Antibiotic resistance is a major threat to public health. This isn’t just my opinion but also that of Dame Sally Davies, the Chief Medical Officer for England, as well as the World Health Organisation and other numerous national and international groups. It is not only the treatment of infections that will become impossible but perhaps an even greater threat is that surgery will no longer be possible without an unacceptable risk that the patient will die from a postoperative infection; who would want a surgeon to operate on their bowel without the availability of antibiotics to stop bowel bacteria causing peritonitis afterwards?
So having been thinking about a case of fusarium keratitis last week I started to wonder whether the new antifungal Isavuconazole might have a role to play. I then got to thinking that it would be good to write a summary of Isavuconazole for a blog… so here it is…. :-)
I was walking down the corridor when one of the Medical Registrars walked passed looking perplexed, we said hello and passed on by, then he called after me “oh can I ask your opinion on…” A standard start to many a query for a Microbiologist! But this question was different, he was reading around the subject of endocarditis and was frustrated by the “guidelines” put out there by the expert bodies… he went on “their advice is sometimes different and even contradictory! How do you know what to follow?”
I agreed, which didn’t seem to satisfy him at all. So let me explain further in this blog, as it will take longer than a passing corridor conversation, unless you have the old Victorian corridors still, I may be able to explain it in the time it takes to walk one of those, ah the days when we all got more exercise at work.
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.
The microbiologist had gone to review a patient on the wards when they were stopped and asked for an opinion about a different patient. This patient was being treated for infective endocarditis caused by Staphylococcus aureus and had been on IV Teicoplanin for 2 weeks because they said they were allergic to penicillin. The current problem was that the patient’s renal function was deteriorating and it was thought that the Teicoplanin might be part of the problem (although the patient was also on a few other nephrotoxic drugs but these couldn’t be stopped easily).
The Microbiologist knew that the best antibiotic for the infection was a penicillin, Flucloxacillin, so decided to try and get to the bottom of the penicillin allergy story. Side effects from antibiotics are common (e.g. diarrhoea and vomiting) but do not usually represent allergy. They sat down with the patient and asked them to describe what happened when they were last given a penicillin.
On the ward round a patient reported to the doctor that she had developed diarrhoea on the antibiotics that had been given for her community acquired pneumonia (CAP). She had already had 5 days of antibiotics and other than the diarrhoea was feeling much better. The doctor noted the patient was afebrile and looked at the blood tests which showed the white blood cell count and C-reactive protein had reduced considerably. Knowing that the hospital antibiotic guidelines said the treatment for CAP was seven days the doctor decided to call the Microbiologist for advice.
The Microbiologist went through the story and the said “okay, you can stop the antibiotics”.
“But the guidelines say we should give seven days”, replied the doctor.
“Yes, but the patient is better” replied the Microbiologist.
“So why do the guidelines say seven days then” persisted the doctor.
Good point thought the Microbiologist…
So why do we have defined durations for courses of antibiotics? Why do these appear to be carved in stone so that no doctor or patient dares to deviate from the principal of “you must finish the course of antibiotics”? Surely the correct length of course is whatever makes the patient feel better?
Okay, it may not look like much but the antibiotic in the diagram above may just represent the saviour of antimicrobial therapy! Or rather, the method by which this antibiotic was created may be what really saves us! I’m very excited!!!
The picture shows a modified version of the antibiotic Vancomycin from a paper in Proceedings of the National Academy of Sciences of the United States of America (PNAS… unfortunate acronym!). The authors Okano et al have “manufactured” this new version of Vancomycin to have potent activity against normally Vancomycin-resistant bacteria.
How do you manage patients with an acute cough in primary care? It’s a common problem and one that accounts for over £15 million worth of antibiotic prescribing every year in the UK.
So are antibiotics really necessary? What happens if you don’t give antibiotics immediately or give the patient a delayed prescription with clear instructions on when to take them? How many of these patients will come back later? How many will be admitted to hospital and how many might die?!
I think I might have missed my calling in life. In the past there were explorers searching out new lands, then plant hunters looking for the next new thing to put in your garden, and now there are “antibiotic hunters”! I want to be one!! Let me explain why…
An article in one of Nature’s associated magazines called Biofilm and Microbiomes (B&M) caught my eye; “Komodo dragon-inspired synthetic peptide DRGN-1 promotes wound-healing of a mixed-biofilm infected wound”1. What a catchy title?!
The Komodo dragon (Varanus komodoensis) is a massive monitor lizard found on only five islands in Indonesia; Komodo, Rinca, Flores, Gili Motang, and Padar. They grow up to 3 metres long and weigh about 70kg. They have been around for millions of years, a bit like alligators and crocodiles, but are much more dinosaur like than these. They are also capable of short sprints up to 20mph and that’s nearly as fast as Usain Bolt. How do I know all this? I’ve been to Komodo and Rinca to see Komodo dragons and they are amazing.
So what’s special microbiologically about Komodo dragons?
Komodo dragons have about 80 different bacteria in their mouth and many are particularly good at causing sepsis. In fact this is thought to be the way Komodo dragons kill their pray. They have a small amount of venom which after they bite damages local tissue at the site allowing all of those nasty bacteria into the victim which eventually succumbs over the next few days… apparently they have a particularly unpleasant type of Pasteurella multocida a bit like cats and other carnivores.
So if Komodo dragons have such nasty bacteria in their mouths why do these bacteria not harm the dragon? It turns out that Komodo dragon saliva contains antimicrobial peptides which help to protect the dragon… it would be a pretty poor evolutionary development for an animal to die if it bit its own tongue wouldn’t it?
Enter the dragon; DRGN-1
DRGN-1 (derived from dragon) is the synthetic peptide produced by the authors of the B&M paper based upon a peptide from the saliva of the Komodo dragon, VK25 (VK from the dragon’s latin name Varanus komodoensis). I have no idea how they collected saliva from a Komodo dragon but I bet it was exciting! The modification of a couple of amino acids in VK25 enhanced the antimicrobial properties of DRGN-1 making it a better candidate for study.
How does DRGN-1 work?
DRGN-1 is a cationic antimicrobial peptide which has bactericidal activity through disruption of the bacterial cell membrane causing increased permeability and depolarisation resulting in rapid bacterial cell death. It is thought that DRGN-1 also has an activity inside the cell as well but this is yet to be properly described. So far DRGN-1 has shown activity against both Staphylococcus aureus and Pseudomonas aeruginosa in laboratory studies. It is thought that the antimicrobial activity of peptides like DRGN-1 might display antibacterial, antiviral and antifungal activity all at the same time.
It is hypothesised that it would be difficult for resistance to DRGN-1 to evolve naturally in bacteria due to the multiple mechanisms of action which would all need to be prevented at the same time for a bacterium to survive. Unfortunately it appears that there are already naturally occurring bacteria which are resistant to DRGN-1 including Francisella novicida and Burkholderia thailandensis… goodness knows where you might find these in nature but I’ve never seen them as human pathogens.
Another potential benefit to the use of DRGN-1 in the treatment of infections is its ability to prevent biofilm formation. Biofilms are essentially “slime cities” of bacteria which are relatively more resistant to antibiotics and therefore more difficult to treat. Biofilms are commonly found on infected prosthetic material and are one of the main reasons why infected prosthetics need to be removed. DRGN-1 has been shown to be able to prevent biofilm formation in the laboratory which might make it useful in treating infections where biofilm formation is a problem e.g. prosthetic joint infection, central venous catheter infection, urinary catheter infection.
DRGN-1 has also been shown to promote wound healing through a mechanism on keratinocytes (skin cells) which makes these cells migrate into wounds leading to enhanced healing. As a result DRGN-1 would be an ideal candidate for treating skin and soft tissue infections.
Does DRGN-1 make wounds heal better?
So far DRGN-1 has only been investigated in animal studies. In a mouse model of an infected wound with mixed S. aureus and P. aeruginosa, all wounds treated with DRGN-1 had healed by day 11 compared to none of the control wounds. Currently the only oral option we would have is to use PO Ciprofloxacin over the same time period. However, Ciprofloxacin is the main risk factor for Clostridium difficile, MRSA and multiple-antibiotic resistant Gram-negative bacteria.
So whilst it is still in the early stages of evaluation it is possible that DRGN-1 or something based upon it will eventually be available to treat skin and soft tissue infections. The initial results are promising but there is still a very long way to go before I might be recommending Komodo dragon spit as a treatment option, but you never know!
It has got me thinking though. What other animals might be a source of naturally occurring antibiotics. Cat saliva is said to have antimicrobial properties (and like Komodo dragons they have Pasteurella multocida in their normal mouth flora), and it’s no secret that I like cats (I have five domestic moggies at home!) so maybe I should start to study cat saliva… lions, tigers, jaguars, cheetahs, servals (but maybe not at home!)… if only I could….
1. Komodo dragon-inspired synthetic peptide DRGN-1 promotes wound-healing of a mixed-biofilm infected wound. Chung E, Dean S, Propst C et al Biofilms and Microbiomes 2017, 3:9 published online 11 April 2017
The Microbiologist had a recent call from a worried colleague who had been contacted by an even more worried patient. The patient had just found out she was pregnant but was unaware of this while she was taking Doxycycline as malaria prophylaxis whilst on holiday. She had been on the internet and read that Doxycycline should never be given in pregnancy as it can do all sorts of horrible things to babies. The patient’s doctor had double checked in the British National Formulary (BNF) and sure enough Doxycycline was contraindicated in pregnancy. The Microbiologist confirmed what the BNF said; however exactly how big was the risk? The Microbiologist realised he didn’t actually know… time to start looking at the evidence and get back to the patient’s doctor as soon as possible.
Throughout my medical career I have been told never to give any tetracyclines, including Doxycycline, to pregnant women or children under 12 years of age. The reason given for this is that tetracyclines cause congenital abnormalities and problems with teeth and bone development in children and the developing fetus, as well as liver problems in the mother during pregnancy. But is this true? What is the evidence? Are there any circumstances where using Doxycycline is justified in these patients?