Infrequent COVID-19 Co-Infections Are Frequently Treatment Resistant

Bacterial co-infections are uncommon with COVID-19, but frequent empirical use of antibiotics in patients with COVID-19 is linked to emergence of antimicrobial resistance (AMR) in co-occurring and secondary infections, in the largest meta-analysis to date of bacterial infections and AMR occurring with COVID-19.

“Antimicrobial resistance is a major problem and one of the leading causes of global mortality, so the potential of COVID-19 to hasten this problem is a significant public health concern,” study lead author Bradley Langford, PharmD, Public Health Ontario, Toronto, ON, told Contagion.

“We previously identified that about 75% of patients with COVID-19 receive antibiotics, despite the relative low rate of co-infection of less than 10%,” he recounted.

In the current analysis of 148 studies, conducted in more than 40 countries involving 362,976 patients, the prevalence of bacterial co-infection (identified within ≤48 hours of presentation) was 5.3% (95% CI 3.8-7.4), while 18.4% (14.0-23.7) of patients treated for COVID-19 as outpatients or in the hospital manifested secondary bacterial infection (≥48 hours). Moreover, 60.8% (38.6-79.3) of the bacterial infections occurring in patients with COVID-19 demonstrated AMR; with 37.5% (26.9-49.5) of isolates found resistant.

“Our systematic review identified that, in fact, the prevalence of AMR in COVID-19 patients with bacterial infections is substantial, particularly for Gram-negative organisms,” Langford said.

112 of the studies were conducted in high-income countries, 35 in low- and middle-income countries, and 1 across multiple regions. Compared with the Americas region, the odds of antibiotic-resistant isolates were higher in the Eastern Mediterranean, South-East Asia, and Western Pacific regions. The odds of antimicrobial resistance, on both a per-patient and per-organism level were higher in low-income and middle-income than in high-income countries.

“It is important to note that there was very high heterogeneity in reported prevalence of AMR across studies and regions,” Langford commented. “This reflects, in part, the multifactorial nature of AMR. Several factors could play a role in this variability, including the underlying volume of antibiotic use and the pre-existing prevalence of AMR in the population.”

The higher prevalence of bacterial infections occurring secondary to, rather than co-occurring with COVID-19, was attributed, in part, to the heightened risk of exposure after hospitalization. Intensive care patients, in particular, were more likely to require invasive interventions with concomitant increased risk of nosocomial infection

The highest prevalence of resistance was reported for multidrug-resistant Stenotrophomonas spp (100%, 95% CI 82.6-100.0%);Acinetobacter spp, 96.5% (86.9-99.1) multidrug resistant and 95.9% (84.1-99.0) resistant to carbapenems;and klebsiella spp, 88.3% (6.7-99.9) resistant to colistin and 69.2% (49.6-83.6) to carbapenems.

There was substantial prevalence of AMR for several of the bacterial pathogens which have been designated as priority by the WHO, including carbapenem-resistant Acinetobacter baumannii (96% of isolates were carbapenem resistant) and carbapenem-resistant Enterobacterales (69% of klebsiella spp resistant to carbapenem).

To discern the effect of specific population-level variables on bacterial infection and AMR, the investigators applied univariable meta-regression of patient characteristics, health-care settings, geographical region, and end month of study to assess temporal trends.Their analysis revealed that, in addition to antibiotic use and admission to ICU, patients with cardiovascular disease, diabetes, and IL-6 inhibitor use were also at increased risk of infection with a resistant pathogen.

“Our findings highlight the importance of surveillance in tracking antimicrobial resistance over time to better understand the trends and predictions,” Langford said. "Secondly, this work reinforces the need for robust antimicrobial stewardship and infection prevention efforts, particularly in patients with COVID-19.”