intra-hospital spread of MDROs through excellent hand hygiene and the use of personal protection equipment. The inconsistent results from previous studies, which were conducted in the early stages of the COVID-19 pandemic and included relatively short observation periods,
      • Bork J.T.
      • Leekha S.
      • Claeys K.
      • Seung H.
      • Tripoli M.
      • Amoroso A.
      • et al.
      Change in hospital antibiotic use and acquisition of multidrug-resistant gram-negative organisms after the onset of coronavirus disease 2019.
      • Lemenand O.
      • Coeffic T.
      • Thibaut S.
      • Colomb Cotinat M.
      • Caillon J.
      • Birgand G
      Decreasing proportion of extended-spectrum beta-lactamase among E. coli infections during the COVID-19 pandemic in France.
      • Taylor L.
      COVID-19: antimicrobial misuse in Americas sees drug resistant infections surge, says WHO.
      • Duverger C.
      • Monteil C.
      • Souyri V.
      • Fournier S.
      Decrease of carbapenemase-producing enterobacteriaceae incidence during the first year of the COVID-19 pandemic.
      • Segala F.V.
      • Bavaro D.F.
      • Di Gennaro F.
      • Salvati F.
      • Marotta C.
      • Saracino A.
      • et al.
      Impact of SARS-CoV-2 epidemic on antimicrobial resistance: a literature review.
      warrant close monitoring of the epidemiology trends of MDROs in various. We aimed to investigate the changing trends in new case and bacteremia with MDROs before and after the COVID-19 pandemic in South Korea, where the frequency of MDROs is high.
      • Lee H.
      • Yoon E.J.
      • Kim D.
      • Jeong S.H.
      • Won E.J.
      • Shin J.H.
      • et al.
      Antimicrobial resistance of major clinical pathogens in South Korea, May 2016 to April 2017: first one-year report from Kor-GLASS.
      This multicenter retrospective cohort study included six medical university-affiliated hospitals that were located in three different provinces of South Korea. We collected the monthly numbers of new case (first identification in clinical specimens or stool) and first bacteremia of extensively drug-resistant Acinetobacter baumanii (XDR-ABA), difficult-to-treat Pseudomonas aeruginosa (DTR-PAE), vancomycin-resistant Enterococci (VRE), and carbapenem-resistant Enterobacterales (CRE) as well as numbers of stool examinations for VRE and CRE between January 2012 and December 2021. The VRE or CRE stool tests were categorized into two kinds of data: (1) total negative results, best reflecting the efforts to detect VRE and CRE, and (2) first examination after hospitalization, including positive and negative results (except for the stool tests performed after VRE or CRE was detected in a clinical sample), which would represent the active surveillance performance appropriately. We divided the case of MDROs into pre- and post-COVID-19 periods, using the cutoff date of January 2020. The study was approved by the local Institutional Review Board from each hospital with the waiver of the informed consent (YUHS:3–2022–0176, KUAM:2022AN0027, KNUH:2022–01–002, and HUCH:2022–01–016).
      Isolates were categorized as XDR when they showed non-susceptibility to ≥1 antimicrobial agent in all but ≤2 antimicrobial categories. Isolate were categorized as DTR when there was no susceptibility to the antimicrobial categories of carbapenems, antipseudomonal β-lactams, and fluoroquinolones. We included CRE isolates that were not susceptible to any carbapenem, regardless of carbapenemase-producing strains (CPE).
      • Magiorakos A.P.
      • Srinivasan A.
      • Carey R.B.
      • Carmeli Y.
      • Falagas M.E.
      • Giske C.G.
      • et al.
      Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance.
      We applied the Bayesian structural time series (BSTS) model, which is the state-space analysis proposed by Google, Inc.,
      • Brodersen K.H.
      • Gallusser F.
      • Koehler J.
      • Remy N.
      • Scott S.L.
      Inferring causal impactusing Bayesian structural time-series models.
      using the R-language (version 4.1.3). The BSTS model can determine the causalities and regression of an intervention using its counterfactual prediction function by artificial control of what would have taken place had the intervention not occurred and the observed data.
      • Brodersen K.H.
      • Gallusser F.
      • Koehler J.
      • Remy N.
      • Scott S.L.
      Inferring causal impactusing Bayesian structural time-series models.
      We expressed the relative ([observed–predicted]/predicted × 100) causal effects as percentages and 95% credible prediction intervals (CIs). The autoregressive integrated moving average (ARIMA) model was adjusted for the stool examinations in VRE or CRE using SAS (version 9.4) to minimize the impact of test numbers on the new case. A two-tailed p-value < 0·05 was considered statistically significant.
      The BSTS models revealed that both new case and first bacteremia of XDR-ABA (relative effects; 47% [95% CI:19–79%], p = 0.003 and 150% [93–211%], p = 0.001, respectively) and DTR-PAE (41% [17–67%], p = 0.002 and 103% [65–145%], p = 0.001, respectively) had significantly increased in the post-COVID period. In addition, the observed values of VRE were significantly higher than the predicted values after the COVID-19 pandemic for both new case (10% [3–17%], p = 0.007) and first bacteremia (65% [48–83%], p = 0.001). The first CRE bacteremia numbers also showed a significant increase in the post-COVID-19 era (106% [78–135%], p = 0.001). However, the observed data for new case of total CRE (p = 0.056) did not differ from the predicted values (Table 1 and Fig. 1). After adjustment for stool test numbers, which were decreased in the post-COVID-19 period, the new case (32% in model 3 adjusted for total negative and first examination) and first bacteremia (12%) of VRE showed a significant increase compared to the predicted values (all p < 0.001). The reduction in stool examinations did not affect the number of first bacteremia of CRE (4%, p = 0.025) (Table 2).
      Table 1Changes in new case and first bacteremia with MDROs during the pre- and post-COVID pandemic using the Bayesian structural time series model.
      MDROsVariablesCOVID-19 pandemic
      Before (2012∼2019)After (2020∼2021)
      Observed (N)Observed (N)Predicted (N)Absolute effect (N)Relative effect (%)p-value
      VRENew case
      Total54.986.078.2 (72.3–84·1)7.7 (2.4–13.6)10 (3–17)0.007
      VR-E. faecium24.554.033.7 (28.9–38·3)20.3 (16.2–24.8)60 (48–73)0.001
      New bacteremia
      Total12.223.514.3 (12.2–16·9)9.2 (6.8–11.8)65 (48–83)0.001
      VR-E. faecium9.518.811.4 (9.2–13·0)7.4 (5.3–9.6)64 (46–84)0.001
      CRENew case
      Total57.974.367.2 (58.1–75·9)7.2 (−1.5–16.6)11 (−2–25)0.056
      CR-Klebsiella spp.36.451.649.7 (42.7–56·2)1.9 (−4.6–9.1)4 (−9–18)0.301
      CR-E. coli14.516.014.0 (11.1–17·3)2.0 (−0.7–4.8)14 (−5–35)0.073
      New bacteremia
      Total10.215.47.5 (5.3–9·5)7.9 (5.8–10.1)106 (78–135)0.001
      CR-Klebsiella spp.5.210.04.7 (3.2–6·1)5.2 (3.8–6.8)111 (81–143)0.001
      CR-E. coli3.93.82.4 (1.4–3·4)1.4 (0.5–2.5)59 (19–102)0.005
      XDR-ABANew case64.752.835.8 (24.8–46·4)17.0 (6.7–28.2)47 (19–79)0.003
      New bacteremia9.18.53.4 (1.3–5·3)5.1 (3.2–7.1)150 (93–211)0.001
      DTR-PAENew case46.345.932.7 (23·8–41.2)13.3 (5.4–21.8)41 (17–67)0.002
      New bacteremia4.05.52.7 (1.6–3.7)2.8 (1.8–3.9)103 (65–145)0.001
      Data are expressed as numbers or numbers (95% credible prediction intervals).
      Fig 1
      Fig. 1Changes in numbers of new case and first bacteremia patients of several MDROs before and after the COVID-19 pandemic evaluated by the Bayesian structural time series model (A) New case (B) First bacteremia.
      Fig 1
      Fig. 1Changes in numbers of new case and first bacteremia patients of several MDROs before and after the COVID-19 pandemic evaluated by the Bayesian structural time series model (A) New case (B) First bacteremia.
      Table 2Multivariable analyses adjusted by numbers of VRE or CRE stool tests in the autoregressive integrated moving average (ARIMA) model.
      MDROsVariablesModel 1Model 2Model 3
      Estimate (SE)p-valueEstimate (SE)p-valueEstimate (SE)p-value
      VRENew case
      Total29.85 (7.24)<0.00132.36 (5.50)<0.00131.76 (5.45)<0.001
      VR-E. faecium25.43 (4.72)<0.00124.45 (4.76)<0.00125.06 (4.89)<0.001
      New bacteremia
      Total11.98 (2.07)<0.00111.88 (2.01)<0.00111.97 (2.06)<0.001
      VR-E. faecium9.83 (1.75)<0.0019.84 (1.69)<0.0019.81 (1.71)<0.001
      CRENew case
      Total12.39 (7.44)0.09912.40 (7.53)0.10312.53 (7.67)0.106
      CR-Klebsiella spp.18.73 (10.34)0.07418.93 (5.50)<0.00115.77 (7.02)0.027
      CR-E. coli0.92 (1.66)0.5820.96 (1.63)0.5580.98 (1.63)0.549
      New bacteremia
      Total4.51 (1.93)0.0224.51 (1.93)0.0224.45 (1.96)0.025
      CR-Klebsiella spp.4.51 (1.45)0.0024.52 (1.44)0.0024.52 (1.45)0.003
      CR-E. coli0.15 (0.61)0.8030.15 (0.62)0.8130.15 (0.62)0.809
      The estimate (standard error) is expressed as a percentage. Model 1: adjusted for total negative results of stool VRE or CRE tests (category 1); model 2: adjusted for total stool VRE or CRE tests performed as the first examination after admission (category 2); model 3: adjusted for categories 1 and 2.
      Two recent studies presented the protective effect of the COVID-19 pandemic against extended-spectrum β-lactamase-producing E. coli isolates and CPE using data until December 2020 in France.
      • Lemenand O.
      • Coeffic T.
      • Thibaut S.
      • Colomb Cotinat M.
      • Caillon J.
      • Birgand G
      Decreasing proportion of extended-spectrum beta-lactamase among E. coli infections during the COVID-19 pandemic in France.
      ,
      • Duverger C.
      • Monteil C.
      • Souyri V.
      • Fournier S.
      Decrease of carbapenemase-producing enterobacteriaceae incidence during the first year of the COVID-19 pandemic.
      The authors attributed these results to the decrease in antibiotic usage or testing of urine samples and hospital visits due to the overall lockdown as well as increased implementation of NPIs.
      • Lemenand O.
      • Coeffic T.
      • Thibaut S.
      • Colomb Cotinat M.
      • Caillon J.
      • Birgand G
      Decreasing proportion of extended-spectrum beta-lactamase among E. coli infections during the COVID-19 pandemic in France.
      ,
      • Duverger C.
      • Monteil C.
      • Souyri V.
      • Fournier S.
      Decrease of carbapenemase-producing enterobacteriaceae incidence during the first year of the COVID-19 pandemic.
      It seems unclear whether these beneficial effects would extend beyond developed countries or after a period of well-executed strong national policies mitigating COVID-19 and beyond β-lactamase-producing MDROs because other studies have reported conflicting results.
      • Bork J.T.
      • Leekha S.
      • Claeys K.
      • Seung H.
      • Tripoli M.
      • Amoroso A.
      • et al.
      Change in hospital antibiotic use and acquisition of multidrug-resistant gram-negative organisms after the onset of coronavirus disease 2019.
      ,
      • Segala F.V.
      • Bavaro D.F.
      • Di Gennaro F.
      • Salvati F.
      • Marotta C.
      • Saracino A.
      • et al.
      Impact of SARS-CoV-2 epidemic on antimicrobial resistance: a literature review.
      1The vertical dotted lines in all graphs represent January 2020, the beginning of the COVID-19 pandemic. The straight and dotted lines in the original panels indicate the observed and predicted values using the BSTS model, respectively. The dotted lines in the pointwise impact panels indicate the differences between the observed and predicted values, which are called residuals. The dotted lines in the cumulative impact panels represent the accumulated residuals.
      Our study showed that the occurrence of the most problematic MDROs had increased after the COVID-19 pandemic, especially in case of bacteremia. Surprisingly, the MDR-ABA and DTR-PAE, which had been steadily decreasing before the pandemic, showed an increasing trend in both new case and first bacteremia after COVID-19 (Figs. S1 and S2). Our results are similar to the trends of national data from the Korea Centers for Disease Control and Prevention. The total number of CRE infections and colonization, designated as a legal infectious disease in June 2017 and converted to a surveillance system with mandatory reporting within 24 h in South Korea, significantly increased since the COVID-19 pandemic (Fig. S3).
      As a limitation, we did not quantify the performance rate of various elements of NPIs and ASP as well as an overload of HCWs at several hospitals. As the duration of the pandemic increases, the rate of implementation of initially strong policies would decrease. Taken together, our findings are concerning because the effects of MDROs on global health are critical, and it is difficult and time-consuming to reduce the resistance to the same levels as before. Hence, we need to actively and continuously monitor the increase in infections with MDROs as well as occurrence of new resistance in various regions.

      Appendix. Supplementary materials

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