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ExPEC Vaccine: Another Tool in the Toolbox?

Julie Ann Justo, PharmD, MS, FIDSA, BCPS

Clinical Associate Professor
Department of Clinical Pharmacy and Outcomes Sciences
University of South Carolina College of Pharmacy
Infectious Diseases Clinical Pharmacy Specialist
Department of Pharmacy
Prisma Health Richland Hospital
Columbia, South Carolina

Julie Ann Justo, PharmD, MS: consultant/advisor/speaker: bioMérieux, Entasis Therapeutics, Gilead Sciences, Merck, Shionogi, Spero Therapeutics, Therapeutic Research Center; stock ownership: Vaxart.

View ClinicalThoughts from this Author

Released: August 31, 2022

Key Takeaways

  • Extraintestinal pathogenic Escherichia coli (ExPEC) are a major healthcare burden and the cause of many serious infections, including sepsis, bacteremia, urinary tract infections, and neonatal meningitis.
  • Many strains of ExPEC are resistant to β-lactams and other classes of antibiotics, so there is a need for prophylactic strategies such as vaccination.
  • Vaccine development for ExPEC has been limited by the heterogeneity of virulence factors among ExPEC strains.

Every day in my inpatient clinical practice, I come across at least 1 patient with an infection caused by extraintestinal pathogenic Escherichia coli (ExPEC). Many of these clinical cases manifest as bloodstream infections, cystitis and/or pyelonephritis, skin and soft tissue infection, and/or osteomyelitis. The management of these cases is even more complex when the ExPEC strain is resistant to first-line antibiotics such as β-lactams (an increasingly common occurrence). Trying to treat and effectively cure the infection before a resistant strain pops up can feeI like a game of whack-a-mole. As an antimicrobial steward, this is particularly discouraging, because every day of antimicrobial use increases the risk that a strain with antimicrobial resistance will emerge. It is a necessary consequence we must accept to treat infections in the short term, yet I still find myself searching for a better way.

It would be a welcome shift to treat infections caused by ExPEC with something other than an antibiotic—or, better yet, to prevent an infection from ever occurring. Such an option could be possible with a safe and effective ExPEC vaccine, although the ideal patient population requires further clarification. Future vaccines likely will focus on high-risk populations, such as those with recurrent urinary tract infections, at extremes of age, and/or at high risk of serious infections.

Why No US Vaccine Yet? It’s Complicated
E coli is well-known by both healthcare professionals and the public, but the sheer diversity and complexity of its strains are impressive. Finding unique features that separate commensal and pathogenic E coli strains while still covering the broad swath of pathogenic strains has proven challenging. ExPEC vaccines are in development for prevention and/or treatment, and these efforts are attempting to find the ideal combination of strains and virulence factors to optimize vaccine effectiveness and safety.

Two ExPEC vaccines to prevent recurrent urinary tract infections are available internationally, (eg, OM-89), but no ExPEC vaccines are approved by the FDA in the United States. This may be surprising considering the burden of ExPEC infection on the healthcare system, but a closer look at ExPEC structure and pathophysiology illustrate some interesting challenges.

Classifying E coli
The complexity of E coli is apparent in the number of classification systems used to categorize isolates: by strain (ie, pathotype or phylogroup), virulence factor(s), and/or antibiotic resistance profile. Historically, E coli strains were classified by disease presentation/pathotype as intestinal pathogenic E coli or ExPEC, with ExPEC further subdivided by clinical syndrome, such as uropathogenic E coli (UPEC), neonatal meningitis E coli (NMEC), or sepsis-causing E coli (SEPEC).

A second system classifies E coli strains by variations in the bacterial genome using phylogroups. There are 4 major phylogroups (A, B1, B2, D) and 5 minor phylogroups (C, E, F, G, cryptic clade I). Phylogroups B2 and D contain many ExPEC strains, whereas phylogroups A and B1 contain most commensal ExPEC. Phylogroups are further subdivided into clonal complexes and sequence types (STs). Since 2000, the most common sequence type associated with human disease worldwide has been ST131.

ExPEC are well-known for harboring antibiotic resistance genes conferring resistance to first-line antibiotics. For instance, resistance mechanisms to β-lactams include extended-spectrum β-lactamases and carbapenemases, and resistance to fluoroquinolones is caused by altered DNA gyrase and topoisomerase IV, porin-channel downregulation, efflux pumps, and/or plasmid-mediated quinolone resistance genes. As many as 30% to 46% of antibiotic-resistant clinical isolates of E coli are found to be ExPEC strains (eg, ST131, ST69); however, not all ExPEC sequence types routinely exhibit antibiotic resistance. In addition, antibiotic resistance profiles within a single ExPEC sequence type can vary over time and by geographic region. This suggests antibiotic resistance phenotype is not a sole determinant of clonal dissemination of ExPEC.

Virulence Factors as Vaccine Targets
It may seem logical to devise an ExPEC vaccine targeting specific pathotypes or phylogroups, but various virulence factors contribute to infection, making it more difficult to target several strains at once. Virulence factors include surface polysaccharides (eg, O and K antigens), adhesins (eg, FimH on fimbriae, type 1 pili), toxins (eg, α-hemolysin), and iron acquisition systems (eg, siderophores, outer membrane receptors).

Research using virulence factors as vaccine targets demonstrate mixed results to date. Some have failed due to insufficient immunogenicity. For example, the capsular K1 antigen has structural similarities to human neural tissue and fails to elicit a sufficient antibody response post vaccination. However, vaccine development is ongoing for more promising virulence factors, including O antigen and FimH. Many of the leading candidates are multivalent vaccines containing up to 10 ExPEC serotypes.

Potential Impact on Antimicrobial Resistance
ExPEC vaccines, if successful, will be a key tool in our toolbox for decreasing antibiotic use and thereby combatting antimicrobial resistance. Such a multimodal approach is in line with the current global strategy for combatting antimicrobial resistance.

Want to learn more about ExPEC?
Join me and a panel of experts as we discuss ExPEC at our upcoming live virtual symposium. We’ll discuss the burden of ExPEC, populations at risk for infections caused by ExPEC, and prevention strategies, including the current landscape of ExPEC vaccines.

Your Thoughts?
Would you recommend an ExPEC vaccine for your adult patients if approved? Join the discussion by posting a comment.

Provided by Clinical Care Options, LLC

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