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When bad enzymes do good

3/1/2018

 
Sometimes you come across an idea so brilliant and yet so simple that you think to yourself “I wish I’d thought of that!” Well that’s what happened to me at the Federation of Infection Societies annual conference at the beginning of December.
 
I guess I should start by saying I have no affiliation to, or sponsorship from, any company, pharmaceutical or otherwise. I can therefore say I am totally objective, but I was impressed!
 
So what was it I was so impressed by? Well, it’s a beta-lactamase… What, a beta-lactamase!?! But they’re bad, they breakdown antibiotics and stop them working, how can they be a good thing? Well, before we consider the beta-lactamase let’s think about why antibiotics can be bad for you.
Dysbiosis
All antibiotics are indiscriminate when it comes to which bacteria they kill. They don’t just kill the bacterium you want to target but also any other bacteria that are sensitive to that antibiotic. This can cause devastation to the patient’s normal flora which can take months to return to normal. This disruption of normal flora is called “dysbiosis”.
 
Disruption of the normal flora, especially in the gut, causes side effects and can predispose to other infections.

  • Side effects
Most people are aware that antibiotics often cause diarrhoea as a side effect, this is because the antibiotics cause gut dysbiosis. It doesn’t just happen with oral antibiotics but with intravenous antibiotics as well; many IV antibiotics are either excreted in bile into the gut or cross the bowel wall to get into the gut. Whatever the route, the antibiotic is present in the gut and starts to kill gut bacteria. The most probable reason for this diarrhoea is that the loss of bacteria that help with the digestion of food leads to more of the food molecules staying in the gut. This in turn draws water into the gut (by osmosis) which then leads to watery stool and hence diarrhoea. Often the worst offenders for this are the penicillins and cephalosporins.

  • Other infections
Another effect of disruption to the gut flora is that the removal of many bacteria leaves an ecological niche for other bacteria to exploit. The best known of these bacteria is Clostridium difficile. This bacterium gets into the gut where it produces a toxin that causes colitis, known as Clostridium difficile associated disease (CDAD). The incidence of CDAD in the UK in 2016 was 12,840 down from 55,000 in 2007. CDAD is a potentially life-threatening infection. It accounts for 15.3 deaths per million population and causes 0.8% of hospital deaths (2010-12) down from 2% in 2007-2009. CDAD still costs the NHS millions of pounds in extra care every year.
 
Antibiotic resistance
Not only do antibiotics cause dysbiosis but in addition they drive antibiotic resistance. Selective pressure from the antibiotic kills off sensitive bacteria and leaves behind resistant bacteria. These resistant bacteria then proliferate to fill the space left behind by the killed bacteria and the patient’s normal flora becomes more resistant as a result. Being a carrier (colonised but not infected) makes it more likely resistant bacteria are present in the person’s environment e.g. toilet, kitchen surfaces, towels or bedding etc. and therefore more likely to be spread to others.
 
As well as selecting out resistant bacteria selective pressure also selects out resistance mechanisms within the bacteria themselves which can then spread to other bacteria such as plasmid mediated enzymes e.g. E. coli spreading an extended spectrum beta-lactamase (ESBL) to Klebsiella pneumoniae, or transposon mediated Vancomycin resistance from Enterococcus spp. to Staphylococcus aureus.
 
So the question is, “how can antibiotics be used without them causing unwanted effects on the normal flora of the gut?” The answer may well lie in a beta-lactamase! This is the concept of a new drug in clinical trials called Ribaxamase made by a small American company called Synthetic Biologics. The drug is also known by its original trial designation SYN-004.
Picture
What is Ribaxamase?
Ribaxamase is “an oral prophylactic therapy designed to degrade IV beta-lactam antibiotics within the GI tract” (Synthetic Biologics). Ribaxamase is a beta-lactamase enzyme, formulated to be taken as a capsule by mouth which then breaks down and releases the beta-lactamase enzyme into the gut. Simple!
 
Ribaxamase is an Ambler Class A beta-lactamase with activity against penicillins and Cephalosporins, including 3rd generation (or extended spectrum) cephalosporins such as Ceftriaxone.
 
The theory is that the Ribaxamase beta-lactamase breaks down any beta-lactam antibiotic in the gut and stops it having its antimicrobial activity on gut bacteria. This should mean that there is no active beta-lactam antibiotic in the gut and therefore no resulting dysbiosis. No dysbiosis should mean no side effects, no CDAD and no selective pressure to drive antibiotic resistance. Brilliant! Just brilliantly simple. Here’s the video produced by Synthetic Biologics about Ribaxamase (SYN-004) to explain how it works.
So does Ribaxamase work?
It is still early days to say whether Ribaxamase will fulfil its promise.
 
In the early experiments looking at the gut flora of animals, Ribaxamase was shown to protect the diversity of bacteria in animals which were given antibiotics plus the enzyme compared to animals just given the antibiotic with no enzyme. The effect was striking. The animals given Ribaxamase appear to have the same gut flora as animals not given any antibiotic at all. So Ribaxamase appeared to protect gut flora, at least in animals.
 
Ribaxamase has completed Phase 1 clinical trials (safety and dosage) where it has been shown to be safe and Phase 2 clinical trials (efficacy and side effects) where it has been shown to effectively degrade Ceftriaxone in the gut of patients given intravenous Ceftriaxone.
 
Ribaxamase itself is not absorbed from the gut and therefore it has no systemic activity. This is a good thing as you wouldn’t want to take a drug that stopped your antibiotic from having its intended therapeutic effect in the rest of the body.
 
The only real drawback to Ribaxamase I can see so far is that it will not work for antibiotics given orally. Think about it. If you take a beta-lactam orally hoping it will be absorbed from the gut to treat a systemic infection and you also take a beta-lactamase that breaks down the beta-lactam in the gut, the beta-lactamase will breakdown the antibiotic before it can be absorbed to provide treatment. So Ribaxamase will only work for IV antibiotics.
 
This has a potential clinical limitation too, in that it might prevent IV to oral switching of antibiotics. Gut transition time is 24-48 hours for most people therefore it will take at least 24-48 hours for Ribaxamase to leave the gut. How long do you have to stop Ribaxamase in order to switch to an oral beta-lactam? If Ribaxamase is stopped too early the patient will lose the protection from the Ribaxamase leading to dysbiosis. If the patient continues taking Ribaxamase whilst taking an oral beta-lactam they will not be on effective treatment. Therefore Ribaxamase may inadvertently lead to an increase in the use of IV antibiotics over oral antibiotics leading to increased risks of IV device associated infections, increased length of hospital stay and higher treatment costs.
 
Another point is that this particular enzyme will only work on beta-lactam antibiotics; it will not work for all antibiotics therefore it’s mopping up effect is limited to one class of antibiotic. Other antibiotics will continue to cause disruption to the normal flora. Ribaxamase won’t work on carbapenems, macrolides, tetracyclines or quinolones, etc.
 
The next step is to see whether Ribaxamase is effective in a Phase 3 clinical trial in order to test how the drug will interact with the human body, monitor for adverse reactions and test whether the new treatment is better than existing treatments.
 
Can the Ribaxamase enzyme spread to other bacteria?
Surely if this is a beta-lactamase enzyme, produced normally by bacteria, it must be bad to give this to people? Well, actually the answer is probably not. The beta-lactamase enzyme exerts no selective pressure itself as it has no antimicrobial activity. It has no effect on the gut flora directly; it only breaks down the beta-lactam antibiotic that might have an effect or side effect.
 
Also the capsule only contains the enzyme, not the genes required to manufacture the enzyme, and therefore there is no possibility of another bacterium acquiring the ability to produce its own “Ribaxamase” and thereby become more resistant itself.
 
What other enzymes could this concept be applied to?
So what does this mean for the future of antibiotic treatment? Well it’s not just beta-lactamase enzymes that break down antibiotics. There are lots of different enzymes and they don’t just affect beta-lactams. In theory the “Ribaxamase concept” could be applied to any enzyme that breaks down an IV antibiotic when it is excreted in the gut. Examples that come to mind include:
  • Carbapenemases that breakdown all beta-lactams including Co-amoxiclav and Piptazobactam as well as carbapenems e.g. Meropenem, Ertapenem, Imipenem, Doripenem
  • Aminoglycoside modifying enzymes (AME) that break down aminoglycosides e.g. Gentamicin, Amikacin, Tobramycin
  • Acetyltransferases affecting tetracyclines and Chloramphenicol
  • Methylases affecting macrolides e.g. Erythromycin, Clarithromycin, Azithromycin and the lincosamide Clindamycin.
  • Fluoroquinolone modifying enzymes which are a rare modification of an AME which confer reduced susceptibility to fluoroquinolones e.g. Ciprofloxacin, Levofloxacin and Moxifloxacin.
 
Why not produce a capsule that delivers enzymes against the “4 Cs”? So far we have enzymes that can inhibit Co-amoxiclav, Cephalosporins and Clindamycin as well as reduce the activity of Ciprofloxacin. It’s only a matter of time before a more effective enzyme against Ciprofloxacin is developed or evolves naturally and then we are there! This could have a major impact on the incidence of CDAD.
 
It’s also not beyond the realms of possibility that other mechanisms for mopping up excess antibiotic in the gut and interfering with antibiotic activity could be manufactured for delivery to the gut to protect gut flora from antibiotics such as giving excess target for the antibiotic to bind to before it can reach its main target in the bacteria e.g. penicillin binding proteins to stop beta-lactams, synthetic ribosome targets to bind ribosomally active antibiotics such as aminoglycosides, macrolides and lincosamides.
 
So what now for Ribaxamase?
Ribaxamase is now about to enter Phase 3 clinical trials to assess its full therapeutic effect. Will it prevent gut dysbiosis, CDAD and antimicrobial resistance? Time will tell, but I for one am excited to see what this can do, and what other products it may lead to in the future…! Well done Synthetic Biologics.
Makayla
8/1/2018 05:02:52 pm

It has amazed me that antibiotics can not only kill the targeted bacteria but also bacteria that it is sensitive to the antibiotic. Im excited to see if Ribaxamase will prevent gut dysbiosis, CDAD, and antimicrobial resistance.

David
15/1/2018 02:00:08 pm

Me too Makayla, so simple yet so brilliant!
David

Alecia
9/1/2018 10:13:58 pm

I'm a microbiology student following this blog. I found this article interesting. I was just wondering if you think the Beta-lactamase will reduce the effectiveness of the antibiotic?

David
15/1/2018 02:04:54 pm

Hi Alecia
I don't think the Beta-lactamase will affect the antibiotic as it shouldn't be absorbed from the gut into the blood stream. In this way it will only affect the antibiotic after it has entered the gut. The only real effect will be if there is significant enterohepatic circulation normally in which case the enzyme will stop this from happening. In practical terms this is unlikely to be a problem for IV antibiotics as they are normally IV because they are not absorbed well enough from the gut to be therapeutic.
Hope that answers you question
David

Alecia
19/1/2018 01:25:40 am

Excellent! Sounds promising! Thank You!

shawn
11/1/2018 04:25:33 am

This could be a promising step if they can find other enzymes that may work on different antibiotics. How long did they wait between administering the antibiotic and the enzyme?

David
15/1/2018 02:07:01 pm

Hi Shawn
I'm not sure exactly of the timing of the different drugs but I suspect the Ribaxamase would have to be given either before or at the same as the antibiotic (and before would probably be better). Iguess we have to wait to see what the formal FDA application shows.
David

Liz Cabbage
12/1/2018 06:30:57 pm

Thank you for the nice discussion.

Ribaxamase has completed several phase two trials, the most recent of which prevented C. difficile infection and new colonization with vancomycin resistant enterrococii (VRE)--with a statistically significant p-value.

The FDA requires that trial endpoints relate to actual clinical diseases, and so far they don't recognize dysbiosis as a disease--hence the C. diff indication.

Also, Synthetic Biologics has a deep pipeline, including a modified Ribaxamase which works with oral antibiotics, as well as a 2nd enzyme which targets carbapenem antibiotics.

They are on it!!!

David
15/1/2018 02:08:23 pm

Hi Liz
I'm glad you like the blog. I'll look forward to seeing what else come for other enzymes. This is such a great idea that is applicable to so many different enzyme/antibiotic combinations.
David

Kellyn Hyatt
29/1/2018 08:58:23 pm

I've always found the topic of what antibiotics can do to the body as well as antibiotic resistance. Great article read and can't wait to see if this is a good step forward.


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    Blog Author:

    David Garner
    Consultant Microbiologist
    Surrey, UK

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