What is the potential of antivirulence antimicrobial therapy?

The most likely future for antivirulence therapies is that they become adjuncts rather than alternatives to antibiotic therapy.

That’s the case for one of the first modern antivirulence therapies, bezlotoxumab (Zinplava) for prevention of recurrent C. difficile infections. Bezlotoxumab targets one of the toxins produced by C. diff, rather than the bug itself. It was shown to lower the recurrence rate in high-risk patients from 33% to 20%, in conjunction with antibiotic therapy[1] .

It is unlikely that any antivirulence therapy will replace antibiotics for life-threatening infections. Antibiotics have been the standard of care for 70 years. Despite rising rates of resistance, most antibiotic prescriptions work most of the time. Very few (far less than 1%) of serious infections are resistant to all antibiotics.

Doctors just won’t take the risk of withholding antibiotics and giving antivirulence therapies instead. Similarly, the FDA and IRBs are very unlikely to approve trial designs in which antivirulence compounds are given as stand-alone therapy. Not for complicated infections, anyway.

The most plausible scenario for antivirulence compounds as stand-alone therapy might be uncomplicated urinary tract infections. Several trials of symptomatic (eg., ibuprofen) vs antibiotic therapy have been approved and executed[2] [3] , so there is no obvious reason why an antivirulence vs antibiotic trial could not be conducted. It’s known that antibiotics are ineffective for preventing recurrent cystitis[4] , and so there is a definite need for alternative therapeutic approaches.

Antivirulence strategies that include blocking toxins and blocking adhesion of bacteria to the bladder are being investigated. One trial found that D-mannose (a sugar that blocks adhesion) significantly reduced UTI recurrence vs standard antibiotic therapy[5]. A number of other small molecules and vaccines are being developed that will treat UTIs by blocking adhesion.

From Adhesive Pili in UTI Pathogenesis and Drug Development

Another general barrier to adoption of antivirulence therapies is that they tend to be more narrow-spectrum than antibiotics. Most antibiotics target biochemical processes that are conserved between bacteria, such as cell wall growth, protein synthesis or DNA/RNA synthesis. They thus tend to have fairly broad spectra of action.

In contrast, antivirulence therapies tend to target processes that are more species-specific: toxins, signal transduction, quorum sensing, biofilm formation. That’s actually one of their attractive properties – by precisely targeting the infecting bugs, they spare disruption of the host microbiome.

But prescribing a narrow-spectrum therapy requires identifying the pathogen first. There are some rapid tests out there that can do this, but they are relatively expensive, don’t cover a wide range of bugs, and are confined to use in hospital microbiology labs. Until rapid tests for bacterial infections become cheaper and better, antivirulence therapies will be at a disadvantage compared to antibiotics.

Antivirulence therapies definitely have a future, but they are not going to replace antibiotics.

Footnotes

[1] Bezlotoxumab (Zinplava) for Prevention of Recurrent Clostridium Difficile Infection

[2] Recurrent urinary tract infections and complications after symptomatic versus antibiotic treatment: follow-up of a randomised controlled trial.

[3] Symptomatic treatment of uncomplicated lower urinary tract infections in the ambulatory setting: randomised, double blind trial.

[4] Urinary Tract Infection: Pathogenesis and Outlook.

[5] Oral D-mannose in recurrent urinary tract infections in women: a pilot study