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How antibiotics may worsen drug-resistant bacterial infections

Cell Press

In recent decades, methicillin-resistant Staphylococcus aureus, or MRSA, has evolved from a controllable nuisance into a serious public health concern. A pre-clinical study published November 11 in Cell Host & Microbe now reveals that treatment with first-line antibiotics may actually make MRSA skin infections worse, ironically by activating the body's own pathogen-defense system. The next step will be to obtain human data.

"Individuals infected with MRSA who receive a beta-lactam antibiotic--one of the most common types of antibiotics--could end up being sicker than if they received no treatment at all," says co-senior study author George Liu of Cedars-Sinai Medical Center. "Our findings underscore the urgent need to improve awareness of MRSA and rapidly diagnose these infections to avoid prescribing antibiotics that could put patients' lives at risk."

Staphylococcus aureus, often referred to simply as "staph," is a type of bacteria commonly carried on the skin or in the nose of healthy people. About one-third of the population is colonized with staph, but approximately 1% is colonized with MRSA, which is resistant to methicillin and many other antibiotics. These antibiotic-resistant strains are the most common cause of skin and soft tissue infections in the United States. MRSA is also more likely to cause severe illness or death compared with methicillin-sensitive S. aureus, but the underlying reasons have not been clear.

Based on their past findings, Liu and co-senior study author David Underhill of Cedars-Sinai Medical Center suspected that MRSA's harmful effects could be caused by the very gene that confers antibiotic resistance. Beta-lactam antibiotics kill many bacteria by inactivating proteins involved in cell wall synthesis. But MRSA bypasses the drug's actions by stimulating a gene called mecA, which in turn activates a back-up pathway for cell wall synthesis. This genetic change allows MRSA to survive antibiotics, but at the same time it alters the structure of the bacterial cell wall.

In the new study, the researchers tested whether the immune system responds to these structural changes in a way that worsens MRSA infections. They found that exposure of MRSA to beta-lactam antibiotics induced mecA activation, which weakened the chemical bonds between molecules in the cell wall and rendered the bacteria more easily degradable by immune cells. The degradation of the cell wall released fragments that were recognized by the immune system, activating a harmful inflammatory response that worsened skin infections in MRSA-infected mice.

"We now have evidence that the very factor that defines certain S. aureus as MRSA is a factor that can also make MRSA more pathogenic," says first study author Sabrina Mu?ller of Cedars-Sinai Medical Center. "However, this pathogenic factor is not unleashed unless MRSA is exposed to beta-lactam antibiotics. Therefore, a poor choice of antibiotic can make MRSA infection worse compared to no treatment."

The findings could have important clinical implications, given that the lives of many MRSA-infected patients are put at risk by initial inappropriate antibiotic treatment with beta-lactam antibiotics. Currently, diagnostic procedures involve sending a sample to a lab where bacteria are allowed to grow for 2 days. However, newer tests that can detect staph DNA in a matter of hours are now becoming more widely available. This will help healthcare providers decide on the proper treatment regimen for a patient more quickly, potentially preventing deaths associated with inappropriate antibiotic treatment.

But the authors urge caution in extending the interpretation of this preclinical study to humans until more research is conducted. "The obvious next step is to verify whether this occurs in humans," Underhill says. "If human data suggest that beta-lactam antibiotics given alone could make MRSA infection worse, then we may need to rethink whether beta lactams should be our first choice of empiric antibiotic before the source of the infection is known, especially in case of severe infections."


This study was supported by the US National Institutes of Health.

Cell Host & Microbe, Müller et al.: "Poorly Cross-Linked Peptidoglycan in MRSA Due to mecA Induction Activates the Inflammasome and Exacerbates Immunopathology"

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