Research News

When a patient presents with a staph infection, healthcare providers face a dilemma. They need to act quickly and choose an antibiotic to prescribe for their patient, often before lab tests can determine whether the infection is caused by methicillin-resistant S. aureus (MRSA), or its treatable cousin MSSA (methicillin-susceptible Staph. aureus). A new PNAS study from Cleveland Clinic shows that the most common approach, using the antibiotic vancomycin, can influence how the bacteria evolve. This evolution unexpectedly changes how susceptible the bacteria is to other antibiotics and impact treatment down the line. 

"Antibiotic therapy depends on knowing which drugs a bacterium is sensitive to," says the study's senior author, Jacob Scott, MD, DPhil. "If that sensitivity changes during treatment, a drug that should work might suddenly fail, leading to longer illness, more complications, and fewer options for the patient." 

The unintended consequences of a common practice 

To investigate the evolutionary consequences of preemptively using vancomycin the research team, led by co-first author Kyle Card, PhD, experimentally evolved populations of MSSA under increasing concentrations of vancomycin. At certain levels of exposure, the bacteria evolved resistance to the antibiotic. 

The study found that as the MSSA populations evolved vancomycin resistance, they followed two distinct genetic paths. Some evolved mutations in a pathway that controls cell wall metabolism, while others altered their global stress response systems. These different evolutionary routes created predictable but opposing vulnerabilities to other antibiotics. For example, bacteria that mutated their cell-wall pathway became more sensitive to nafcillin, a standard treatment for MSSA. Bacteria that mutated their stress response became more resistant to both nafcillin and another first-line drug, cefazolin. 

"Our research indicates that the manner in which bacteria evolve vancomycin resistance is important, as it can impact the effectiveness of other drugs in the future," says Dr. Card, who is also a Howard Hughes Medical Institute Hanna Gray Fellow. "Even if a staph infection would initially respond well to an antibiotic, our findings reveal that this outcome could change with evolution under empiric therapy." 

The collateral response score is a new tool to predict evolution 

To help clinicians navigate the uncertainty that comes with choosing the right antibiotic, Dr. Card and the team used their data to develop a new metric called the Collateral Response Score (CRS). The CRS is a standardized way that estimates how susceptible a bacterium will become to other drugs, after being exposed to an initial antibiotic. 

"Our ultimate goal is to implement the CRS in clinical decision support systems to help physicians weigh the risks and benefits of different antibiotic choices based on a patient's treatment history," Dr. Card says. "Nevertheless, it is too early to recommend changes to patient care now; follow-up studies are necessary to validate our findings and assess how other experimental contexts might impact the results. Our study does, however, hint at a promising path toward precision medicine that is worth further investigation." 

The Scott Lab uses evolutionary modeling to understand and combat treatment resistance in bacterial infections and in cancer. This newest study builds on those insights and offers a new layer of understanding about how early treatment decisions can shape the entire course of an infection. 

"In fields like oncology and cardiology, clinicians are constantly weighing risks," Dr. Card says. "It's time we brought that same level of risk assessment to infectious disease, because bacterial evolution is an important factor we can no longer afford to overlook."