What’s Old is New: Rediscovering Antibiotic Utility

We are continuing our new series, Media Day, where we spotlight individual medical institutions and infectious disease (ID) programs. Today, we spotlight UC San Diego’s Skaggs School of Pharmacy and Pharmaceutical Sciences and the university’s extensive research programs and community-based health programs to serve the local population.

Victor Nizet, vice chair for Basic Research in the Department of Pediatrics, chief of the Division of Host-Microbe Systems and Therapeutics, UC San Diego, says his lab has been examining ways in which the immune system and existing medicines interact so they can look to repurpose these therapies for other indications. He is enthusiastic about this work, especially as they are already FDA-approved and safe for use in infectious disease.

For example, he and his team published a paper a few years back that studied how ticagrelor (Brilinta), the antiplatelet medication, which is used to prevent blood clots actually boosted the ability of platelets to kill bacteria in the bloodstream, especially MRSA infections. Since the publication of that paper, Nizet said other groups around the world have been studying how to repurpose therapies.

“I just learned last month that a large Clinical Trials Network studying the optimal therapy for staph infections is going to include an arm in the trial where they're going to repurpose this platelet medicine to help treat staph infections. And this was all from our observation that patients who had a lower platelet count were having more trouble with staph infections,” Nizet said.

When it comes to repurposing antibiotics, Nizet and his team have looked at the seesaw effect of drug resistance with regards to infections and how this phenomenon observed, especially with MRSA, where increasing resistance to a drug like daptomycin or vancomycin leads to increased susceptibility to a different class of antibiotics, such as beta-lactams.¹

“We were studying strains of staph that were becoming resistant to the alternative medicines like daptomycin that people were using for MRSA infections. And in the laboratory, we found that those strains that became resistant to daptomycin, which is a cationic peptide antibiotic derived from bacteria, were becoming more susceptible to beta-lactam antibiotics like nafcillin and cefazolin. And so, we wondered if we could bring that to treatment advantage. We showed that there was synergy between daptomycin and beta-lactam antibiotics and killing MRSA. Daptomycin reminded us that our own body makes antimicrobial peptides.”

He reiterates the importance of looking at how the immune system and the body reacts to individual agents, especially in cases where getting patients on the right antibiotic in a timely manner—Gram-negative infections—has a heightened priority.

“We know from experience that if you have a deep seated Gram-negative infection or staph infection, the mortality rate is very high if you've not responded to initial therapy. So we think in those patients, instead of just going back to the simple laboratory tests, we need to think a little bit more holistically, like bring in the immune system. Perhaps do the same testing in the patient's own blood or the patient's own serum,” Nizet said. “We can get more information, and I think that's the way that we do most other fields of medicine, right? There's no laboratory test where we can test a blood pressure medicine or a Parkinson's medicine in a test tube, and say it's effective. We study them in the context of the patient and the patient responses.”

In the next episode, Jennifer Le, PharmD, discusses her work on the 2020 Vancomycin Guidelines for children as well as her efforts with CIPER and the collaborative efforts in Vietnam to implement Bayesian therapeutic drug monitoring for the pediatric population.

Reference
1.Werth BJ, Steed ME, Kaatz GW, Rybak MJ. Evaluation of ceftaroline activity against heteroresistant vancomycin-intermediate Staphylococcus aureus and vancomycin-intermediate methicillin-resistant S. aureus strains in an in vitro pharmacokinetic/pharmacodynamic model: exploring the "seesaw effect". Antimicrob Agents Chemother. 2013;57(6):2664-2668. doi:10.1128/AAC.02308-12