Bacterial and Fungal Co-Infections in Patients with COVID-19 Related Pneumonia: A Retrospective Cohort Study

Research Article

J Bacteriol Mycol. 2021; 8(5): 1183.

Bacterial and Fungal Co-Infections in Patients with COVID-19 Related Pneumonia: A Retrospective Cohort Study

Bedini A¹*, Menozzi M¹, Cuomo G¹, Franceschini E¹, Orlando G¹, Santoro A¹, Cozzi-Lepri A², Meschiari M¹, Carli F¹, Puzzolante C¹, Milic J¹, Del Monte M¹, Gaetano MD¹, Bacca E¹, Franceschi G¹, Dolci G¹, Busani S³, Biagioni E³, Tutone M¹, Sarti M4, Girardis M³, Guaraldi G¹ and Mussini C¹

1Department of Infectious Diseases, Azienda Ospedaliero-Universitaria di Modena “Policlinico di Modena”, Italy

2Centre for Clinical Research, Epidemiology, Modelling and Evaluation (CRÈME), Institute for Global Health, University College London, London, UK

3Department of Anaesthesia and Intensive Care Unit, Azienda Ospedaliero-Universitaria di Modena “Policlinico di Modena”, Italy

4Clinical Microbiology Laboratory, Azienda Ospedaliero-Universitaria di Modena “Policlinico di Modena”, Italy

*Corresponding author: Andrea Bedini, Department of Infectious Diseases, Azienda Ospedaliero-Universitaria di Modena “Policlinico di Modena”, Via del pozzo 71, 41124 Modena, Italy

Received: June 04, 2021; Accepted: July 19, 2021; Published: July 26, 2021


Background: The study analyzed risk factors for bacterial and fungal coinfection in patients with COVID-19 and the impact on mortality.

Methods: This is a single-center retrospective study conducted on 387 patients with confirmed COVID-19 pneumonia admitted to an Italian Tertiarycare hospital, between 21 February 2020 and 31 May 2020. Bacterial/fungal coinfection was determined by the presence of characteristic clinical features and positive culture results. Multivariable logistic regression was used to analyze risk factors for the development of bacterial/fungal co-infection after adjusting for demographic characteristics and comorbidities. Thirty-day survival of the patients with or without co-infections was analyzed by Kaplan- Meier method.

Results: In 53/387 (13.7%) patients with COVID-19 pneumonia, 67 episodes of bacterial/fungal co-infection occurred (14 presented >1 episode). Pneumonia was the most frequent co-infection (47.7%), followed by BSI (34.3%) and UTI (11.9%). S. aureus was responsible for 24 episodes (35.8%), E. coli for 7 (10.4%), P. aerugionsa and Enterococcus spp. for 5 episodes each (7.4%). Five (7.4%) pulmonary aspergillosis, 3 (4.4%) pneumocystosis and 5 (7.4%) invasive candidiasis were observed. Multivariable analysis showed a higher risk of infection in patients with an age >65 years (csHR 2.680; 95% CI: 1.254-5.727; p=0.054), with cancer (csHR 5.243; 95% CI: 1.173-23.423; p=0.030), with a LOS >10 days (csHR 12.507; 95% CI: 2.659 - 58.830; p=0.001), early (within 48h) admitted in ICU (csHR 11.766; 95% CI: 4.353-31.804; p<0.001), and with a SOFA score >5 (csHR 3.397; 95% CI: 1.091-10.581; p=0.035). Estimated cumulative risk of developing at least 1 bacterial/fungal co-infection episode was of 15% and 27% after 15 and 30 days from admission, respectively. Kaplan-Meier estimated a higher cumulative probability of death in patients with bacterial/fungal co-infection (log-rank=0.031). Thirty-day mortality rate of patients with pneumonia was 38.7%, higher than those with BSI (30.4%).

Conclusions: Bacterial and fungal infections are a serious complication affecting the survival of patients with COVID-19- related pneumonia. Some issues need to be investigated, such as the best empirical antibiotic therapy and the need for possible antifungal prophylaxis.

Keywords: COVID-19; SARS-CoV-2 pneumonia; Bacterial co-infection; Aspergillosis; CAPA; Fungal co-infections


COVID-19: Coronavirus Disease 2019; SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus-2; ARDS: Acute Respiratory Distress Syndrome; BSI: Bloodstream Infections; ICU: Intensive Care Unit; LOS: Length of Stay; SaO2: Oxygen Saturation; UTI: Urinary Tract Infection; PCR: Polymerase Chain Reaction; ABSSIs: Acute Bacterial Skin and Soft Tissue Infections; CRP: C-Reactive Protein; SOFA: Sequential Organ Failure Assessment; NIV: Non-Invasive Ventilation; MDR: Multi-Drug Resistant; ESBL+: Extended-Spectrum Beta-Lactamase Producer; GNB: Gram-Negative Bacilli; CR: Carbapenem-Resistant; VRE: Vancomycin- Resistant Enterococcus; MR: Methicillin-Resistant; MRSA: Methicillin-Resistant Staphylococcus aureus; SIMIT: Italian Society of Infectious Diseases; csHR: cause-specific Hazard Ratio; IQR: Interquartile Range; CI: Confidence Interval


The outbreak of COVID-19, due to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), began in Wuhan, Hubei Province, China, and has subsequently spread all over the world. Up to 30% of patients admitted to hospital with COVID-19 need admission to Intensive Care Units (ICUs) to receive ventilation assistance because they develop Acute Respiratory Distress Syndrome (ARDS) [1-3].

Early reports from China suggested that co-infection with other respiratory pathogens was rare. If this were the case, patient’s positive for other pathogens might be assumed unlikely to have SARSCoV- 2. The Centers for Disease Control and Prevention endorsed testing for other respiratory pathogens, suggesting that evidence of another infection could aid the evaluation of patients with potential COVID-19 in the absence of widely available rapid testing for SARSCoV- 2 [4].

The prevalence of co-infection varied among COVID-19 patients, ranging from 0% to 50% among non-survivors. Chinese publications reported at least 10% of co-infection during COVID-19 in patients hospitalized in ICU for ARDS, among them Aspergillus infections [1,2]. Besides, the incidence of Invasive Pulmonary Aspergillosis (IPA) in ICU patients admitted for severe influenza A and B is high, reaching 19% versus 5% in patients with severe pneumonia other than flu [3].

A recent Spanish retrospective cohort study [5] showed that bacterial or fungal co-infection at COVID-19 diagnosis is uncommon (3.1%) and that few patients developed co-infections during hospitalization (5.1%). Overall, patients with co-infections resulted to have worse outcomes.

The prevalence of laboratory confirmed bacterial superinfection in critically ill COVID-19 patients admitted in ICU is around 14% (95% confidence interval 5-26%) according to a recent metaanalysis [6]. However, in most included studies there was no distinction between early and late infections. This is a key point in deciding whether antibiotic prescribing in the critical ill patients with COVID-19 is truly helpful in preventing infection or is a risk factor for the development of antimicrobial resistance. Many studies of hospitalized patients with COVID-19 note the empiric use of antibiotics in a majority of patients [7-9]. However, there is evidence that the inflammatory serological markers that are usually associated with bacterial infection, such as raised procalcitonin and C-reactive protein, may appear in patients with COVID-19 without a corresponding bacterial co-infection occurring [10,11].

The aim of the study was to describe the bacterial and fungal co-infections in the patients admitted for COVID-19 pneumonia, evaluating the risk factors for co-infection and the impact of the coinfections on the 30-day mortality rate.


This retrospective cohort study was performed at the “Policlinico di Modena” Hospital (Italy), a 550-bed University Centre that provides broad and specialized medical, surgical, and intensive care for an urban population of 150,000 adults. All patients (≥18 years) admitted for COVID-19 pneumonia from 21 February to 1 May 2020 were included. Diagnostic criteria for COVID-19 pneumonia comprised the presence of any of the following respiratory symptoms, including sore throat, congestion, cough, dyspnoea, new loss of taste and/or smell, as well as uni- or bilateral interstitial infiltrates in the chest X-ray. The diagnosis was confirmed by real-time Reverse Transcription Polymerase Chain Reaction (RT-PCR) testing performed on nasopharyngeal throat swab specimens.

Patients’ demographic, epidemiologic and clinical data were collected in an electronic patient chart.

All patients received treatment according to the Italian Society of Infectious Diseases’ Guidelines (SIMIT) recommendations [12] including oxygen supply to target SaO2 >90%, hydroxychloroquine with or without azithromycin, and low molecular weight heparin. Lopinavir/ritonavir or darunavir/cobicistat was also used up to 18 March, when a clinical trial on the former did not show any benefit of protease inhibitors against the standard of care [13].

The aim of the study was to describe the bacterial and fungal co-infections in the patients admitted for COVID-19 pneumonia, evaluating the risk factors for co-infection and the impact on the survival.


Bloodstream Infection (BSI) was defined in presence of at least one positive blood culture for bacteria or fungi; for coagulasenegative staphylococci and other common skin contaminants, at least two consecutive blood cultures positive for the same pathogen were necessary to define BSI. Bacterial and fungal pneumonia was defined by the appearance of new consolidation or interstitial lung infiltrates associated to respiratory signs (coughing, dyspnoea, production of purulent exudate) and the identification of the responsible microorganism through culture or real-time Polymerase Chain Reaction (PCR) test from sputum and/or lower respiratory tract specimens, or the detection of a urinary antigen for Streptococcus pneumonia or Legionella species. Urinary Tract Infection (UTI) was defined as the appearance of fever with or without urinary signs of infection, with the isolation of a microorganism from the urine culture test. If diagnosis was at onset or within the first 48h of COVID-19 hospital admission, these infections were defined as community-acquired co-infections. If diagnosis occurred ≥48h of admission for COVID-19, these infections were defined as hospitalacquired co-infections.

Data collection

The following data were collected from the patients’ electronic medical records: age in years; gender; Sequential Organ Failure Assessment (SOFA) score at the admission in the hospital [14], Length of Stay (LOS), admission in Intensive Care Unit (ICU), the need for Non-Invasive (NIV) and invasive mechanical ventilation (intubation) for severe respiratory failure, and the possible treatment with antiinflammatory drugs (tocilizumab, anakinra and steroids). The antiinflammatory therapy was administered in the following dosages: tocilizumab, intravenously or subcutaneously, at 8mg/kg, possibly repeated after 12 hours if inflammatory activity persists; anakinra subcutaneously at the dose of at 1-2 mg/kg/24 hours, increasing by 0.5-1 mg/kg/die until the control of active inflammation, never exceeding the 8mg/kg/die; and intravenous methylprednisolone at 1mg/kg/24 hours.

Statistical analyses

Demographic and clinical characteristics of the patients were summarized with number and percentages for categorical variables, and with median and Interquartile Range (IQR) for continuous variables. The possible association of demographic and clinical variables with development of bacterial/fungal infections was first tested in univariable Cox regression models for estimating the unadjusted cause-specific Hazard Ratio (csHR) for development of infection. Then, variables potentially associated with infections in univariable comparisons (p ≤0.09) were included in a multivariable Cox regression model for calculating the adjusted csHR for development of co-infection.

In the analysis of the risk factors for bacterial/fungal co-infection, cases where the infection had occurred within the first 48 hours of admission were excluded. The following risk factors for infection were assessed: gender, age >65 years, LOS >10 days, SOFA Score >5, chronic renal failure, cancer, leucocytes>10x10³/μL, C-reactive protein >10 mg/dl, beginning of symptoms >10 days, early admission in ICU (within 48 hours of admission), and early need of noninvasive ventilation (within 48 hours of admission). The cumulative risk of in-hospital acquired co-infections was calculated using the Aalen-Johansen method, considering the first occurring co-infection as the event of interest, death and discharge from the hospital as competing events. Chi-square test was used to evaluate the impact of empirical antibiotic therapy on the development of co- infection by Multi-Drug Resistant (MDR) microorganisms: Methicillin-Resistant Staphylococcus spp. (MR-S), Extended-Spectrum Beta-lactamase producer bacilli Gram-negative (ESBL+GNB), carbapenemresistant Gram-negative bacilli (CR-GNB), Vancomycin-resistant Enterococcus species (VRE). ESBL+, CR, MRSA, VRE). Thirty-day survival of the patients with or without co-infections was described with the Kaplan-Meier method, with death as the event of interest and discharge from hospital as right censoring events.

Statistical analyses were performed using SPSS Statistics version 26.0 (IBM Corp., Armonk, NY, USA).


Between 21 February and 1 May 2020, 387 patients with COVID-19 pneumonia were admitted to the University Hospital of Modena, Italy. In all patients, the diagnosis was confirmed by PCR method on nasopharyngeal swab. The study population was represented by 267 males (69.0%) and the median age was 64 years (IQR 24-94 years). Median LOS was 12 days (IQR: 1-89 days) and 101 (26.1%) patients were admitted to ICU for at least 24 hours. Three hundred and fifteen (81.4%) patients received empirical antibiotic therapy on admission, represented in 84.1% (265 patients) by thirdgeneration cephalosporin. In the Table 1, clinical and demographic characteristic of the study population are summarized. One hundred and fifty-two (39.2%) patients had severe respiratory failure and needed mechanical ventilation: 76 (19.6%) patients required also an invasive mechanical ventilation, while 76 (19.6%) underwent noninvasive mechanical ventilation, only. One hundred and seventy-one (44.2%) patients received tocilizumab therapy (8 mg/kg/12 hours for a total of 2 administrations administered intravenously in 99 patients, and 2 doses of 162 mg subcutaneously, 1 per tight, in 72 patients). Fifteen (3.9%) patients received anakinra; all these patients were in ICU at the moment of the administration. One hundred and seven (27.6%) patients received also glucocorticoid therapy (methylprednisolone 1 mg/kg/24h).