Fighting Antimicrobial Resistance With Rational Combination Therapy

Imagine a patient in your clinic with a stubborn Pseudomonas aeruginosa infection that refuses to clear up. Standard antibiotics are failing, and you wonder why.

Antimicrobial resistance (AMR) is a growing concern. This article summarizes the latest research on AMR and its clinical implications.

Understanding the problem & its root cause

When bacteria grow, they copy their DNA, much like copying text from a book. Mistakes—called mutations—can happen while copying, and they can be good or bad for the bacteria.

Usually, a system called Mismatch Repair (MMR) fixes these errors. But some Pseudomonas strains lose this MMR system. Without it, they collect more and more mutations. Surprisingly, these extra genetic mistakes can make them stronger and able to resist many different antibiotics. Scientists call these fast changing bacteria “hypermutators,” and they are very hard to treat.

In short, these extra mutations help the germ learn quickly —how to fight off many antibiotics.

Why is this important?

Think about how we treat infections. We usually pick one antibiotic and use it until the infection is gone. But in these hypermutators, one antibiotic can drive the bacteria to become resistant to other antibiotics. The bacteria use big protein pumps (efflux pumps) that push out many different drugs at once. So, if you are only using one antibiotic, you may accidentally teach the germ to resist several others. Soon, you are left with fewer options to treat your patient.

How to solve this problem:

The scientists tested different antibiotics in the lab. They watched hypermutator bacteria quickly develop resistance to more than one drug. But they also found a helpful trick. If you combine two antibiotics that work in very different ways, it is harder for the bacteria to become resistant to both. They call this strategy “rational combination therapy.” It means picking antibiotics that do not share the same path to resistance.

They also looked at bacteria from real patients. They saw the same pattern: bacteria missing the MMR system were often resistant to many drugs or became resistant later. This can happen in lung infections (common in cystic fibrosis), but also in other parts of the body, like the urinary tract. The same method of checking for these “mutation patterns” in the bacteria’s DNA can show if they have the hypermutator feature. If so, doctors know that they might need special treatments.

How does this research matter for clinicians?

Sometimes, we see Pseudomonas aeruginosa in wounds, sinus issues, or other infections. When it becomes resistant, it is very hard to treat. Knowing about hypermutators and how to spot them helps us plan better care. By using combined antibiotics, we may prevent the spread of multi-drug resistant germs.

In the end, the big lesson is that not all Pseudomonas germs are the same. Some are sneaky and mutate fast. But if we can spot them through whole genome sequencing (looking at all their DNA) and use smart combinations of drugs, we might stay one step ahead.

Whole Genome Sequencing (WGS) can characterize the new mutations acquired in the absence of MMR, and help us identify MMR-deficient bacteria that already are multi-drug resistant (MDR) or will rapidly acquire MDR.

Clinical implications of this research

This rapid identification should help guide clinicians for potentially effective precision treatment, such as rational combination therapy, rather than relying on empiric therapy that could potentially drive further resistance.

This new knowledge brings hope for preventing infections that do not respond to any antibiotics. It is an important reminder: the more we learn about germs, the better we can protect our patients.

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