Combination therapy promising against blindness-causing bacterial keratitis

November 12, 2018, American Society for Microbiology
Staphylococcus aureus, in yellow, interacts with a human white blood cell. Credit: National Institute of Allergy and Infectious Disease

Multidrug-resistant bacterial infections of the cornea are a leading cause of blindness and cannot be effectively managed with current ophthalmic antibiotics. A team of investigators has now devised a combination therapy that largely circumvents resistance, and quickly and effectively eradicated bacterial keratitis in 70 percent of animal models treated. The research is published in Antimicrobial Agents and Chemotherapy, a journal of the American Society for Microbiology.

Staphylococcus aureus and Pseudomonas aeruginosa are the leading causes of , an of the cornea. Fast, effective antimicrobial treatment is required to prevent scarring, corneal perforation, and/or endophthalmitis, an inflammation of the eye's interior.

"I have witnessed first-hand patients who have failed all commercially available antibiotic therapies who, in the face of rapidly deteriorating vision, are desperate for effective therapies," said corresponding author Rachel Wozniak, MD, Ph.D., Assistant Professor of Ophthalmology, University of Rochester Medical Center, Rochester, NY. "Unfortunately, this occurs all too often, as resistance to levofloxacin, the last antibiotic approved for this indication, can be as high as 72 percent for some bacterial infections."

The investigators chose to develop a with existing antimicrobials rather than a new compound because they anticipated that doing so would be considerably faster, said co-corresponding author Paul Dunman, Ph.D., Associate Professor of Microbiology and Immunology, University of Rochester Medical Center, Rochester NY.

"Our discovery platform was based on polymyxin B/trimethoprim (PT), a currently available ophthalmic antibiotic used to treat mild ocular infections such as conjunctivitis, but with narrow use in serious infections due to its slow-acting antimicrobial activity," said Dr. Wozniak. "Using high throughput screening of FDA approved drugs in combination with PT, we identified PT plus rifampicin as a lethal antibacterial combination toward both drug-resistant S. aureus and Pseudomonas aeruginosa, two predominant causes of bacterial corneal infections."

The improved activities of the combination is almost certainly due to each component having an independent mechanism of antimicrobial action, according to the report. Rifampicin inhibits bacterial DNA transcription by binding to the enzyme that assembles ribonucleotide bases into RNA. Trimethoprim inhibits bacterial DNA synthesis. Polymyxin B acts as a detergent, disrupting the oily outer and inner membranes primarily of Gram-negative bacteria—a category which includes both S. aureus and P. aeruginosa.

That membrane-disruptive activity of polymyxin B may also improve antibiotic penetration, thereby adding to the combination's effectiveness, the investigators speculate.

The combination has shown a low rate of development of spontaneous resistance, which is likely is due to the need for multiple simultaneous mutations to evade the combination's multiple modes of attack, according to the report. This common strategy has been used against resistance notably in HIV, malaria, and tuberculosis.

"While there may be unforeseen effects of combination drugs with respect to toxicity, both rifampicin and PT are currently FDA-approved drugs with favorable safety profiles, and thus their combination may provide a significant advantage for further drug development," according to the report.

In preclinical testing on mouse models, the combination therapy eradicated infections in 70 percent of treated animals, according to the report.

Globally, bacterial keratitis is a leading cause of blindness, with two million new cases annually. In the United States, overnight contact lens wear is the leading cause of keratitis, and an estimated 30,000 new cases occur annually.

Explore further: Research may help rescue antibiotics' effectiveness in the face of drug-resistant bacteria

Related Stories

Research may help rescue antibiotics' effectiveness in the face of drug-resistant bacteria

August 10, 2018
Bacteria—especially Gram-negative strains—are becoming increasingly resistant to current antibiotic drugs, and the development of new classes of antibiotics has slowed. Faced with these challenges, investigators are studying ...

Researchers cure drug-resistant infections without antibiotics

October 17, 2018
Biochemists, microbiologists, drug discovery experts and infectious disease doctors have teamed up in a new study that shows antibiotics are not always necessary to cure sepsis in mice. Instead of killing causative bacteria ...

Triclosan, often maligned, may have a good side—treating cystic fibrosis infections

July 11, 2018
Maybe you've had the experience of wading in a stream and struggling to keep your balance on the slick rocks, or forgetting to brush your teeth in the morning and feeling a slimy coating in your mouth. These are examples ...

Researchers find a better way to save eyesight in third-world countries

November 14, 2016
Bacterial keratitis, an infection of the cornea often caused by contact lenses, malnutrition, or an injury, can lead to corneal scarring, one of the leading causes of blindness around the globe, according to the World Health ...

Novel therapies for multidrug-resistant bacteria

October 23, 2017
During this innovative study published in PLOS One, researchers found that novel classes of compounds, such as metal-complexes, can be used as alternatives to or to supplement traditional antibiotics, which have become ineffective ...

Recommended for you

PET scans to optimize tuberculosis meningitis treatments and personalize care, study finds

December 6, 2018
Although relatively rare in the United States, and accounting for fewer than 5 percent of tuberculosis cases worldwide, TB of the brain—or tuberculosis meningitis (TBM)—is often deadly, always hard to treat, and a particular ...

Silicosis is on the rise, but is there a therapeutic target?

December 6, 2018
Researchers from the CNRS, the University of Orléans, and the company Artimmune, in collaboration with Turkish clinicians from Atatürk University, have identified a key mechanism of lung inflammation induced by silica exposure, ...

Infectivity of different HIV-1 strains may depend on which cell receptors they target

December 6, 2018
Distinct HIV-1 strains may differ in the nature of the CCR5 molecules to which they bind, affecting which cells they can infect and their ability to enter cells, according to a study published December 6 in the open-access ...

Protecting cell powerhouse paves way to better treatment of acute kidney injury

December 6, 2018
For the first time, scientists have described the body's natural mechanism for temporarily protecting the powerhouses of kidney cells when injury or disease means they aren't getting enough blood or oxygen.

New study uncovers why Rift Valley fever is catastrophic to developing fetuses

December 5, 2018
Like Zika, infection with Rift Valley fever virus can go unnoticed during pregnancy, all the while doing irreparable—often lethal—harm to the fetus. The results of a new study, led by researchers at the University of ...

Study highlights potential role of bioaerosol sampling to address airborne biological threats

December 5, 2018
As a leading global city with a high population density, Singapore is vulnerable to the introduction of biological threats. Initiating an early emergency response to such threats calls for the rapid identification of the ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.