The Underlying Threat of Multidrug-Resistant Pathogens in the COVID-19 Era

The beginning of the COVID-19 pandemic will be remembered as a time of rapid change. The threat was severe and imminent, but the virus had yet to be fully characterized and the widespread implications were unknown. Infection prevention specialists who previously focused on mitigating nosocomial spread of multidrug-resistant organisms (MDROs) pivoted to take on the challenge of COVID-19 isolation and prevention. Public health officials and hospital administrators were forced to implement unprecedented mitigation measures at a breakneck pace. In the face of an emergency, we lacked the time and resources to understand the second or third order effects of these policy changes.

The predictions of those who study MDRO epidemiology reflected the uncertainty of the times, and 2 general tenets emerged. One highlighted an increased awareness of infection control measures among hospital staff, believing that the pandemic would drive improvements in adherence to standard practices, such as hand hygiene and use of personal protective equipment. The other cited data from the 2002 to 2004 severe acute respiratory syndrome (SARS) outbreak demonstrating stagnant and sometimes worsening isolation rates for methicillin-resistant Staphylococcus aureus (MRSA).^1,2 The conclusion at the time was that increased stress on health care systems from SARS led to poor compliance with existing infection control policies designed to prevent spread of MDROs. A similar lapse seemed likely to occur with the COVID-19 pandemic.

Two years later, the impact of the COVID-19 pandemic on rates of MDRO isolation is beginning to come into focus. The results of several prominent studies are summarized in the Table.^3-10 Taken in the context of varying pandemic responses, it is unsurprising that these early articles often reported contradictory findings. In resource-rich settings, a general decrease in isolation of MDROs was observed. For example, a case-control study at an academic center in Italy reported decreased rates of overall MDRO isolation in March to June 2020 compared with previous years. Rates of MDRO isolation were decreased among both patients with COVID-19 and patients without COVID-19, although the differences were less pronounced and not statistically significant within the COVID-19 group. This improvement was driven by a dramatic decline in MRSA isolation.³

A similar decrease in new-onset MRSA colonization was observed among inpatients at a large Singapore hospital after infection prevention policies aimed at COVID-19 were implemented.4 Lower monthly MDRO rates from 2019 to 2020 were also noted in articles written by investigators at California and Australia facilities.^5,6 Reports from other regions were not as favorable for rates of MDR gram-negative pathogens. Across Japanese hospitals, Hirabayashi et al found a decrease in MRSA rates, contrasting with a relative increase in isolation of MDR Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa.⁷ Similar reports showcasing higher rates of MDR gram-negative acquisition among patients with COVID-19 emerged from academic centers in Baltimore, Maryland, and Terni, Italy.^8,9 Most alarmingly, data from a hospital dedicated to COVID-19 in São Paulo, Brazil, noted a 23% increase in MDRO infections during the pandemic driven by outbreaks of both MRSA and carbapenem-resistant Acinetobacter baumannii.¹⁰

Factors associated with the increased transmission of MDRO during the pandemic include liberal antibiotic utilization, prolonged hospital courses, and individual outbreaks. Evidence from the literature demonstrates that clinicians frequently ordered empiric antibiotics for patients with COVID-19. To understand the appropriateness of this empiric prescribing, the frequency of early bacterial coinfection and superinfection in COVID-19 has been investigated. Wang et al examined microbiological specimens of all patients with a positive SARS-CoV-2 test within 48 hours of admission at 2 London hospitals, reporting a 2.7% rate of clinically important bacterial coinfection, with urinary tract infections identified as the most common infectious source.11 A similar study performed at a Barcelona hospital found a 9.1% rate of early bacterial coinfection; however, a positive pneumococcal urine antigen accounted for 79% of coinfections.¹² These discordant results may be explained by differences in methodology. For instance, the latter study only included patients who had procalcitonin and microbiological samples collected and excluded those with positive urine cultures.

Although institutional culture plays a large role in antibiotic prescribing, reports suggest that a majority of inpatients with COVID-19 have been treated empirically for bacterial coinfection or superinfection. One study of 2 hospitals in northwest London reported that 95% of patients with COVID-19 received antimicrobial therapy at the time of admission,¹¹ whereas a recent systematic review by Al-Hadidi et al analyzing 141 studies and 28,093 patients reported a more palatable rate of 58.7%.¹³

Prescribing patterns were examined more closely in a retrospective observational study of patients diagnosed with COVID-19 at 716 US hospitals by Rose et al. Among these patients, 77.3% received at least 1 day of antibiotics, and 81.3% of antibiotics were started on admission. The most commonly ordered agents were antibiotics used to treat pneumonia, such as third-generation cephalosporins and macrolides. Patients admitted to critical care units were more likely to receive broad-spectrum agents such as vancomycin, piperacillin-tazobactam, cefepime, and meropenem.¹⁴ This level of antibiotic use far exceeds estimates for the burden of bacterial disease among inpatients with COVID-19.

A reasonable exception for which antimicrobial use may be justified is among patients with severe COVID-19 who require mechanical ventilation and extended intensive care unit (ICU) stays. Yang et al reported a bacterial superinfection rate of 13.5% among patients critically ill with COVID-19 in Wuhan, China.¹⁵ Investigations into the microbiology of superinfection in this population have identified a variety of culprit organisms that reflect the local epidemiology. Patients with COVID-19 in ICUs in Spain and Italy with high baseline rates of MDR Enterobacterales typically developed ventilator-associated pneumonias (VAPs), catheter-associated bloodstream infections, and urinary tract infections due to these same organisms.^16-18

Resistant organisms appear to be less common in US ICUs with lower baseline rates of MDRO isolation overall. Analyzing data from a US tertiary care center, Pickens et al found that only 20.8% of patients who underwent a bronchoalveolar lavage for an initial VAP episode had bacteria resistant to standard therapy for community-acquired pneumonia.¹⁹ Regardless of the setting, isolation of MDRO occurred more frequently with prolonged hospitalizations among patients with COVID-19.

Differentiating between respiratory distress due to COVID-19 or bacterial pathogens is a significant challenge. Retrospective studies have found that patients with bacterial coinfection and superinfection tend to present with a higher severity of illness and require prolonged hospital courses. In aggregate, these patients show more pronounced elevations in white blood cell count and inflammatory markers.¹¹ Procalcitonin is not a specific marker, but it may yet be useful for its high negative predictive value among patients with COVID-19.¹² Unfortunately, each of these features is also commonly seen in severe COVID-19, so clinical judgment must still play the largest role in the decision to treat empirically for bacterial infection.

Outbreaks among patients admitted to COVID-19-dedicated wards have also been cited for increased MDRO rates. Factors associated with outbreaks include a medication room mistakenly excluded from terminal cleaning, flawed proning protocols, double-occupancy rooms, and a team nursing model in which multiple nurses shared direct care responsibilities over a large group of patients.^9,20,21 Taken together, poor staff compliance with infection control appears to be a key determinant of outbreak settings.

This is concerning, as nurses and patient care technicians are experiencing unprecedented levels of burnout and job departures. It was recently reported that 18% of US health care workers resigned during the pandemic, with an additional 31% considering leaving their positions.²² Frontline workers in understaffed settings may find themselves in situations in which they don’t have time to comply with infection control measures while also providing essential bedside care.

A potential blueprint for reducing antibiotic use can be found within reports from centers that have successfully managed antibiotic prescribing among patients with COVID-19. Highly engaged antimicrobial stewardship practices were a commonly reported theme. At a center in Tokyo, Murakami et al demonstrated an overall decrease in antibiotic days of therapy per 1000 patient days to below prepandemic levels by April 2021, despite a 39.7% spike in intravenous antibiotic use at the time of the emergency declaration.²³ In Tel Aviv, Henig et al reported significant decreases in the proportion of patients who received antibiotics in COVID-19 wards relative to prepandemic rates in 2019, from 44.9% to 30.2% during the June to November 2020 wave and 50.1% to 30.5% during the December 2020 to March 2021 wave. These results were achieved through the development and frequent updating of institution-specific guidelines that addressed bacterial therapy and the involvement of an infectious disease specialist in weekday rounding.²⁴ Seaton et al reported a 38.3% rate of antibiotic use among patients with COVID-19 across 15 Scottish hospitals and explicitly attributed the success to the impact of antimicrobial stewardship.²⁵

At the outset of the pandemic, many hoped that increased visibility and emphasis on infection control measures would lead to a decrease in rates of MDRO isolation. The data we have now paint a more uneven picture, with some groups reporting improvement and others stagnation. Patients hospitalized with COVID-19 receive antibiotics at a rate far in excess of the observed burden of bacterial illness, and this is likely contributing to gram-negative resistance in this population.

Assessing a patient with COVID-19 for superimposed bacterial infection often presents a diagnostic challenge, and fearful providers frequently prescribe empiric therapy. It is imperative that we standardize our approach to antibacterial therapy in this population and decrease antibiotic use among these patients. To accomplish this, we must empower antimicrobial stewardship programs, which are best equipped to address the problem. We must also take measures to address the impending hospital staffing crisis and ensure that frontline workers have the support they need so that infection prevention does not compete with direct patient care.

Acting now will allow us to expand pandemic-era improvements in MDRO isolation beyond the most resource-rich settings and—in the case of the hardest-hit areas—prevent stagnation from deteriorating into an antibiotic-resistance crisis.

REFERENCES

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