- Massachusetts General Hospital researchers used a combination of methylene blue, potassium iodide and photodynamic therapy (PDT) to clear urinary tract infections in rats
- Recurrence of infection was significantly less likely in rats that received triple treatment than in those that did not receive potassium iodide, suggesting that potassium iodide produced long-lived bactericidal reactive oxygen species
- The outer layer of the urothelium regenerated rapidly after triple treatment, even when superficial cells were killed by PDT
- Methylene blue and potassium iodide are FDA approved; if this treatment approach is successful in human studies, it could be incorporated into clinical practice rapidly
Catheter-associated urinary tract infections (UTIs) are a significant challenge in the community—especially in hospitals and long-term care facilities. These infections are most frequently caused by Escherichia coli and Klebsiella, which are increasingly resistant to antibiotic therapy. What's worse, uropathogenic E. coli can form biofilms that are even harder to kill.
Researchers at Massachusetts General Hospital have been studying antimicrobial photodynamic therapy (PDT), which combines laser light with a nontoxic dye called a photosensitizer. In the presence of oxygen, this technology produces highly reactive oxygen species that rapidly kill microbes regardless of drug resistance.
Another plus: As long as the light is delivered to infected tissue soon after the photosensitizer, antimicrobial PDT is significantly selective for microbial cells over host cells.
In Scientific Reports, Urologist Anton Wintner, MD, and colleagues describe the first success treating UTIs with antimicrobial PDT in a rat model. They chose this indication because urine contains oxygen.
Two FDA-approved Compounds
The researchers made use of two simple chemical compounds that are approved by the Food and Drug Administration for use in medicine. One of them was methylene blue (MB), a photosensitizer long used in medicine. It is known to have an antimicrobial effect on E. coli and other gram-negative organisms, but its activity is rather weak.
The researchers boosted MB with the second compound: potassium iodide (KI). This nontoxic inorganic salt is highly water soluble, and the researchers considered it likely to come into close contact with the bacterial surface.
The researchers used a transurethral catheter to introduce a bioluminescent strain of a cystitis isolate into the bladders of female rats. One hour after infection, they instilled MB for 15 minutes, then withdrew that solution and instilled KI solution. Some animals were instilled with MB but not KI, and another control group was instilled only with saline.
Most animals then underwent illumination of the bladder with laser light for 32 minutes. (As an additional control, some rats that were instilled with both MB and KI did not receive PDT.) A bioluminescence imaging system was used before, during and for up to 16 days after the infection.
The researchers observed that mean luminescence in the rats that received MB + KI + PDT was significantly lower, indicating greater clearance of infection, than in those who received MB + PDT.
On histologic examination, the MB + KI + PDT group showed the least inflammation and the least neutrophil infiltration at 24 hours after infection. Photodynamic damage was confined to the urothelium of the bladder wall, without damage to the underlying muscle layer.
Results Over Time
One of the principal drawbacks to using antimicrobial PDT to treat infections is that the bactericidal reactive oxygen species are very short lived. Once light delivery stops, the bacteria tend to grow back.
An aim in using KI was to see whether it would produce the stable, long-lived bactericidal species I2/I3–. This did appear to be the case. In three of eight rats, MB + KI + PDT was a complete success, and there was no recurrence of infection.
In other rats in the MB + KI + PDT group, infection recurred the day after treatment. However, up to six days after treatment, the percentage of rats with recurrent infection was significantly lower in the MB + KI + PDT group than in the controls. On histologic examination, the bladder urothelium in the MB + KI + PDT group was back to normal appearance within two weeks after treatment.
Potential for Rapid Clinical Translation
It's possible that the very catheter that can cause bacterial urinary tract infections can be turned into a way of delivering antimicrobial PDT with or without conventional antibiotic therapy.
Because the researchers used two compounds that are already approved in the U.S., their novel approach in rats might be rapidly translatable into clinical treatment of drug-resistant urinary tract infections.
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