Pseudomonas Aeruginosa

Pseudomonas aeruginosa

Pseudomonas aeruginosa bacteria are versatile and highly resilient. They can use many sources of nutrition and resist damaging environmental challenges by a broad range of mechanisms (see below). They are ubiquitous in the environment, including soil, water, and the surfaces of plants, animals, and the human body. Static water, such as that in flower vases or bath toys, can be a rich source of the bacteria, often growing in a thick, protective slime layer, in part due to the production of alginate (slime) by the bacteria themselves.

While usually harmless on intact skin or body surfaces, Pseudomonas aeruginosa can cause a variety of damaging infections if the protective layers of the skin are breached. These involve the production of a wide range of toxins, and extracellular enzymes which aid in breaking down that host tissues. As well as causing hundreds of thousands of serious infections each year in the community, 10-15% of hospital acquired infections are due to Pseudomonas aeruginosa, with approximately 100,000 cases annually in the EU and US. In some situations, the frequency is even higher. Among burn patients, over a quarter have this infection. Skin grafts can be destroyed and if not controlled, the infection can kill. Lung infections are also a serious issue, particularly in cystic fibrosis, where it has been referred to as “the dreaded infection”.

Drug resistance

Pseudomonas aeruginosa is naturally resistant to many antibiotics, both because of the thick, multi-layered cell wall typical of the Gram-negative bacteria and because it carries multiple genes coding for such resistance by a variety of mechanisms. This is enhanced by its ability to grow on available surfaces in the complex layers known as biofilms which can render antibiotics ineffective, and by the release from these durable sites of infection of planktonic “swimmer” cells which can reseed infections to other areas:

The combined effects of these factors can make the bacteria immune to clinically achievable concentrations of antibiotics – even when tests show that they are vulnerable to them under laboratory conditions. Only a limited number of antibiotics are effective, and even these are not active against all strains. Pan-drug resistant (PDR) strains that are effectively immune to all available antibiotics have already been reported from many different countries around the world.

Multiple priority lists have been prepared, identifying highly resistant species of bacteria for which there is an urgent need for new antibacterial approaches. Pseudomonas aeruginosa figures strongly in such lists. The 2019 CDC AR Threats Report lists multidrug resistant Pseudomonas aeruginosa as “urgent“, while the WHO Global Priority List of Antibiotic-resistant Bacteria classifies the need for new drugs to combat resistant Pseudomonas aeruginosa as “critical”.

Infection and disease

Pseudomonas aeruginosa is usually harmless on intact skin or body surfaces, but can cause a wide variety of infections if the normal protective layers are breached:

Ear infections

One serious and chronic infection caused by Pseudomonas aeruginosa is that of the ear. This is seen in both the human and the animal ear, particularly in dogs.

In dogs

Ear infections in dogs are extremely common, with approximately 20% of the canine population affected at any time. With approximately 70 million companion dogs in the EU and USA, this indicates approximately 14 million dogs with this condition. Around 100,000 specimens are referred for testing each year in the USA and Europe. Many other cases are not referred but are likely to merit treatment. The situation is one of significant unmet clinical need.

Pseudomonas aeruginosa tends to dominate in late stage, chronic ear infections that are highly refractory to any existing treatment. It is these chronic infections that can provide an initial target. For such infections, antibiotics are used at very high doses and side effects (including seizures, deafness and blindness) can be significant. Costs for even the simplest treatments typically exceed $100 per dog, although this may be far higher and is supplemented by veterinary costs associated with repeated visits and, eventually, surgery which destroys the hearing. Eventual costs for resolving the infection may be several thousand dollars or even more for an individual dog.

In humans

In humans, infection of the outer ear (otitis externa or “swimmer’s ear”) is common. Pseudomonas aeruginosa is a major cause of these infections. While these are usually caused by many types of bacteria in the early stages, the late stages are again dominated by Pseudomonas aeruginosa. The resultant infections can severely damage the ear, spreading into the middle ear (otitis media) or beyond. Such infections can be extremely distressing and are highly refractory to antibiotic treatment. As a result, they often become chronic and may persist for decades.

Burns and wound infections

Where the skin barrier is damaged by wounds or burns, colonisation with Pseudomonas aeruginosa is frequent. Infection can cause severe effects from graft destruction to death despite the use of high-dose antibiotics. The role of Pseudomonas aeruginosa biofilms in keeping wounds open and producing chronic disease appears to be significant. Such infections can progress to systemic infections, with associated high levels of mortality.

Eye infections

Infections of the eye by Pseudomonas aeruginosa can be very serious, leading to corneal ulcers, keratitis, and ophthalmia. Loss of sight or even of the entire eye can result.

Lung infections

Lung infections typically occur when the lung itself is compromised in some way. One example is cystic fibrosis, where the infection is extremely difficult to clear. Todar’s Textbook of Bacteriology notes that “the futility of treating Pseudomonas infections with antibiotics is most dramatically illustrated in cystic fibrosis patients, virtually all of whom eventually become infected with a strain that is so resistant that it cannot be treated.” Pseudomonas infection of the lung is also associated with the ongoing lung damage known as bronchiectasis, and can result in severe lung impairment, leading to death.

Other infections

Other areas affected by Pseudomonas aeruginosa infections include the urinary tract, the heart, the brain, and infections of the blood (bacteremia/septicaemia) which are associated with very high levels of mortality.

Pseudomonas aeruginosa as a target for phage therapy

Pseudomonas aeruginosa is a challenging target for antibiotics. As noted above, it exhibits high levels of natural and acquired resistance, due to multiple characteristics including cell wall structure, transferable genetic factors, and growth in biofilms. This has resulted in high levels of unmet clinical need. At the same time, it has been described as a “perfect storm” for phage therapy which, due to its high specificity, is well suited to treating infections with a single bacterial cause. In part this is due to the nature of the disease, but also reflects the ready availability of suitable bacteriophages. As a result, a great deal of effort has been focussed on this infection. Though clinical work to date has produced variable results, work carried out under the direction of Evolution’s CEO includes the first successful trials in both animals and humans (see Phage Therapy).

Evolution’s approach

Evolution Biotechnologies sees Pseudomonas aeruginosa as the key initial target for its phage therapy products. The high costs of progressing to human clinical trials have been a problem for companies working on phage therapeutics. Evolution has developed a unique approach, based on its extensive experience in the area. The company is working to achieve validation of both regulatory and commercial viability by taking a veterinary product to market, generating revenues before moving on to human therapeutics. This stepwise approach is intended both to minimise risks and to reduce investor dilution, taking products to market in a commercially sustainable way.

Phage therapy

References

T. Bjarnsholt et al (2008). Why chronic wounds will not heal: a novel hypothesis. Wound Repair Regen. 16: 2-10.

CDC (2019). AR Threats Report. https://www.cdc.gov/drugresistance/biggest-threats.html

CDC (2019). Pseudomonas aeruginosa in Healthcare Settings. https://www.cdc.gov/hai/organisms/pseudomonas.html

D.R. Harper and M.C. Enright (2011). Bacteriophages for the treatment of Pseudomonas aeruginosa infections. Journal of Applied Microbiology 111: 1-7.

K. Todar (2012). Pseudomonas, in “Todar’s Online Textbook of Bacteriology”. http://textbookofbacteriology.net/pseudomonas.html

WHO (2019). Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. https://www.who.int/medicines/publications/WHO-PPL-Short_Summary_25Feb-ET_NM_WHO.pdf