The widespread use of antibiotics in COVID-19 patients poses a significant threat to global health by accelerating the development and spread of antimicrobial resistance (AMR). A previous systematic analysis estimated that bacterial AMR was responsible for 0.9-1.7 million deaths in 2019, highlighting its global impact. The empirical prescription of antibiotics for suspected bacterial infections in COVID-19 patients, both upon admission and during hospitalization, further increases the risk of AMR. While existing literature suggests a generally low prevalence (3-8%) of bacterial co-infections (diagnosed within 48 hours of admission) in COVID-19 patients, antibiotic usage remains high (50-75%), varying considerably across studies. Furthermore, evidence indicates a correlation between surges in COVID-19 hospital admissions and an increase in antibiotic-resistant infections, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). This study aimed to comprehensively assess the available evidence to establish the prevalence and predictors of both bacterial infections and AMR in individuals diagnosed with COVID-19, thus guiding improved clinical management strategies.

Prior to this study, there was concern regarding the potential exacerbation of antimicrobial resistance due to inappropriate antibiotic use in COVID-19 patients. Published reports indicated a low prevalence of bacterial co-infection (within 48 hours of presentation), but a higher prevalence in critically ill patients, specifically as secondary bacterial infections (after 48 hours). Despite the low overall prevalence of bacterial infections (3-8%), the high rate of antibiotic use (50-75%) raised concerns about overuse and the selection of antimicrobial-resistant pathogens. Existing studies lacked the scale and comprehensive data needed to fully understand the extent of AMR in this context.

This systematic review and meta-analysis followed the Cochrane Rapid Reviews Methods Group guidelines to estimate the prevalence and predictors of bacterial infections and antimicrobial resistance among patients with laboratory-confirmed COVID-19. The study included studies of hospitalized patients or a mix of hospitalized and non-hospitalized patients, excluding those solely focusing on community patients. A comprehensive search of the WHO COVID-19 Research Database was conducted for cohort studies, case series, case-control trials, and randomized controlled trials with at least 50 participants investigating bacterial infections, published in any language between January 1, 2019, and December 1, 2021. Reviews, editorials, letters, preprints, conference proceedings, studies using only nasopharyngeal swabs for infection testing, studies not differentiating bacterial infections from fungal or viral infections (other than COVID-19), and studies without microbiological confirmation of bacterial infection were excluded. Bacterial infections were classified as co-infection (diagnosed within 48 hours), secondary infection (diagnosed after 48 hours), or unspecified. Title and abstract screening was done independently by multiple reviewers, followed by full-text assessment. A ten-item risk of bias tool was used to assess study quality. Random-effects meta-analysis (generalized linear mixed models) was used to pool prevalence data, with heterogeneity assessed using the I² statistic. Meta-regression analysis explored the effects of patient characteristics, healthcare settings, geographic region, and study end month on bacterial infection and antimicrobial resistance. The primary outcomes were the prevalence of bacterial co-infection and secondary infection, and the prevalence and predictors of antibiotic-resistant pathogens in patients with laboratory-confirmed COVID-19 and bacterial infections. Secondary analyses stratified data by healthcare setting and type of bacterial infection. Data extraction was performed and validated by multiple team members to ensure accuracy.

The analysis included 148 studies encompassing 362,976 patients, published between December 2019 and May 2021. The majority (81%) were retrospective cohort studies. The studies were conducted across various geographical regions, with a significant proportion (69%, 253,777 patients) from Europe. The prevalence of bacterial co-infection was low at 5.3% (95% CI 3.8-7.4), while the prevalence of secondary bacterial infection was considerably higher at 18.4% (14.0-23.7). Co-infection was more frequent in ICU patients (8.4%) compared to general hospital patients (4.9%), while secondary infections were dramatically more common in ICU patients (39.9%) compared to general hospital patients (8.4%). Among studies reporting antimicrobial resistance data for at least four species, the prevalence of antimicrobial-resistant bacterial infections was high, reaching 60.8% (95% CI 38.6-79.3) per patient and 37.5% (26.9-49.5) per organism. There was substantial heterogeneity in the reported prevalence of antimicrobial resistance (I² = 95%). Meta-regression analysis revealed that study-level predictors of increased antimicrobial resistance included low-income or middle-income settings, ICU admission, IL-6 inhibitor use, and diabetes. The most common organisms identified were Staphylococcus aureus, Klebsiella spp., and Pseudomonas spp. Multidrug resistance was prevalent for several WHO critical pathogens, including carbapenem-resistant Acinetobacter baumannii and carbapenem-resistant Enterobacterales.

This large-scale systematic review and meta-analysis confirms previous findings indicating a low prevalence of bacterial co-infections in COVID-19 patients presenting to hospitals, suggesting that routine antibiotic therapy should be avoided unless there is strong suspicion of bacterial infection. Conversely, the study highlights the considerably higher risk of secondary bacterial infections in critically ill patients admitted to ICUs, necessitating careful risk-benefit assessments before initiating antibiotic treatment. The remarkably high prevalence of antimicrobial resistance in bacterial infections associated with COVID-19, particularly in ICU patients, underscores the urgent need for global surveillance of AMR. The significant differences in resistance rates between high-income and low-income/middle-income countries highlight the need for investment in diagnostic capabilities and antimicrobial stewardship in resource-limited settings. The study emphasizes the critical role of judicious antibiotic use in COVID-19 patients to mitigate the global threat of AMR.

This meta-analysis provides robust evidence of a high prevalence of antimicrobial resistance in bacterial infections among hospitalized COVID-19 patients, particularly in ICUs. The findings emphasize the need for global surveillance of antimicrobial resistance and highlight the importance of responsible antibiotic prescribing practices. Future research should focus on understanding the societal impact of AMR beyond hospitalized patients and explore the long-term consequences of the COVID-19 pandemic on antimicrobial resistance trends.

The study acknowledges several limitations. The limited reporting of resistance data in many studies, often restricted to a few common resistant organisms, might have led to an underestimation of the true prevalence of antimicrobial resistance. The underrepresentation of regions outside North America and Europe, especially low-income and middle-income countries, could have introduced bias. The meta-regression analysis might have lacked the statistical power to detect smaller associations due to the limited number of studies comprehensively assessing antimicrobial resistance. The focus on hospitalized patients might not fully capture the societal risk of AMR related to COVID-19.