Antimicrobial resistance has not disappeared, so we must not forget our stewardship principles.
"Antibiotics don’t work for viral infections."
We all know this important message to limit unnecessary prescriptions for sore throats, coughs and colds to reduce the risk of antimicrobial resistance. But this message has not played out in relation to COVID-19: antibiotic prescribing rates against the disease have been high.
Early in the pandemic, for example, reports from China suggested that antibiotic prescribing for those hospitalized with severe SARS-CoV-2/COVID-19 infection was nearly universal; and as the virus spread, high rates of antibiotic prescribing continued in Europe and America. In April 2020, in Scotland, a survey of antibiotic use in hospitalized patients with suspected COVID-19 suggested that 29% received an antibiotic before admission, while 62% received empiric antibiotic therapy after admission.
So what drove these high prescribing rates in this viral infection?
There may be lessons learned from history. In the last major viral pandemic, the 1918-1919 influenza pandemic, before antibiotics, the case fatality rate was 2 to 3 per 100 people, not unlike COVID-19. In that pandemic, post-mortem studies showed that secondary bacterial pneumonia was probably the leading cause of death. There is little doubt that if antibiotics had been available in 1918, hundreds of thousands of lives could have been saved.
Bacterial co-infection remains an important consideration in severe seasonal influenza. However, it was not a significant factor with any of the other novel coronavirus outbreaks – the severe acute respiratory syndrome (SARS) epidemic in 2003 or the Middle East respiratory syndrome (MERS) first recognized in 2012 – and we should be aware of this.
In the current pandemic, disease severity and progression in the second and third weeks of illness may have been interpreted as the result of superinfection (occurring in addition to infection) with bacteria. This assumption is compounded by ongoing clinical uncertainty, limited diagnostics and, most importantly, in the first wave of the pandemic, the lack of other proven therapeutic options. On top of that, antibiotics are readily available and their potential harms may not be considered by our COVID prescribing workforce.
Data on antibiotic prescribing for COVID-19 during the second wave is not yet available, but anecdotally, rates have been high. This has attracted little attention in the public consciousness, but the long-term effects on antimicrobial resistance should not be underestimated. COVID-19 has significantly challenged the robustness of our antimicrobial stewardship programs, but when it comes to antibiotics for respiratory infections, we must remain vigilant.
Diagnose to differentiate
One problem is that it may be difficult to differentiate COVID-19 pneumonia from bacterial pneumonia, due to overlapping clinical features, particularly cough, fever, hypoxia, and changes on chest x-rays. As in bacterial pneumonia, the blood concentration of C-reactive protein (CRP) generally increases in COVID-19 and generally increases significantly with severity, reflecting a virus-mediated inflammatory response .
Although a moderate increase in CRP can be seen in other viral infections (and sometimes significantly elevated in influenza), doctors frequently use an elevated CRP to differentiate between viral and bacterial infection. Prior to the onset of the pandemic, point-of-care CRP testing in primary care has been a useful antibiotic stewardship tool supporting the reduction of antibiotic prescribing in lower respiratory tract infection when CRP is low.
Little evidence of bacterial coinfection
There is little or no published data on bacterial infection complicating SARS-CoV-2 in non-hospitalized patients, but many will receive empiric antibiotic therapy. In those who are hospitalized (the majority of whom have community-onset SARS-CoV-2 infection), the evidence to date points to a low probability of bacterial co-infection: multiple cohort studies and systematic reviews have estimated that bacterial coinfection is rare (<4%) in hospitalized patients.
In a well-researched cohort from the Netherlands, bacterial co-infection was observed in only 1% of patients during the first week of hospitalization.
It is reasonable to assume that the lack of proven microbiology may be a consequence of the lack of respiratory tract sampling, due to infection control concerns surrounding obtaining sputum samples. However, in the vast majority of COVID-19 patients, the cough is dry or associated only with white or non-purulent sputum, making it unlikely to produce significant pathogenic bacteria. In the time before COVID-19, the lack of sputum purulence in the context of cough and/or fever is a clear impediment to the prescription of antibiotics, whether in primary or secondary care.
In patients hospitalized with severe COVID-19 pneumonia who progress to mechanically ventilated infection, the risks inherent to critical care are amplified by requiring barrier infection control precautions, prolonged intubation (and the challenges of prone ventilation). ) and the need for hemofiltration. Microbial investigations are more comprehensive in the acute care setting and are crucial to support targeted prescribing for ventilator-associated pneumonia and catheter-related bloodstream infections.
Little evidence of the benefits of antibiotics
The antibiotics azithromycin and doxycycline have been postulated to have anti-inflammatory or antiviral properties, and both have been investigated in COVID-like illnesses in primary care through the UK PRINCIPLE study.
So far, comprehensive data have been published for azithromycin showing no improvement in time to recovery at 28 days; Similar data have been reported with respect to doxycycline, although they have not yet been fully published. In patients hospitalized with COVID-19 pneumonia, azithromycin was not associated with benefit in either the Brazilian Coalition II randomized controlled trial or the UK randomized adaptive platform RECOVERY study. And on 28 January 2021, the Department of Health and Social Care warned that these antibiotics should not be used to control confirmed or suspected COVID-19.
Antibiotics should rarely be prescribed
Infections in primary care
If COVID-19 is suspected in primary care, routine use of antibiotics should be strongly discouraged . Antibiotics should be reserved for those in whom there are specific clinical features indicating another bacterial infection (e.g., urinary tract infection).
Bacterial coinfection of the respiratory tract is unusual, so antibiotics should be restricted to those with purulent sputum in the setting of an infectious exacerbation of chronic obstructive pulmonary disease (IECOPD), or if there is a strong suspicion of respiratory tract-acquired bacterial pneumonia. community (NAC).
PCR should not be used as a guide to starting antibiotics in the context of COVID-19
In contrast to pre-pandemic advice, in primary care, CRP should not be used as a guide to initiating antibiotics in the context of COVID-19, although its usefulness will likely return as COVID-19 infection becomes less prevalent. Amoxicillin or doxycycline is preferred for IECOPD and local guidelines for CAP should be followed. Treatment duration should be limited to five days (due to lack of additional benefit after this time and impact on antimicrobial resistance with longer courses).
Patients hospitalized with COVID-19
Bacterial co-infection is also unlikely to be a factor in the severity of COVID-19 in hospitalized patients, so again, antibiotics are not routinely required ; and CRP should not be used as a guide to initiate antibiotic administration. In those patients starting antibiotics, initial investigations including sputum culture and blood culture should be performed and the need for an antibiotic should be critically reviewed, particularly after a positive PCR result for SARS-CoV-2.
It is important to stop simply completing the "antibiotic cycle" and be proactive in stopping antibiotics that are not necessary. Where PCR has been performed, lack of reduction at 48 hours likely reflects SARS-CoV-2 infection rather than “antibiotic failure” and should prompt consideration of discontinuation rather than intensification of antibiotics. .
In those started on antibiotics, a procalcitonin (PCT) <0.25 micrograms also suggests a nonbacterial infection and should encourage discontinuation of antibiotics.
Patients requiring mechanical ventilation
The risk of bacterial superinfection (particularly ventilator-associated and vascular device-related nosocomial infection) is significant. Rapid microbiological diagnoses and empiric therapy based on local epidemiology and antibiograms are essential. In the critical care setting, procalcitonin (PCT) may help guide discontinuation of empiric therapy, although the significance of persistently elevated PCT in severe COVID-19 remains to be defined.
Thoughts for the future
Our knowledge of the pathophysiology and therapeutics of COVID-19 continues to grow. To date, the greatest therapeutic benefits have been seen with drugs that modulate the inflammatory response to viral infection. Both corticosteroids and IL-6 inhibitors have been shown to reduce mortality from COVID-19; however, they have the potential to increase the risk of secondary bacterial (and potentially fungal) infection and future studies will help to adequately define this risk.
In the meantime, vaccination is our best tool to reduce the risk of severe infection and hospitalization with SARS-CoV-2. Reducing this risk also has an important effect on reducing demand for antibiotics, and we should not underestimate effective vaccine programs as our cornerstones of antimicrobial stewardship.
Author : R Andrew Seaton, Infectious Diseases Consultant and Antimicrobial Stewardship Team Leader, Queen Elizabeth University Hospital, Glasgow; Chair, Scottish Antimicrobial Prescribing Group, Health Improvement Scotland.
The Royal Pharmaceutical Society has made this article free to access to help healthcare professionals stay informed on an issue of national importance.
