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Antibiotic resistance

Of the responses to our initial survey, 40 of the 86 were related to Medicine and Health. Inspired by a talk given by Professor Dame Sally Davies: “A ticking time bomb: the infectious threat of antibiotic resistance” and the public responses, antibiotic resistance stood out to us as an issue we could tackle with synthetic biology. To confirm that we were on the right track, we approached the public again with the question: To what extent do you feel that antibiotic resistance is a problem that needs addressing in society today? This graph clearly shows that, according to the general public, antibiotic resistance is an important problem that needs solving.

Urinary Tract Infections (UTIs)

It was our team member George Driscoll’s work at the Hornsey UTI clinic in London which helped us to select UTIs as a specific cause to focus on. Due to the unaesthetic nature of the infection, it often receives less attention with regard to research. Having worked in the clinic, George knew first-hand that UTIs are a problem for a significant proportion of the population, and that resistance to the antibiotics used to treat UTIs is growing. In fact the clinic’s primary treatment method is long, high-dose courses of multiple antibiotics to overcome long-lasting infections despite the clinic’s awareness that their treatment choice may lead to further resistance.

Interaction with nurses

To learn more about catheter associated UTIs (CAUTIs), we visited the Churchill Hospital in Oxford. Our first visit to the hospital was to the outpatient clinic during which we spoke with Jan Harris, one of the nurses on the ward. Jan explained to us the current treatment of UTIs. The protocol for treatment is to first take a urine sample to test for the presence of bacterial colonies. If the dip test comes back as positive, the patient is treated with a wide spectrum antibiotic, after which an antibiotic treatment specific to the type of bacteria identified may be given. Whether or not a catheter is fitted with prophylactic antibiotic treatment is the doctor’s decision.

Up to this point, we weren’t fully aware of the potential seriousness of UTIs. Jan told us about a case of a person getting septicaemia as a result of a UTI. The patient had received antibiotics for seven days and had come back for a check up. Their urine sample was clear and but, despite this, the patient rapidly went into septic shock. This life threatening infection is caused by the uropathogenic bacteria rising up the ureter to the kidney. If a patient becomes septic the catheter has to be removed or CAUTI can be fatal. This shocking example made our project feel very relevant and we took a lot from this initial conversation. We went on to investigate the pros and cons of the current methods of CAUTI treatment, and compare these to what our solution could offer. Following this meeting, the design of the catheter became an integral part of our project.

Laura Evans, from the Adams Ward (geriatric) in the John Radcliffe Hospital, also talked to us about the current treatment of UTIs, informing us that the use of antibiotics is often ineffective and therefore infections are recurrent. We asked Laura the following questions.

What happens when a catheterised patient tests positive for a UTI?

“Whether or not the catheter is removed if a patient tests positive for a UTI depends largely on the reason that the catheter has been fitted. In most cases, the catheter remains fitted and the patient is treated with a large dose of antibiotics.”

Is antibiotic resistance a problem?

“Yes, particularly on this ward. As we treat elderly patients with recurring infections, the uropathogens they succumb to are often resistant to antibiotic treatment. As a result, we have to try different combinations of antibiotics, but in many cases this does not stop recurrences of the infection.”

Conversation with academics

In collaboration with Oxford University Scientific Society, we organised a public talk “Biofilms: role in health and disease, recalcitrance and in vitro modelling” by Dr. Andrew McBain, Biofilm Research Group, Manchester Pharmacy School. This talk helped the team understand the role of biofilms in causing infection and why they are resistant to antibiotic treatment. During his talk, Dr. McBain explained the role of biofilms in infections and how they confer ABR. He talked to us about persister cells and their importance in the recalcitrance of biofilms to antibiotic treatment. Hence, in the project design, we looked at agents that specifically target these sessile, metabolically inactive persister cells and decided on Art-175 as one of our antibacterial agents.

Professor Timothy K. Lu, from the Synthetic Biology Group at MIT recommended that we use endogenous anti-biofilm agents rather than designing them bottom up. He said that our idea to use synthetic biology as a means of fighting UTIs and ABR was “interesting” but raised to us the the problem of our bacteria being subject to resistance mechanisms depending on the agents used, but that we could overcome this by exploring combinatorial therapies.

During the summer, we also gave two talks, one at the termly Corpus Christi College Biochemistry talks and another to a group of alumni from the Oxford Biochemistry department. Again, the feedback we received in terms of our project idea was positive and our idea was described as “ambitious but achievable”. Max Crispin, Oxford Glycoprotein Therapeutics Laboratory raised the issue of whether the proteins we planned on secreting would be immunogenic. We explored this, and similar issues, in a report we wrote about the urinary biome. Another question we were faced with concerned the issue of whether our solution would make fungal infections more likely. This issue is addressed in the Futher Considerations section.

Return to the public

Having investigated the feasibility of our idea, we approached the public again to seek their opinion. The idea working on paper is one thing, but having the support of the public and the patients who would be using our solution is another aspect entirely.

We asked the public, “If you had the option of using two treatments for an infection, where one was antibiotics and one was bacteria that were designed to cure the infection, which would you choose?”

The majority (70%) of the people we surveyed said that they would take the advice of their doctor on this. This reinforced to us the importance of nurses and doctors backing our project idea. However, encouragingly, of those who wouldn't take the advice of their doctor, our treatment was favourite with just under half saying they would prefer the designed bacteria (48%), compared to 40% who would prefer antibiotics.

We also asked, “If your doctor recommended a treatment for an infection, which involved the use of bacteria that had been engineered to treat the infection, would you use it?”

Our survey showed that if a doctor recommended our treatment, only 6% would not consider it. This is very encouraging data for our project, but again highlights the importance of gaining support from doctors, because without their backing, the use of engineered bacteria as therapeutic agents will not progress from primary research. See the full results to this and our other surveys here.

We had very similar feedback when we spoke to patients. During a visit to the Bedford Ward at the John Radcliffe Hospital, we spoke with one of the catheterised patients there called Mavis. She admitted to having had UTIs in the past, but said she had not contracted a UTI since having a catheter fitted. We found that patients like Mavis could end up using the same catheter for up to 10 weeks. This enforced the importance of being able to keep our bacteria alive for a sustained period of time. When we asked her about treating infection with bacteria, she said she would be happy to, if it had been recommended to her by a doctor. She said, in her view, it is not dissimilar to using antibiotics.

Return to nurses

During this visit we were able to talk to Laura Evans again, this time to ask questions specifically about our project.

Our project involves designing a catheter that prevents the formation of a biofilm on its surface. What do you think of this idea?

A catheter like that would be useful, but it depends on how long your catheter would work for. Patients can have a single catheter fitted for 3 months or longer. Catheters are also removed for other reasons, for example if they become blocked. Catheter blockage is a common issue for patients suffering from UTIs.

Both Laura’s and Mavis’ response regarding how long a catheter remains in place inspired us to research how we could keep our Solution bacteria alive, the results of which can be found in design. Jan Harris, Churchill Hospital, raised the issue that our solution does not tackle intracellular bacterial communities (IBCs) and community UTIs. Jan made the point that UTIs are not just contracted through catheterisation, and it is important for us to also consider community based UTIs. IBCs and community UTIs are complex issues to solve but we have explored the potential of commensal bacteria as a treatment approach (See Commensal Bacteria).

Feedback from doctors

Our interaction with the public highlighted the importance of gaining doctor’s support for our project. With this is mind, George went back to Hornsey UTI clinic to speak with Dr. Sheela Swamy and Professor Malone-Lee, the consultant clinician as well as the principal investigator of the laboratory associated with the clinic. The Professor’s feedback on our project was extremely positive. “Biofilms have a profound effect on antibiotic resistance and so bacteria that can penetrate through biofilms strikes me as a very sensible project direction.”

Dr. Sheela Swamy, Hornsey UTI clinic, said:

“We get through so many buckets of antibiotics here, if your product could prevent infections or reduce our reliance on those antibiotics that is hugely appealing as a practitioner.”

“It will be really great if we actually have bacteria engineered to achieve biofilm and cellular penetration and a bactericidal effect will be a total seller. That may be the answer to the Chronic UTI if we can get it to work.”

The doctors at the UTI clinic left us with a few points to bear in mind as we are currently focused on only killing Escherichia coli and Pseudomonas aeruginosa:

1. The bladder biome is complex with many culturable and nonculturable pathogens. What role each of these have and what concentration they need to be in to cause UTI symptoms is unknown.
2. Uropathogens listed in literature are not the only organisms responsible for UTI as they are also present in normal controls yet don't cause symptoms.
3. Bacteria are opportunistic and a skin commensal if in the bladder can cause symptoms, and we have had many women with pyuric UTIs even though they only grew a Staphylococcus so you may have to try develop something that works on a wide spectrum of bacteria.

Speaking with Patients

During his time meeting with Dr. Sheela Swamy and Prof. Malone-Lee, George was invited to attend a pair of clinic sessions in which chronic urinary infection patients came to see doctors and change their treatment plan or give samples for urinalysis. During these sessions George sat in on 8 consultations and interviewed 6 urinalysis patients to gain an understanding of their symptoms and the way their infection is currently managed. George was also given the chance to interview each of these patients and learn what they thought about antibiotic regimes, catheter-based delivery and our synthetic biology solution to their infections. From the 14 interviews conducted George drew these particular conclusions from his conversations with Hornsey’s patients:

• That comfort levels with catheterisation are reliant on previous experience with catheterisation.
• That antibiotic use often has side effects that significantly decrease the quality of life of patients often through nausea but also induced faecal incontinence.
• Most patients are comfortable with the idea of GM solutions to infection given the backing of the practitioners in the clinic.