Strategies to reduce use of antimicrobial drugs for RSV

March 16, 2022

Strategies to reduce consumption of antimicrobial drugs are needed to contain the growing burden of antimicrobial resistance. Respiratory syncytial virus (RSV) is a prominent cause of upper and lower respiratory tract infections, as a single agent and in conjunction with bacterial pathogens and may thus contribute to the burden of both inappropriately treated viral infections and appropriately treated polymicrobial infections involving bacteria, according to a new study from Berkeley, and published in PNAS.

In a double-blind, randomized, placebo-controlled trial, administering an RSV vaccine to pregnant mothers reduced antimicrobial prescribing among their infants by 12.9% over the first 3 months of life. Our findings implicate RSV as an important contributor to antimicrobial exposure among infants and demonstrate that this exposure is preventable by use of effective maternal vaccines against RSV.

In this randomized, double-blinded, multisite trial, infants of mothers assigned the RSV F vaccine received fewer antimicrobial prescription courses over the first 90 d of life than infants of mothers assigned placebo. While estimated efficacy of the RSV F vaccine against RSV-associated, medically significant LRTI in this trial did not meet the prespecified criterion for success, the findings implicate RSV as a major contributor to antimicrobial prescribing among young infants and demonstrate that this prescribing is preventable by maternal vaccination.

This evidence of protection against all-cause antimicrobial prescribing end points is particularly noteworthy given that the bulk of prescribing is associated with nonsevere conditions against which vaccination may be expected to offer lower degrees of protection; indeed, expanded ITT analyses including trial-specific and hospital record data revealed incrementally higher VE point estimates of 53.8, 58.6, and 73.7% for end points of medically significant RSV-associated LRTI, RSV-associated LRTI with hospitalization, and RSV-associated LRTI with severe hypoxemia, respectively.

Future RSV vaccine candidates achieving higher efficacy may achieve greater reductions than were evident in this trial, underscoring the importance of RSV vaccine development as a strategy to reduce antimicrobial consumption and AMR.

Among US infants who experienced 42.9% VE against prescribing of penicillins during the first 90 d of life, penicillins accounted for nearly all prescribing prevented by maternal vaccination. Our findings likely reflect international guidelines for the management of severe pneumonia with ampicillin/amoxicillin (or penicillin) and gentamicin as the first-line treatment and ceftriaxone as a second-line therapy.

The extended duration over which we identified protection against LRTI-associated prescribing of certain drugs may have been anticipated from adverse event monitoring in the trial, which revealed 24.6, 32.4, and 15.0% lower incidence of all-cause pneumonia, ear infection, and rhinitis, respectively, through the first year of life among infants whose mothers were assigned vaccination. Whereas most prescribing of aminoglycosides occurred during the first 90 d of life, the same was not true for prescribing of other drugs against which we identified protection through the end of follow-up.

While some antimicrobial treatment may occur for LRTI episodes directly attributable to RSV, a substantial proportion may also occur for bacterial infections precipitated by prior and possibly, mild or asymptomatic RSV infection in the respiratory tract. It remains to be determined to what extent the observed efficacy of the RSV F vaccine against RSV-associated LRTI in this trial resulted from prevention of acquisition of RSV or protection against progression to medically significant illness and how these modes of protection may impact risk of diseases that result in antimicrobial prescriptions. Regardless of the specific mechanisms involved, however, our findings signify a similar burden of vaccine-preventable antimicrobial prescribing in the United States and other HICs as compared with South Africa and other LMICs in the context of substantially differing incidence of antimicrobial prescribing due to other causes.

Antimicrobial resistance (AMR) poses a severe threat to human health and well-being. As human consumption of antimicrobial drugs is an important source of selective pressure contributing to the emergence and expansion of AMR (strategies to reduce antimicrobial use in situations where it is avoidable or unnecessary are a focus of AMR action plans.

Vaccines against influenza, pneumococcus, and rotavirus have been found to prevent substantial antimicrobial consumption and prescribing. While understanding the potential for new vaccines to mitigate antimicrobial use and AMR burden could inform priority setting in vaccine development, evaluation, and approval, challenges surround efforts to define the extent of antimicrobial consumption preventable by specific vaccines.

Microbiological diagnosis is seldom undertaken for common, nonsevere infections that precipitate the greatest volumes of prescribing and is often impractical, as many of the pathogens causing acute respiratory, febrile, and diarrheal infections are also prevalent among individuals without symptoms. Due to this challenge, substantial antimicrobial consumption is likely associated with viral infections for which treatment is unnecessary or inappropriate.

Additionally, polymicrobial interactions contribute to the pathogenesis of numerous bacterial infections, as best understood in the context of influenza virus interactions with Streptococcus pneumoniae and Staphylococcus aureus. Such interaction pathways may further implicate viruses in the etiology of conditions that are appropriate to treat with antibiotics. Vaccines against respiratory viruses may thus have importance for preventing infections that lead to both appropriate and inappropriate antimicrobial use.

PNAS report