Cross-Resistance to Host Antimicrobials Induced by Antibiotic

Cross-resistance to colistin and host antimicrobials cathelicidin (LL-37) and lysozyme, which help defend the body against bacterial attack, could mean that patients with life-threatening multi-drug resistant infections are also saddled with a crippled immune response.

Scientists at Emory University (Atlanta, GA, USA) and collaborating colleagues, investigated whether the treatment of patients with colistin can induce not only increased resistance to colistin, but also resistance to host cationic antimicrobials. Colistin remains in use today not so much because it's particularly safe or effective, but because the choices for treating multidrug resistant Acinetobacter baumannii and other resistant infections are few and dwindling.

The investigators noted that colistin works by disrupting the inner and outer membranes that hold Gram-negative bacterial cells together, much the same way two antimicrobials of the human immune system, LL-37 and lysozyme. LL-37 is a protein found at sites of inflammation, whereas lysozyme is found in numerous different immune cells and within secretions like tears, breast milk, and mucus, and both are important defenses against invading bacteria.

By studying A. baumannii isolates from patients around the country, they noted that all the colistin-resistant strains harbored mutations in a regulatory gene that encodes for polymyxin resistance (PmrB), that leads to the modification of polysaccharides on the outside of the cell in response to antibiotic exposure. Tests showed a tight correlation between the ability of individual isolates to resist high concentrations of colistin and the ability to resist attacks by LL-37 or lysozyme.

The scientists studied two pairs of A. baumannii isolates taken from two different patients before and after they were treated for three or six weeks with colistin. The results helped confirm the cross-resistance link as neither strain taken before treatment was resistant to colistin, LL-37, or lysozyme, but the strains taken after treatment showed significant resistance to colistin and lysozyme. Both post-colistin isolates harbored crucial mutations in the PmrB gene that apparently bestow the ability to resist treatment.

David S. Weiss, PhD, the senior author, said, “The way that the bacteria become resistant to colistin allows them to also become resistant to the antimicrobials made by our immune system. That is definitely not what doctors want to do when they're treating patients with this last line antibiotic.” Dr. Weiss plans to follow up on cross-resistance to antimicrobial agents of the immune system, which could well extend to other pathogens that are treated with colistin, including Pseudomonas aeruginosa and Klebsiella pneumoniae. The study was published on May 21, 2013, in the journal mBio.

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