Bacteriological Characteristics of COVID-19 Patients Nosocomially Co-infected at a Designated Hospital: A Retrospective Study

Background: Bacterial co-infection in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a critical factor that increases the complexity and treatment of coronavirus disease 2019 (COVID-19). Methods: We collected the clinical laboratory data of 1799 patients with conrmed COVID-19 who were admitted to Jinyintan Hospital in Wuhan, China, between January 1 to April 26, 2020. The bacterial co-infection along with disease progression was analyzed. Other inammatory markers, including C-reactive protein (CRP), white blood cells (WBC), lymphocytes (L), neutrocytes (N), interleukin-6 (IL-6), and procalcitonin (PCT), were assessed to estimate the progression of COVID-19. Results: We found that 191 of the 1799 (10.62%) patients had bacterial co-infection. The most prevalent causative agents for bacterial co-infection were Klebsiella pneumoniae (91 cases, 5.06%) and Acinetobacter baumannii (66 cases, 3.67%). The most patients with bacterial co-infection showed extensive drug-resistance. The outcomes of patients with bacterial co-infection were worse than those of patients without bacterial co-infection. Conclusions: Secondary bacterial pneumonia during virus infection is a major risk factor for high mortality resulting from severe pneumonia caused by COVID-19. 1st, species responsible for nosocomial co-infection at a designated COVID-19 hospital, and we also describe the antibiotic regimens that were used for the treatment of this cohort. Based on the ndings, we recommend detection tests for inammatory markers and bacteria, as well as drug-resistance tests for continuously monitoring patients with COVID-19 during hospitalization for better outcome[13–15].

From January to April 2020, bacteria co-infection increased dramatically and reached a peak in the second week of February; this trend was similar to that for hospital admission of COVID-19 patients (Fig. 1A). The bacterial strains identi ed each week are shown in Fig. 1B. Previous studies have reported that the levels of in ammatory indicators were associated with the severity of COVID-19 [5][6][7]. Therefore, in this study, we also investigated the correlation of C-reactive protein (CRP), white blood cells (WBC), lymphocytes (L), neutrocytes (N), interleukin-6 (IL-6), and procalcitonin (PCT) with bacterial co-infection in COVID-19 patients. Based on the correlation coe cient values, PCT had the highest correlation, and this was followed by CRP, L%, IL-6, and N%, in descending order.
The antibiotic resistance of bacteria co-infection with COVID-19 K. pneumoniae is resistant to carbapenems, A. baumannii shows multidrug resistance, and Staphylococcus species show methicillin resistance. The details of drug resistant rate of primary 8 bacteria to antibiotics in our study are shown in Table 2. The patients with K. pneumoniae co-infection showed extensive drugresistance but responded to treatment with meropenem and ceftazidine sulbactam, and the patients co-infected with the multidrug-resistant A. baumannii responded to polymyxin B and minocycline. Furthermore, we found that multiple bacterial infections were common in patients with severe COVID-19.   Note: Letter "R"presents resistance; letter "S" presents sensitive; letter "I" presents intermediary.

The prognostic nomogram of COVID-19 patients with bacterial co-infection
The prognostic nomogram of COVID-19 patients with bacterial co-infection was analyzed in our research. The survival curves of patients with COVID-19 with or without bacterial co-infection are shown in Fig. 1C. We found that the outcomes of patients with bacterial co-infection were worse than those of patients without bacterial co-infection (P = 0.032).
According to the ndings of our previous study, carcinoembryonic antigen (CEA) is a prognostic marker of COVID-19[8]; therefore, CEA was included in the present nomogram analysis. Based on the multivariate analysis conducted in the present study, a prognostic nomogram for OS of COVID-19 patients with bacterial co-infection was created (Fig. 1D). Each predictor in the nomogram was assigned a score (top scale), and the sum of these scores indicated the probability of 1-and 2-month OS (bottom scale). The c-index for the nomogram of OS was 0.90 (95% CI = 0.85-0.96), which is indicative of the discriminative ability of the models (Admission classi cation + bacteria + WBC + Neu%+PCT + CEA, Fig. 1D).

Discussion
In the present study, we describe a typical cohort of COVID-19 patients who were co-infected with bacteria during their progression and therapy. Secondary bacterial pneumonia during virus infection is a major risk factor for high mortality resulting from severe pneumonia [9,10]. Based on the evidence from previous outbreaks of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), secondary infection rates with bacteria increase mortality as a result of immunosuppression by corticosteroids [11].
The median duration from admission to detection of bacteria was 6 days. We found that in most 153 cases, bacterial co-infection with SARS-CoV-2 occurred after the application of invasive mechanical ventilation and administration of antibiotics and glucocorticoids. In addition, bacteria co-infection was associated with high levels of antibiotic resistance; for instance, K. pneumoniae is resistant to carbapenems, A. baumannii shows multidrug resistance, and Staphylococcus species show methicillin resistance. In this study, we analyzed the details of drug resistant rate of primary 8 bacteria to antibiotics. Given these variations in the clinical features of the patients, it was essential to assess the bacteria co-infection and adjust the therapeutic strategies so as to prevent drug resistance and improve prognosis.
Additionally, prior antibiotic use is also a risk factor for bacterial co-infection in COVID-19 patients. The hospital environment is a reservoir for bacteria. Medical equipment, especially that used for invasive mechanical ventilation, is one of the important risk factors that predispose patients to infection with bacteria. Accordingly, in the present study, we found that the application of invasive mechanical ventilation and administration of antibiotics and glucocorticoids were risk factors for bacterial co-infection in COVID-19. Additionally, upon infection, SARS-CoV-2 virus triggers the innate immune response in host cells [9,12]. Therefore, SARS-CoV-2 infection itself can enhance susceptibility to bacterial co-infection.

Conclusions
In summary, K. pneumoniae and A. baumannii were the most prevalent bacteria responsible for co-infection. However, the causative species might be different at another hospital. Fungal co-infection also occurred after prolonged administration of antibiotics. Our work aimed to estimate bacterial co-infection in patients infected with SARS-CoV-2. We identi ed the common bacterial species responsible for nosocomial co-infection at a designated COVID-19 hospital, and we also describe the antibiotic regimens that were used for the treatment of this cohort. Based on the ndings, we recommend detection tests for in ammatory markers and bacteria, as well as drug-resistance tests for continuously monitoring patients with COVID-19 during hospitalization for better outcome [13][14][15]