Combining the antibiotic azithromycin with a mucous-clearing drug called N-acetylcysteine within lipid bubbles could provide a new treatment for drug-resistant bacterial infections. Tests by researchers at KAIMRC and King Saud bin Abdulaziz University for Health Sciences suggest the formulation has the potential to improve the ability of azithromycin to inhibit and kill antibiotic-resistant E. coli.

Harmful strains of E. coli, gram-negative bacteria found in the lower intestine of warm-blooded organisms and in fecal matter, can cause urinary tract infections, respiratory illnesses and fatal diarrhoea. Antibiotic-resistant strains are on the rise globally. “Drug-resistant bacteria are a major problem that threatens many lives,” says Alaa Eldeen Yassin, who led the study. “Clinicians need more treatment options.”

Previous research has shown that N-acetylcysteine can be combined with antibiotics to prevent the formation of treatment-resistant microbial biofilms on surfaces such as dental implants and catheters. It is also known the antibacterial activity of azithromycin and other antibiotics can be increased when encapsulated in lipid-based drug delivery systems called liposomes.

The researchers tested azithromycin alone, within a liposome (LA) and combined with N-acetylcysteine within a liposome (LAN). These three formulations were evaluated against an E. coli strain with some resistance to antibiotics and a multi-drug resistant (MDR) strain.

The lowest concentrations needed to prevent growth of the antibiotic-resistant strain and to kill it were 21 times lower for the LA formulation than for azithromycin in its own. Likewise, these formulations were effective against the MDR strain at one-fifth of the concentration needed for azithromycin.

The inclusion of N-acetylcysteine caused a 17% reduction in the lowest concentrations needed to prevent growth of the MDR strain and to kill it but provided no benefit against the antibiotic-resistant strain.

The researchers then tested the lowest concentrations of azithromycin, LA and LAN needed to prevent growth of biofilms of the bacteria. Azithromycin was no more effective against the MDR strain when in the LA and LAN formulations than when alone. However, the LA and LAN formulations were better at reducing biofilm formation by the antibiotic-resistant strain.

Dr Yassin adds that he expects LA and LAN will prove to be effective against other drug-resistant bacteria, not just E. coli.  Despite the fact that LA and LAN were stable at biological temperatures, further tests found that their formulations were unstable when exposed to sputum and blood plasma. The researchers believe this problem can be overcome by changing the lipid content of the liposomes.

The group plans to change the formulation in an effort to further increase its antibacterial activity, and also hopes to test it in animals and, ultimately, in clinical trials.

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