Combination of Antibiotics Could Counteract Resistance in E coli, Study Suggests

A cocktail of common antibiotics could counteract antibiotic resistance, according to a new study that examined multidrug-resistant Escherichia coli causing urinary tract infections.

The study, published in the journal Nature Communications, was completed by a group of investigators in Denmark who looked at the gene CTX-M-15, encoding an extended spectrum beta-lactamase (ESBL). The CTX-M-15 mutation is common globally and makes it difficult to treat urinary tract infection.

"Our research demonstrates how 2 antibiotics (commonly used individually) can overcome a very important resistance problem (ESBL) when used in combination," study author Morten Sommer, PhD, a professor and associate scientific director at Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, told Contagion^®. "Furthermore, we selected these antibiotics to be matched as best possible from a pharmacokinetic perspective to enable co-administration of the existing medicines. Accordingly, our results could be translated into improved treatments for urinary tract infections if clinical testing was initiated."

Mutations with increased resistance to mecillinam were found to confer full susceptibility to cephalosporin drugs. This reciprocal collateral sensitivity limits resistance, allowing wild-type and resistant CTX-M-15 to be eliminated with a combination of mecillinam and cefotaxime, the study showed in vitro and in mice.

The study investigated the evolutionary potential and constraints of CTX-M-15 adaptive change using directed evolution in a more simplified approach than the clinical setting. The approach allows for the assessment of evolutional potential, which is not feasible using traditional adaptive evolution that can often result in increased fitness costs of gene variants.

Mutually exclusive resistance has been noted in other resistance genes such as aminoglycoside-modifying enzymes, indicating that further study into the use of combination therapy to counter resistance is warranted, the study noted.

Mecillinam and cefotaxime can be administered orally and are already approved, providing an advantage over the development of new drugs in the fight against resistance and in treating urinary tract infections, which affect an estimated 50% of women at some point in their lives, according to a news release about the study.

"The results are interesting because we showed that bacteria simply can't survive both drugs," study author Carola Rosenkilde, a PhD student at the Novo Nordisk Foundation Center for Biosustainability at Technical University of Denmark, said in the statement. "Also, the same gene with only one mutation shows this switch-function. Normally, you will find multiple mutations in multiple resistance genes, controlling different mechanisms."

The results of the proof-of-concept study were limited to the specific strain of ESBL E coli, paving the way for further research into resistance genes that may be susceptible to drug combinations.

Antibiotic resistance is a growing public health threat that investigators are keen to tackle. A study released last year found that combinations of up to 4 or 5 antibiotics may be effective in fighting drug-resistant E coli. Most E coli infections are harmless, but a 2018 outbreak in 36 states linked to contaminated romaine lettuce raised concerns after sickening 210 people, leading to 96 hospitalizations, and 5 deaths.

Resistance to ceftazidime-avibactam has emerged since the drug was approved for clinical use in 2015, raising concerns about treatment of carbapenem-resistant Enterobacteriaceae infec­tions, including E coli.