In our retrospective observational cohort of 191 patients, we observed a high prevalence of infection acquired in the ICU and a predominance of Gram-negative bacteria, especially multirresistant Acinetobacter and K. pneumoniae. These data may reflect the challenges within an ICU dedicated to the care of patients with Covid-19, who, in order not to lose focus on maintaining life in the face of a new highly contagious disease without specific treatment, flows and protocols already established for the control of nosocomial infection had to be adapted dynamically, according to the local pandemic scenario. Few studies on secondary infection in the ICU have been published despite the fact it is an important topic for the management of critically ill patients with Covid-19. A meta-analysis of 3,448 patients assessed the prevalence of co-infection and secondary infection in patients with Covid-19 and found 3.5% presence of co-infection and 15.5% of superinfection, with a greater proportion among the most severely ill individuals; interestingly, despite the low incidence of bacterial co-infection, more than 70% of patients received antimicrobials (15). Moreover, as pointed out in a letter, self- administration of antibiotics was 33% among COVID-19 patients in Peru, and although there is some regulation in Brazil, this may have also been a contributing factor to selection of bacterial resistance in our patient cohort (16). Therefore, not only infection control practices play a role in the acquisition of infection in ICU’s during the COVID-19 situation, but antibiotic overuse selects multirresistant bacteria (15). Ripa et al (17) showed that a secondary infection was seen in 9.3% of 731 patients hospitalized for COVID-19 in Italy. Incidence of healthcare related bacterial pneumonia in patients admitted due to COVID-19 was 0.4 per 1000 patient follow up days outside ICU vs 15.2 in ICU, that is, incidence was 37-fold higher in ICU. Gram negatives predominated in their study, of which Acinetobacter accounted for the greater portion (nearly a third). Risk factors for secondary infections on multivariate analysis were early need for ICU, respiratory failure and severe baseline lymphopenia. A report on patients with COVID-19 in 19 ICUs in China showed that carbapenem resistant Acinetobacter (CRAB) was identified in 19/30 isolates related to secondary infection, of which most were VAP. A CRAB outbreak during the COVID-19 pandemic has been reported in the USA (18); the report states that responding to COVID-19 related care needs, changes such as less frequent patient bathing with chlorhexidine gluconate and a 43% reduction in ICU CRAB screening tests occurred; there were critical shortages for nursing and environmental services resulting from staff members’ illness and quarantine. In Lille, France, an OXA-23-producing Acinetobacter baumannii outbreak occurred during the COVID-19 epidemy in their ICUs; CRAB was found in respiratory and blood samples taken from 21 patients, all of them on ventilation (19). Environmental sampling was performed on equipment such as ECG devices, ultrasound scanner, hemodialysis machine, but the isolate was not recovered from these samples. A small Iranian study of 19 patients admitted to ICU, all on mechanical ventilation, showed that all patients acquired infection, and 17 of them had multirresistant Acinetobacter as the causative agent of VAP; mortality was 95% (20). In Spain, of 712 patients hospitalized with COVID-19, 11% developed superinfection, and Acinetobacter sensitive to colistin only was the main pathogen in pneumonia and bloodstream infections, which was attributed to an outbreak at the time; the authors report that this pathogen was most unusual in their hospital. Multivariate analysis showed that bacteremia and superinfections with Acinetobacter were associated with mortality (21). Another Spanish cohort of 989 consecutively hospitalized patients found a 3.8% overall incidence of secondary infection in patients with Covid-19, but the proportion of cases was higher among individuals admitted to the ICU with more than half of the events. Gram-negative bacteria were also the most prevalent and 28% of those who developed infection in the ICU had identification of at least one bacterium with a resistant multi-drug profile. Longer hospital stays and higher mortality were observed in those who evolved with healthcare-related infection (22).
A small Chinese cohort study with 36 ICU patients had a prevalence of secondary bacterial infection of 13.9%. The most common agents found in cultures were Burkholderia cepacia, Stenotrophomonas maltophilia and Pseudomonas aeruginosa, all isolated from tracheal aspirate or bronchoalveolar lavage, showing that exposure to mechanical ventilation preceded the occurrence of infections. In this cohort, multi drug resistant bacteria were not found (23). Another Chinese study with 38 severe and critical COVID-19 patients showed a 57.9% prevalence of superinfection, most of which (21/22) were respiratory, with Gram negatives responsible for half of these. No mention of multiressistance was made (24).
In France, a prospective cohort of 54 ICU patients had 49 of their patients on invasive mechanical ventilation. Cultures of bronchoalveolar lavage identified secondary bacterial infection in 37% of inpatients, and of this total, 75% were VAP. This compares to our 29.8% incidence of superinfection, of which 33/57(58%) were VAP. However, their profile of etiologic agents showed a higher prevalence for Stenotrophomonas maltophilia, Staphylococcus aureus and Pseudomonas aeruginosa with 13%, 20% and 33%, respectively, while in our study we had Acinetobacter, P. aeruginosa and K.pneumoniae, in 28.9%, 22.7% and 14.4% respectively. Patients who developed VAP presented proportionally more ARDS and acute kidney injury and they remained on mechanical ventilation and in the ICU for longer (25). We found similar risk factors in our study: the group of patients with superinfection presented here experienced moderate to severe ARDS, the need for hemodialysis, mechanical ventilation and vasopressor drugs. They also remained for a longer time on mechanical ventilation in the ICU and had a higher proportion of deaths. Furthermore, a study in Qatar evaluated the impact of MDR Gram- negative infections in patients with severe COVID-19 admitted to ICU. They found a total of 78 cases of MDR-Gram negative infection out of 1231 adults (incidence 4.5 per 1000 ICU days); 98 MDR Gram negative isolates were retrieved within a median of 9 days of admission to ICU. More than one MDR Gram-negative were isolated from 17 (21.8%) patients. The most frequent sample sites were the respiratory tract (74, 75.5%) and blood (18, 18.4%). The most frequently isolated MDR Gram-negatives were Stenotrophomonas maltophilia (24, 24.5%), Klebsiella pneumoniae (23, 23.5%), and Enterobacter cloacae (18, 18.4%); the authors hypothesize one or more outbreaks to account for these. Mechanical ventilation days, but not receipt of corticosteroids or tocilizumab, was independently associated with the isolation of MDR Gram negatives. Surprisingly, there was no association between MDR Gram negative infections and 28-day all-cause mortality (26).
A retrospective cohort of 78 patients in Italy investigated the occurrence of CLABSI in ICU patients with Covid-19. They found a high incidence of events, with a higher prevalence of coagulase negative staphylococci, followed by Enterococcus faecalis and Staphylococcus aureus. Multivariate analysis showed only the use of anti-inflammatory agents such as tocilizumab or methylprednisolone as an independent association for the occurrence of CLABSI (27). In our sample, of the 57 patients with secondary infection, 14 were diagnosed with CLABSI, with a predominance of Gram-negative bacteria (Supplement 1).
In our population, the most prevalent gram-negative bacteria with a high profile of antimicrobial resistance were Klebsiella pneumoniae and Acinetobacter baumanii. The first with 57.1% of the cases with sensitivity to ceftazidime/avibactam only and the second with 96.4% of the isolates with sensitivity to colistin and tigecycline only. VAP was the most common type of infection in both cases. In England, an outbreak of Klebsiella pneumoniae infection has been reported in an ICU. Eleven of the 20 cases had a hostile profile of antimicrobial resistance, which was not reported. The site of infection was the bloodstream and mortality was also not mentioned (28).
In Brazil, multidrug resistant Acinetobacter and enterobacteria are prevalent pathogens preceding the COVID-19 pandemic, and VAP is the most frequent ICU-acquired infection (29), as shown in a recent multi-hospital point prevalence study of healthcare-associated infections in 28 adult ICUs. In the European Union, resistance to carbapenems is also worrying and precedes the pandemic, and the impact of COVID-19 on antimicrobial resistance may be deleterious (30). Other intensive care units dedicated to the care of COVID-19 patients both in the public and private sectors in Rio de Janeiro have CRAB as the main infectious challenge (unpublished data).
The concern with infectious complications related to health care and coping with infections by antibiotic resistant bacteria is one of the most important public health issues of our time. The limited available evidence whether to initiate or not antibiotics for patients in the beginning of the COVID-19 pandemic, the scarcity of evidence on antibiotic choice, the work overload of health professionals and rapid patient deterioration probably resulted in the indiscriminate use of antibiotics and contributed to the spread of multi-drug resistant microorganisms (31, 32).
As limitations, ours is a single center observational study, relying on the quality of medical records. Thus our findings may not be extrapolated to other ICUs.
In conclusion, we found a high incidence of healthcare-related infection in patients with Covid-19 admitted to the ICU, with a higher prevalence of Gram-negative bacteria and a high incidence of multidrug resistance. The most common infection was VAP. The SAPS 3 score was the only factor associated with infections acquired in the ICU. Superinfections of any type and VAP were associated with higher mortality.