Implications for antimicrobial use and antimicrobial resistance.
Nearly half of hospitalized patients in the United States receive antibiotics during their stay,1 but 20% to 30% of those antibiotic days of therapy (DOT) have been found to be inappropriate. Moreover, 20% of patients who receive an antibiotic experience an adverse drug event.2,3 The main objectives of antimicrobial stewardship programs (ASPs) are to optimize antibiotic use and minimize harm associated with antibiotics. The coronavirus disease 2019 (COVID-19) pandemic has presented new challenges for ASPs to streamline antibiotic therapy. To accomplish this, data on the prevalence of bacterial coinfections and secondary infections and rates of antimicrobial-resistant (AMR) infections among patients with COVID-19 are needed to inform optimal antimicrobial use.
Bacterial infections among patients with COVID-19 can be divided into 2 categories: community-onset and hospital-acquired infections. Community-onset coinfection generally refers to bacterial infections that exist upon presentation to an acute care setting. Hospital-acquired secondary infection refers to bacterial infections that develop during hospital admission. Although no standard time course has been defined in the COVID-19 literature, one study defined secondary infection as infection occurring 48 hours or more after admission.4
Vaughn and colleagues conducted one of the largest studies of community-onset bacterial coinfection among 1705 patients with COVID-19 at 38 Michigan hospitals.5 Of these patients, 13.8% presented from skilled nursing or subacute rehabilitation facilities and 10.9% were admitted to an intensive care unit (ICU). Blood cultures and respiratory cultures were obtained within 3 days of admission in 62.3% and 7.7% of patients, respectively; 54.8% had nonblood culture testing performed (ie, urine legionella and pneumococcal antigens).
Altogether, 3.5% (59/1705) had a bacterial coinfection, including 3.2% (55/1705) with positive blood or respiratory cultures. However, despite those low rates of bacterial coinfection, 56.6% of patients received empirical antibacterial therapy within 2 days of hospitalization. Empirical treatment included agents covering only community-acquired infection (35.9%); therapy against methicillin-resistant Staphylococcus aureus (MRSA) (14.6%); antipseudomonal therapy (14.9%); and anti-MRSA combined with antipseudomonal therapy (10.8%).
In a similar study of community-onset bacterial coinfection among hospitalized patients with COVID-19, Karaba and colleagues found that 1.2% (12/1016) had proven or probable community-acquired pneumonia, 2% (20/1016) had bloodstream infection (BSI), 3% (30/1016) had urinary tract infection (UTI), and 0.2% (2/1016) had Clostridioides difficile infection.6 The most common organisms associated with BSI were Staphylococcus aureus (6/20), coagulase-negative Staphylococcus (5/20), and E coli (5/20); the most common organisms associated with UTI were E coli (10/30), Proteus spp (5/30), and Klebsiella spp (4/30). Nonetheless, 71% (717/1016) of patients received at least 1 dose of an antibiotic directed at bacterial community-acquired pneumonia. As the study period progressed, a lower percentage of patients were started on antibiotics (61% in May vs 77% and 75% in March and April, respectively) and the median duration of antibiotic therapy became shorter.
Results of another study, by Lehmann and colleagues, showed that 1.2% (7/321) of patients admitted from the community to a hospital in Chicago had community-acquired bacterial coinfection.7 Of those 7 patients, 4 were diagnosed by positive S pneumoniae urinary antigen. Similar to the other studies’ findings, empirical antibiotic use was high, with 69% of patients receiving antibiotics.
The largest study to date to include hospital-acquired secondary infections in the United States during the COVID-19 pandemic was conducted by Nori and colleagues at a single center in New York City.8 Of 4267 patients evaluated, 3.6% (156/4267) had positive blood or respiratory cultures during their initial hospitalization for COVID-19 or a hospitalization within 30 days of their positive test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; the virus responsible for COVID-19 disease). Of patients with coinfections or secondary infections, 65% were admitted to ICUs and 74% received mechanical ventilation.
The study’s results showed that the median length of hospitalization was 13 days. By infection site, 60% of patients had respiratory infection, 54% BSI, and 14% both. The median time between positive respiratory bacterial culture or positive blood culture and SARS-CoV-2 test results was 6 days (interquartile range [IQR], 2-8) and 7 days (IQR, 3-14), respectively. Respiratory culture results were consistent with nosocomial pathogens, including S aureus (44%), P aeruginosa (16%), Klebsiella spp (10%), Enterobacter spp (8%), and E coli (4%). Fifteen percent of the respiratory gram-negative isolates were multidrug-resistant (MDR) and 5% were carbapenem-resistant Enterobacterales (CRE).
The top 3 sources for BSI were catheters (central venous, peritoneal dialysis, and hemodialysis), respiratory tract, and genitourinary tract. The organisms causing BSI most frequently were S aureus (30%), S epidermidis (12%), Streptococcus spp (10%), Enterococcus spp (7%), E coli (7%), and P aeruginosa (6%). Of all bloodstream isolates, 8.5% were MDR gram-negatives and 5% were CRE. Consistent with the evidence from the other studies, 71% of COVID-19 patients, despite low overall rates of infection, received at least 1 dose of antibiotic on admission.
Meta-analyses utilizing data from hospitals mostly in China have included both community-acquired coinfection and hospital-acquired secondary infections and support these US observations. Lansbury and colleagues found that across nearly 4000 patients, 7% of hospitalized patients with COVID-19 had bacterial coinfections or secondary infections and the rate of bacterial infection was higher among patients admitted to ICUs vs non-ICU wards (14% vs 4%).9 Of the studies included that reported antibiotic use, >90% of patients received empirical antibiotics in 10 of the 17 studies. Similarly, Langford et al found that among more than 3000 patients with COVID-19, bacterial coinfection was present upon hospitalization in 3.5% and secondary hospital-acquired infection developed in 14.3%; bacterial infections were more common among patients admitted to ICUs.10 Among the studies that reported antibiotic prescribing, 71.8% of patients received antibiotics. It should be noted that these analyses were limited by differences in diagnostic criteria or case definitions, an inability to differentiate colonization and infection, and the absence of treatment and antimicrobial resistance data. Secondary infections were also not primary end points in most of the studies that were included. Future studies should be conducted to address these shortcomings.
Despite low overall rates of coinfection and secondary bacterial infections among COVID-19 patients, several US studies have reported an increase in overall antibiotic DOT per 1000 patient-days (PDs) during the pandemic.11-13 While our group, the Veterans Affairs (VA) Pittsburgh Healthcare System, also reported an increase in overall antibiotic DOT/PDs, we observed a decrease in absolute antibiotic DOT, primarily driven by decreased overall hospitalizations early in the pandemic.11 A study of national VA data found increases in DOT/PDs of the broad-spectrum agents used for community-onset respiratory infections and of those used for hospital-onset infections.12
In the ambulatory care space, our group described substantial decreases in US prescriptions of the 10 most commonly prescribed outpatient antibiotics.14 Taken together, these data signify that absolute antibiotic use has likely decreased in both the inpatient and outpatient settings. However, antibiotic DOT/PDs have increased in the inpatient setting during the pandemic.
It is possible that an overall decrease in antibiotic use nationally during the pandemic was due to decreased health care access. At the same time, it appears that antibiotic use increased among patients admitted to acute care settings. The impact of such prescribing on national AMR patterns is unknown, but it will be a focal point of future studies. At a single center in Maryland, Bork and colleagues found that while there was no difference in acquisition of MDR gram-negative infections when comparing the same periods in 2020 and 2019, there was a 3% increase in MDR gram-negative infections per PDs for every positive SARS-CoV-2 test per week.13 Notably, antimicrobial resistance patterns may significantly differ among localities, regions, and nations. Within hospitals, there may also be significant differences between general medical wards vs ICUs and COVID-19 units vs non–COVID-19 units.
It is reasonable to hypothesize that as clinical experience and COVID-19 testing protocols were established, more judicious antimicrobial use followed. ASPs can leverage data showing low risk of bacterial coinfections to withhold or discontinue antibiotics among patients admitted for COVID-19 who do not have evidence of bacterial infection. Likewise, the relatively low rate of bacterial secondary infection development can be used to implement antibiotic timeouts and early antibiotic discontinuation if bacterial infection is not diagnosed. Other core stewardship strategies, including the use of rapid diagnostics, culture-directed therapy, short courses, and early oral switches, can also be employed. While the utility of procalcitonin in COVID-19 illness is not fully known, it appears to be useful in guiding the need for antibiotics early during a patient’s course of COVID-19. Among patients who are critically ill, it remains unclear if higher levels of procalcitonin are due to severe disease or related to bacterial coinfection or secondary infection.15
Many questions are still unanswered regarding bacterial infections, antimicrobial use, and AMR among patients with COVID-19. There is significant heterogeneity in the way that bacterial infections among COVID-19 patients have been classified to date. Many studies do not clearly differentiate between community-acquired coinfection and hospital-acquired secondary infection. The risk of bacterial infection stratified by underlying conditions, COVID-19 severity, admission to an ICU, mode of oxygen delivery, and hospital length of stay are not yet clear. The epidemiology and susceptibility patterns of bacterial coinfection and secondary infections are not well defined. Further, the risk of development of AMR infection among COVID-19 patients is not yet clear.
It is possible that an increase in secondary bacterial infections will be observed over time during the pandemic. Patients with severe COVID-19 may have prolonged hospitalizations and necessary admissions to nursing facilities after hospital discharge; they may also experience COVID-19–related complications requiring readmission to hospitals. Substantial changes have also occurred in the management of COVID-19 since the pandemic’s start, such as the use of corticosteroids or other immunosuppressants. Health care systems and health care workers are experiencing strain as cases have surged in the fall and winter. Influenza and other respiratory viruses beyond SARS-CoV-2 may impact rates of secondary bacterial infections. Clearly, additional well-designed studies are needed to focus on describing the epidemiology of bacterial infections among COVID-19 patients, antibiotic use, and long-term effects on local and national AMR patterns.
Deanna J. Buehrle, PharmD, is infectious diseases clinical pharmacist, Division of Infectious Diseases, Department of Medicine, VA Pittsburgh Healthcare System, Pittsburgh, PA.