So basically, people check their brains at the door and just follow what is written down on a piece of paper or on a computer screen, without even thinking about whether it’s the right thing to do. I also suspect that many people think Microbiologists just pluck the names of antibiotics out of the air when giving advice… the ECIC thinks that stat Gentamicin is the answer to every question!
 
But in reality, Gentamicin is not the ONLY answer and guidelines may be the WRONG choice; this leads to mistakes being made every day in the choice of antibiotics to treat patients, and most of these are avoidable.
 
Let me give you some daily scenarios where following a local antibiotic guideline would be the wrong thing to do:

• Patient has frequent urinary tract infections with a Gentamicin resistant E. coli but is treated with Gentamicin because that’s what the antibiotic guidelines say to use for pyelonephritis (Hint, those previous urine results would also have said what the E. coli would actually be sensitive to!) The guideline is NOT applicable in this scenario
• Patient has cellulitis following a dog bite but is treated for cellulitis with Flucloxacillin using the generic cellulitis guidelines, but the prescriber should have looked at the infected bites guideline (Hint, bites often involve Gram-negative bacteria and the generic cellulitis guidelines target Gram-positives) The guideline is NOT applicable in the scenario
• Patient has Clostridium difficile and should be receiving oral Vancomycin, but because someone has decided to make them “nil by mouth” the person has prescribed IV Vancomycin instead even though this will NOT cross into the gut to treat the infection (Hint, making a patient “nil by mouth” doesn’t usually stop them receiving their oral medications)

 
So, how do you avoid making mistakes when choosing what antibiotic to use?
 
First considerations for prescribing
Before deciding whether to prescribe an antibiotic there are a number of things to consider and questions to ask:

• Make sure you know normal flora and the causes of common infections
• Know your speciality’s serious and common infections, the microorganisms that cause these, and the usual treatments for them
• Use the British National Formulary (BNF) for interactions, cautions and contraindications as well as dosing information

Where do "guidelines" come from? 
Empirical antibiotic guidelines are established by answering many of the questions below. It is essential to understand the relevance of these questions and the effect of the answers. Relying on empirical antibiotic guidelines without knowing why or how these guidelines are produced can be dangerous and is poor practice.
 
Important questions to ask when choosing an antibiotic
I have a specific process I follow when choosing what to prescribe. I have been doing this for so long now that much of this is instinctive or I am able to quickly skip the less relevant questions for a given scenario. BUT when you first start prescribing though it is important to be more careful and consider each question IN TURN, all 15 of them!

1. Does the patient have an infection?

There are many non-infectious reasons for “signs of infections”

• Fever caused by drugs, malignancy, connective tissue disorders
• Increased CRP caused by inflammation, malignancy, connective tissue disorders
• Chest crackles caused by heart failure, pulmonary embolus, fibrosis
• Pyuria (white blood cells in urine) caused by appendicitis, connective tissue disorders, malignancy

 
2. If the patient has an infection what is the likely source?

• Urine, respiratory tract, skin, bone, joint, heart, CNS etc.…

 
3. What are the likely causative microorganisms?

• Viruses, bacteria, fungi, parasites

 
4. Does the patient need an antibiotic or is the infection self-limiting?

• Viral infections are usually self-limiting
• Urethral syndrome and gastroenteritis do not usually require antibiotics

 
5. Does the patient need urgent treatment or is there time to make a diagnosis?

There is often time to make a diagnosis before starting treatment HOWEVER certain infections require immediate management without waiting for investigations as delays can lead to serious and permanent harm to the patient:

• Sepsis
• Neutropaenic sepsis
• Meningitis
• Meningococcal sepsis
• Encephalitis
• Epiglottitis
• Spinal epidural abscess
• Necrotising fasciitis
• Toxic shock syndrome

 
6. Is the antibiotic active against the microorganisms?

• See Table of Antibiotic Spectrum of Activity (content from Microbiology N&B)

 
7. Does the antibiotic get into the site of infection?

• See Table of Penetration, content in Microbiology N&B)

 
8. Does the patient need a bactericidal antibiotic or is bacteriostatic adequate?

• Immunodeficient patients require bactericidal antibiotics because they are unable to fight infections themselves

 
9. What route of administration should be used?

• DO NOT use oral antibiotics to treat systemic infections if patients are unable to absorb from the gastrointestinal tract
• Antibiotics with good oral bioavailability rarely need to be given intravenously

 
10. How much antibiotic should be prescribed?

• Patients in renal failure may need doses of antibiotics reducing
• Patients over 60-70kg may need increased doses of antibiotics as normal doses are calculated for previously normal body size (male of 65kg back in the 1950s!)

 
11. Are there any contraindications or cautions for prescribing this antibiotic?

• DO NOT use any Beta-lactam antibiotics if the patient has a history of severe penicillin allergy
• Many antibiotics interact with Methotrexate e.g. Trimethoprim, Ciprofloxacin, Doxycycline
• Many antibiotics are contraindicated in myasthenia gravis e.g. macrolides, quinolones, aminoglycosides, Colistin
• Always check the BNF for interactions, cautions and contraindications as well as dosing information

 
12. What are the side effects of this antibiotic?

• See section Antibiotics, in Microbiology N&B for individual antibiotic agents
• Always check the BNF for side effects

 
13. When should the patient be reviewed?

• Septic patients should be reviewed within 1 hour of starting treatment
• Daily review of ALL patients on antibiotics
• Don’t forget “stop and review” dates as these help prevent over-treatment and CDAD

 
14. When can I switch from IV to oral, and how long should I treat the patient for?
 
15. Do the results of the microbiology investigations identify a specific causative microorganism?

• Once the cause is known, antibiotics should be narrowed down to cover the specific microorganisms identified e.g. CAP caused by Streptococcus pneumoniae can be treated with Penicillin rather than Co-amoxiclav and Clarithromycin

 
So, there it is. When choosing an antibiotic, I run through 15 questions in this order to choose what the right treatment is. It isn’t easy when you start out with prescribing. Like everything it takes time to learn how to do it properly, but it’s worth it. Patients don’t get better on the wrong antibiotic, and prescribers get in trouble when they mess it up, so it’s in everyone’s interest to get it right first time… so give this method a try… it works for me!
 
Don’t forget to order your copy of Microbiology Nuts and Bolts; it’s the perfect size for a stocking filler! Yep that’s a desperate plug for Xmas sales to cover the cost of ECIC’s stocking fillers: a tube of orange smarties, drumstick sweets and refreshers :-)

“Quick” exclaimed the Senior ICN, “quarantine the ward. Shut everyone in… and put up that nice new shiny sign that says No Entry by order of the ICNs”.
 
“But does that include shutting us in, we’re ICNs, surely we have immunity, don’t we!?!” asked the more junior ICN in a fragile voice.
 
“Yes! It includes us” the Senior ICN said in a sober tone. This heroic act saw the loss of two ICNs but before they succumbed to whatever this was, they called back to the IC team office…
 
“This is bad, really bad, and it is spreading quickly. So quick there is no time to even set up an outbreak meeting. You need to act and act now…” …the word “now” faded into harrowing cackles and the line went dead.
 
“I’ve lost contact with the ICNs on Phlegming Ward” sobbed the Nurse Consultant ICN
“It’s probably just a normal black spot in the Trust’s mobile phone coverage”, piped up another ICN, trying to hide his fear.
 
Another phone rang making them all jump. The caller ID showed it was the Phlegming Ward Nurses Station. Tentatively one of the ICNs picked up the phone… all they could hear were screams and munching sounds. Either someone had eaten the last of the box of chocolates in front of everyone else, or Phlegming Ward had fallen to the Enemy!
 
“It’s not bad comms” quivered the Nurse Consultant ICN, “I’m afraid they’re goners, we’re going to need more than mops and clinical waste bags on Phlegming Ward!”
 
The ICN team scrambled into action, once they had each done 3 circuits of the office with hands aloft screaming in panic, they reverted to the calm unflappable professional front they put on to the rest of the hospital and called a meeting with the IC Microbiologist, the Microbiology Registrar and the Antimicrobial Pharmacist.
 
Soon they had a plan of action. They gathered as many antibiotics as they could find including Meropenem, Amikacin, Linezolid, Tigecycline, and even some left over “Cefiderocol grenades” from “that other patient from last week”, and loaded them into their newest infection prevention devices, the semi-automatic syringe-dart guns! (Note: Cefiderocol is IV only and does not come in “grenade” form, but it can be used for severe drug-resistant infections caused by Gram-negative bacteria… and sadly we don’t currently have semi-automatic syringe-dart guns).
 
“Good work, we’re going to have to split into teams. At least two people per team, each armed with as much antibiotic as they can carry. Then we will track it down and blast it with the antibiotics. We have the ‘tools’ team, so let’s get this done!” The IC Microbiologist seemingly had practised this motivational speech a bit too much! Sharing out the antibiotics the team wished each other good luck and moved off along their separate trails.
 
“We’re going to need stronger antibiotics!” shrieked the Registrar much to the annoyance of the IC Microbiologist but she refrain from starting an impromptu lecture on antibiotic strength verse appropriateness!
 
They also dispatched the Cleaning Bots to monitor and control the Phlegming Ward environment… they would have liked to have the skills of the professional cleaning staff but as they are part of the Unison industrial action over the rubbish pay offer they have been given, they are understandably “on strike” (yes an extra 72p per hour is rubbish and insulting for such an important job!!!).
 
The Thing’s trail was unmistakable. Pink slime was everywhere, moist and glistening. The Thing was not subtle, it was covering everything in its path, doors, walls, the floor, even those posters that extolled the Trust’s values, nothing was sacred.
 
“Come in boss” said the Senior ICN quietly into her comms set. “We’ve got eyes on the target, it has somehow spread to the Critical Care unit, and it is huge. It’s evolving even as we watch. It appears to be smothering an Anaesthetist but hasn’t seen us yet. We’re moving into position”.
 
The ICNs let rip with every tool they had: hand washing, appropriate PPE, universal precautions, careful antibiotic choices, numerous posters, and they even tried the “glow and tell” machine (yep, that’s what they call the UV light box that helps teach people how to wash their hands properly)!
 
“Errrrr, boss? Bad news. We gave all our standard advice, used everything we had against the Thing. Meropenem, Amikacin and even a few Cefiderocol grenades just for good measure, and nothing. It shrugged it all off like it was just a stiff breeze. This is the most damn antibiotic-resistant Thing we’ve ever seen. It’s even gone through the wall, and we’ve lost it. Sorry boss, we tried.”
 
As everyone listening into this tried to digest the devastating news, the lights went off. In a sudden moment, darkness fell. A few moments later the emergency generators kicked in and a dim light rose to bathe the frightened faces of the remaining Infection Control Team.
 
“It cut the power”, shrieked the Registrar into his handset.
 
“What do you mean IT cut the power?” said the IC Microbiologist, “the Thing is just a… bacterium! It does not have opposable thumbs?”
 
“Back to the Office,” ordered the Nurse Consultant ICN, “get back to the office. We need another plan!”
 
Trying to keep the IC team calm, the IC Microbiologist attempted to reassure them that the situation wasn’t dire, “Now here’s what we’re gonna do. This Thing CANNOT spread faster than we can track and contain it; after all, we are the Infection CONTROL team! So, hold your position and do not, I repeat, do not draw attention to this Thing!! It will all be OK, don’t worry, I’ll speak to the Duty Microbiologist, just keep an air of calm, help is on the way”, but the IC team were having none of it.
 
The IC Microbiologist went to see the Duty Microbiologist to explain the situation.
 
The Duty Microbiologist jerked awake, wrenched out of his pleasant dreams of chocolate and ice-cream, to a screeching sound. Flailing his arms around to try not to fall of his chair he sent his cold cup of coffee flooding across his desk, staining his worklist and removing all remaining legibility from his scruffy handwritten notes.
 
It took a moment to realise it wasn’t the fire alarms but something more sinister, the IC Microbiologist, who was concerned about a highly transmissible “Thing” on Phlegming Ward!
 
“Oops, this morning I asked for advice by the ward doctor of Phlegming Ward about a patient being seen by Critical Care Outreach, and I told them to send a patient’s sputum sample to the lab” said the Duty Microbiologist.
 
“No! Then it’s escaped Phlegming Ward already and that’s how it got to Critical Care... that means… it’s not contained!” cried the IC Microbiologist.
 
“Oops” said the Duty Microbiologist.
 
“Is that all you can say, this is dire!?” cried the increasingly terrified IC Microbiologist.
 
“Yes…oops… sorry?!” answered the Duty Microbiologist with a wide “Wallace and Gromit style” grin.
 
“Are you crazy? Did you not get your coffee this morning!?”
 
“Oops, no, I spilt most of it just now! You frightened me!” answered the Duty Microbiologist.
 
“Right drink the rest of that cold cup of coffee and come with me, this is getting away from us…! We need to stop this in the lab…please tell me they were going to label it hazardous and high risk so that the lab don’t process it on the open bench… Not that old chestnut again! It is becoming tedious through constant repetition” muttered the IC Microbiologist under her breath.
 
“I did ask them to mark it High Risk” the Duty Microbiologist said pathetically.
 
“Good, then let’s go” …The IC Microbiologist and the Duty Microbiologist peered through the lab’s glass door… the lab was a scene of carnage, with the shattered remains of petri dishes everywhere.
 
“Looks normal” said the Duty Microbiologist.
 
“Looks like the Kiestra machine has packed up again” said the IC Microbiologist, thinking about the last “oops episode” when the unstoppable demand from a bulging laboratory network piled up and there was no backup machines for when things “like this” went wrong.
 
Reluctant to open the door, instead they called the lab to see what was going on.
 
“MaldiTOF identify it as Psychrolutes marcidus; it sounds like a new bug. It evolved so fast. Our normal containment couldn’t hold it. Once we knew it was getting out of hand, we threw everything at it. Nothing touched it. It shrugged it all off like it wasn’t even there, and it just kept evolving. It broke through all of our barriers and attacked the staff, and then it smashed its way through the wall and escaped!” Then as an afterthought they added, “what were we meant to do?”
 
“But did you make sure the lab had taken the necessary precautions? Was it labelled as a High-Risk specimen?” asked the IC Microbiologist, rather insensitively considering they could now see the lab staff huddled to one side of the room, their normally white coats sprayed bright pink!
 
“Errrr… Yeh, we used Cat 3” said the Biomedical Scientist, “but you know those building works, and the water leaks, and then the power cuts because of the increasing costs of energy… well… it wasn’t quite Cat 3, so whatever it was, it escaped, it isn’t contained, and we’re all potentially contaminated… do you think I should I fill out an incident form?”
 
The IC Microbiologist groaned, it had gone way-passed an incident form… already word was getting out; the Thing that had escaped Phlegming Ward and the lab had been seen on Critical Care and was now rampaging through the hospital. You couldn’t hide a giant pink gelatinous blob that was busy tearing apart anything it could get its hands own. It had even taken one of the tea ladies who had made a valiant last stand firing sugar cubes with surprisingly great accuracy, but all to no avail.
 
Just then the Antibiotic Pharmacist came breathlessly into the room clutching boxes of latex gloves and masks in her arms. It was going to take much more to get this back under control. …They needed a new plan of action!
 
They started to bounce ideas around the room:

1. “Get me another one of those nice new shiny signs that says No Entry by order of the ICNs, and quarantine the lab!”

 

1. “Let’s put Fosfomycin in the hospital sprinkler system, stat”.

 

1. “Get some fancy new yellow Hazmat suits before the price goes up further with the cost-of-living crisis”.

 

1. “And order in some packets of shortbread… I need another coffee” added the less-than-helpful Duty Microbiologist

 
Whilst they were debating their expert response over coffee and shortbread in the staff tea-room, they caught sight of the TV which was on with the sound turned down. The headline text on the BBC News read, “Antibiotic resistant mutant escapes from local hospital!”
 
The two Microbiologists looked at each other.
 
“Errrr… do you think it’s too late to ask everyone to wash their hands?” asked the IC Microbiologist.
 
“Don’t ask me, I’m going home to hide under the bed” replied the Duty Microbiologist.
 
“ARGH we’re doomed, move to step 5. Burn the place down….It has gone passed its serviceable date by 10 years anyway; the hospital is a temporary building built in the 1970s”.
 
She was about to give the order to evacuate when she heard the office door behind her start to open, being pushed by bright pink slime…
 
The inevitable had happened; the post-antibiotic era had arrived… Queue dramatic music and fade to bright pink…
 
***
 
Okay, so uncontrollable bright pink slime isn’t a problem yet, but it’s getting closer! We are already seeing bacteria such as E. coli and Klebsiella pneumoniae resistant to one of our last line antibiotics, Meropenem, with countries like Greece reporting 70% resistance in blood culture isolates with these bacteria.
 
Even Colistin, which we thought would be difficult for bacteria to become resistant to, has been found to be ineffective for some bacteria; 25% of meat at the point of sale in China has been found to contain Colistin resistant bacteria due to the use of this antibiotic in animal husbandry.
 
Antibiotic resistance is already a nightmare for Microbiologists. It is one of the biggest threats to public health in the UK today and it is imperative we do everything we can to preserve what we have left, only using antibiotics when we need to, not for every cough and cold, preventing spread of bacteria through good infection control practices and basic hygiene, and supporting the NHS so it can cope with the increased winter pressures and post-Covid back log.
 
Happy Halloween… and don’t have nightmares, this story is entirely fictional and no tea ladies, patients, Nurses, Anaesthetists, BMSs, Microbiologists, Pharmacists or Infection Control Nurses were harmed in the writing of this blog… the Registrar though… 😊

Also, when I went to medical school in 1992 there was only one treatment for HIV, Azidothymidine (AZT). Over my career the treatments for HIV have increased dramatically and now there are many drugs for treating HIV infection BUT they all have one thing in common… THEY DO NOT CURE SOMEONE OF HIV.
 
Since the HIV pandemic began more than 70 million people have been infected with HIV and 35 million have died, and yet we still cannot cure anyone.
 
Why can you not cure someone of HIV?
There is a very good reason why someone cannot be cured of HIV. It has to do with the way the virus infects human cells.
 
HIV is a retrovirus. The name refers to the way that the virus enters into CD4 lymphocytes where it converts its RNA to DNA using its own enzyme called reverse transcriptase and inserts it into the cell’s DNA inside the cell’s nucleus. The DNA is then irreversibly implanted into the host cell. Every time the cell divides it carries the new DNA with it. Slowly the virus kills the cells and the CD4 count drops to almost nothing and the patient becomes at risk of opportunistic infections.
 
The drugs used to treat HIV essentially halt the infection and stop it getting worse. They can stop the virus spreading between cells and help the CD4 count recover to effective levels again. But they can’t remove the viral DNA from infected cells, and without the drugs the virus would just start spreading again. So, once you have HIV you always have HIV.
 
Well, that is until recently…
 
Can you actually cure HIV?
Now that is an excellent question. Theoretically it would be possible to cure HIV if you could remove all of the virally infected cells and replace them with uninfected cells. OK, this may sound like science fiction, but it actually isn’t.
 
We use a process for replacing white blood cells in routine medicine; it’s called a bone marrow transplant (BMT).
 
Now I say its “routine medicine” but that may be a bit of an exaggeration. We use BMTs to treat haematological cancers such as leukaemia when chemotherapy hasn’t worked. The basic principle is to kill off the patient’s original cancerous bone marrow using horrendously toxic chemotherapy and then give them someone else’s normal bone marrow instead. You have to wipe out all of the original bone marrow or the two different sets of white blood cells will start to attack each other, and the patient may well die. Also, there is the chance that the new bone marrow may not engraft, and the patient will be left with no immune system at all, and then they’ll die from that instead. So BMT is a bit of a risky procedure, and only undertaken when there is no better choice. It’s not that routine!
 
But you can see how this might treat HIV. The CD4 lymphocytes infected with HIV would be killed off by the chemotherapy and then uninfected cells could be put into the patient instead. However, the problem would be that there would still be some virus around outside of the cells and this will just infect the new CD4 cells, and the disease will reoccur… damn, and it was looking so good there for a moment…!
 
Hold on! What if you could find bone marrow resistant to HIV? Could you then donate bone marrow, and the new bone marrow wouldn’t get infected and the person would be cured of HIV? That sounds even more fantastical!
 
Well, it turns out you can…!
 
The “City of Hope” patient
A 66-year-old man from California, known as the “City of Hope” patient after the place where he was treated, has been cured of HIV.
 
This patient acquired his HIV in 1988 and has been living with the infection for many years, taking medication every day to keep it in check. When he was 63 years old he developed leukaemia for which it was eventually decided he needed a bone marrow transplant. A donor was found and by coincidence the donor is immune to HIV!
 
Yep, some people are immune to HIV. HIV enters lymphocytes through a protein called CCR5 (C-C chemokine receptor 5) on the cell wall. Some people have a mutation in the gene encoding CCR5 which makes the receptor resistant to HIV1 (you can still get HIV2 infection though!) added to this you have to have 2 copies of the resistant gene to have the resistance to infection. It is estimated that about 1% of European Caucasians have two mutated genes conferring resistance to HIV1. It is very rare!
 
So, in the case of the City of Hope patient, he was “coincidently matched” to a bone marrow donor who had two mutations in the CCR5 gene and was essentially given a bone marrow transplant resistant to infection with his HIV. His infected cells were killed, and he was given new ones that couldn’t get infected.
 
And it worked! Nearly a year and half later, not taking any HIV drugs, the “City of Hope” patient has no detectable HIV virus. He has been cured. He no longer has HIV.
 
And it turns out he isn’t the only person where this has happened.
 
Over the years 3 other people have been cured of HIV in this way. The first person is known as “The Berlin Patient” after where he was treated in 1998, but after him came an American called Timothy Ray Brown in 2008 and then a person in Britain called Adam Castillejo. Both of the later patients eventually waived their anonymity and hence why we know their names and their remarkable stories.
 
BUT before everyone starts to think this is this answer to HIV infection, just remember that bone marrow transplant is a risky procedure with significant risks to health and safety. And we have very good drugs now for controlling HIV such that if someone is diagnosed with HIV today, they will die from something else like old age. HIV is not the death sentence it appeared to be back in the 1980s when I was growing up.
 
It’s a great story though, and an amazing outcome for the “City of Hope” patient. It may also pave the way for future treatments of this virus.
 
In the meantime, if you are looking for a film to watch then I heartily recommend Philadelphia. It is not easy watching, you will need a box of tissues, but if you want to know what some of the public attitude to HIV was like when it was first discovered then this film will show you… and Tom Hanks won his first Oscar in 1993 for his role in this film… although he admits if the film was made today, it wouldn't be a straight white guy playing the role... True! it shows how influential this film was at changing societies perceptions. I think it should be a “must watch” for every healthcare professional.

​Well, maybe it helps to be a little bit old-fashioned and remember what life was like before all of this IT came along… nowadays it’s called contingency planning, back in the day it was normal practice….
 
The problems with modern day pathology
Okay, I could go on and on about this, but I’ll try and stay on topic 😊
 
Pathology laboratories are just TOO BIG! There has been a trend since the mid-1990s, following the Carter Report, to merge pathology laboratories to make use of economies of scale. The idea of Lord Carter was to make tests cheaper by having them done in large batches at big centres so as to bring the cost/test down. This then would save money that could be invested back into the pathology services. Lord Carter was very clear; this was about investing in pathology… However the problem was that everyone else heard “save money, blah, blah, blah”. Services were merged and the investment didn’t come, then they were merged again and again and yep, you guessed it, investment was never a priority. The result is we now have a few massive laboratories that have workloads so big that if they have a problem the workload is too much for anyone else to take on and no “neighbour” exists to help out, so the service fails. BOOM!!
 
I believe there is an over-reliance on technology. Everything in the modern healthcare service runs on computers, even old-fashioned paper patient notes are becoming a thing of the past. And this is good in some ways; has anyone else dropped 3 volumes of paper notes all over the floor and then had to try and get them back in chronological order using those odd plastic paper fastener-thingies? No, only me then?! Hey, those things have a name “Jalema paper fastener”…who knew? and they still sell them!! So what happens when the power goes off, or the computer breaks, or the various different pieces of software stop talking to each other for some reason. What happens if a virus gets into the system (no, not SARS CoV2, a computer virus!)? When IT systems fail, they can bring down the whole system.

​Added to this we have less staff to deal with the workload. A consequence of both of the above is that people have been replaced with machines and merged. I understand that some labs have problems recruiting due to the local costs of living etc., and that machines can run 24/7, but people matter. Trained lab staff really matter! The lab staff I have worked with over the years are amazing. They are highly skilled, highly qualified and highly conscientious. And like one of my old mentors in Nottingham once said in a laboratory talk “give me a person over a machine any day of the week”… see Bob, I was listening!
 
So, what do you do when the stool sample hits the rotary ventilation device? You go back in time…
 
Back to the future
When I started in microbiology 21 years ago pretty much everything was done with pens and paper. Okay, we used agar, and sugar tests, and Gram stain, but you’re missing the point…
 
Requests forms for specimens sent to the lab had hand-written numbers marked on the front of the form, and then the same number was hand-written on all the agar plates and other tests for that specific sample. This was time consuming and prone to possible error if the wrong number was written down, but surprisingly this very rarely happened.
 
Once specimens had been set up on agar, or any other tests, the plates were stacked in specimen number in metal holders and loaded into large incubators. If there was a problem with an incubator, then there were plenty of others to use, there was capacity. The biggest problem would occur if you dropped a stack of plates, (I wasn’t allowed into the lab too frequently for obvious reasons) but it didn’t take long to pick them up and sort them again. The main issue way back then was the time it took to stack, load and unload the incubators, or find the specific plates you were looking for. That could take ages!
 
When the lab staff were working on a sample, they documented any results on the back of the request form sent down to the lab with that sample. They often used lab shorthand such as STAA for Staphylococcus aureus, GAS for Group A beta-haemolytic streptococcus, or my favourite Nottingham-ism Pyo for Pseudomonas spp. (from the chemicals pyocyanin, pyoverdin, pyorubin, etc that the bacterium produces). Very Olde fashioned Microbiologists like me still use the term “back of form” to refer to the results of tests done and the work in the lab on specimens that aren’t going to be reported out to the user. Admittedly, most modern lab staff look at me oddly without a clue what I’m wittering on about…
 
The lab also printed daily work lists using a dot-matrix printer (remember those?) and A3 concertina paper. This kept the results in numerical order and provided a single reference for what was going to be reported on the result later. Again, much of this was in lab shorthand. The worksheets were kept chronologically in a plastic A3 ring binder until all of the samples on that sheet were finished then it was filed away. These lists were essential though, and if the computers or printers failed it wasn’t a big deal, we still had the back of form.
 
When the specimen had been processed the lab staff and the Microbiologists sat down together on the “bench round” and decided how best to report the result. I love bench rounds, they are such fun. This is when we did the BBC Radio 2’s daily pop master quiz together too. Okay, so we did then use computers as the results were then uploaded to a computer to be sent back to the user, but any urgent results were telephoned to the user if they had put their contact details on the form, or the ward if not… so we did have computers…an “old BBC computer with a tape drive” or something modern like Windows95 J.
 
So, what does a contingency service look like?
Well, funnily enough, a contingency service in Microbiology looks just like an old-fashioned laboratory, but without the pop quiz!
 
All specimens and agar plates are hand labelled. Tests are loaded manually into incubators. Results are written down on paper using pens or pencils. Urgent samples and tests are prioritised (usually sterile fluids and CSF as well as blood cultures). Important results are telephoned to the clinical teams or wards where the patients are located.
 
Easy! So, what is the problem?
 
Okay, the actual handling of the tests isn’t too bad. One problem now, which we never faced before, is that the lab is often handling the workload of multiple hospitals and GPs, This now all comes in “continuously” as we have added capacity of hours and automation even though there is in fact A PROBLEM! Then factor in that the workforce has been significantly reduced to fund these fancy pieces of IT that now aren’t working!!!
 
In reality, “A PROBLEM” means not everything can be done and so contingency often involves choosing what not to process. Added to the shrinking hours of the 48 hour weekend-from-hell shift is the fact that “those significant” results need telephoning out to different hospitals, which means negotiating hospital switchboards which are always extremely busy, and this is very time consuming. And finally, when the IT starts working again (Monday morning!!), all of those paper results need manually entering into the IT systems and this takes a massive amount of time, is prone to transcription errors, and has to be done whilst all of the new days work has just arrived from all of the hospitals and GPs covered by the laboratory.
 
So, merging labs with a reliance on IT might be good when everything is working, but when the IT stops working it is the lab staff who have to manage the situation, and it always amazes me how well they do. I was even e-mailed to say the lab had sent me chocolates… then I was reminded this was the results of the chocolate agar plates (lab staff can occasionally disappoint me too!)
 
So yep, I’m with Bob, give me people over machines every day of the week… and if all else fails try some “percussive maintenance” and hit the machine with a bigger hammer! It may not work, but it might make you feel better!

Sources of S. aureus bacteraemia
In my experience the most common causes of S. aureus bacteraemia fall into 4 categories… it is almost a mantra to me… skin and soft tissue, bone and joint, heart and finally intravascular devices.

• Skin and soft tissue – the most common infections caused by S. aureus are cellulitis and abscesses. Cellulitis is a bit of an odd one as not many people with cellulitis are bacteraemic, but cellulitis is so common that even though not many of these patients have positive blood cultures they still make up a big chunk of all S. aureus bacteraemias. Deep abscesses are a common cause of bacteraemia, especially abscesses in muscles e.g. psoas, known as pyomyositis.
• Bone and joint – septic arthritis, of both native and prosthetic joints, and osteomyelitis, are common causes of S. aureus bacteraemia and this can include “less obvious” bones and joints such as in the spine.
• Heart – approximately 10% of patients with S. aureus in their blood have infective endocarditis (infection of a heart valve), and this can overlap with the other categories here in that they can have both infective endocarditis and septic arthritis for example because the heart infection has led to the joint becoming infected through spread via the blood stream.
• Intravascular devices – S. aureus loves to stick to bits of plastic and other prosthetic materials. It is particularly fond of cannulas and central venous access catheters such as Hickman lines, Groshong lines and Portacaths, but any intravascular material will do.

 
In order to find the source of an infection you need to take a history from the patient, perform an examination and order some investigations. In my experience over 90% of the diagnosis is made on the history; the examination and investigations are there to prove your diagnosis and aid treatment.
 
History
This is the key skill of a doctor. Talk to the patient, let them tell you their tale, ask questions to clarify points, but let the story unfold.
 
Does the patient have any red areas on their skin, any new lumps or bumps, any painful lesions? Have they had any recent injections? Have they recently over exercised or “pulled” a muscle; pyomyositis usually occurs a few days after damaging a muscle even if that damage at first seems minor e.g. going for a long walk or straining to reach something on a high shelf. Skin and soft tissue infections like cellulitis hurt so the patient can usually pinpoint where that pain is coming from.
 
Can the patient move all of their joints? Have they had any operations to replace joints? Have they had any medicines injected into joints recently like steroids? Have they got back pain, has it recently got worse? Have they got any swollen joints? Again, infections of bones and joints are painful, and patients will be able to tell you this.
 
Does the patient already have a problem with their heart? Do they know they have abnormal heart valves that might allow bacteria to stick to them e.g. congenital valve abnormalities? Have they been getting increasingly short of breath when walking? Do they get short of breath lying down or wake at night short of breath? These might be symptoms of a heart valve that is being damaged by infection.
 
Does the patient have ANY prosthetic material in their body? You won’t believe the amount of times I’m told no prosthetic material only to pull up an x-ray and see a blindingly white “medically inserted foreign body”. Do they have cannulas or IV catheters? Do they have grafts in blood vessels? If they have cannulas and catheters do these hurt, is there any redness around the insertion site, is there any pus coming out of or around the device? Again, these types of infections are usually painful.
 
So, taking a history involves seeing the patient, not just reading the notes from someone else’s history taking! If there is nothing obvious from the oral history, or if the history has thrown up something that needs further investigation, we move on to examining the patient.
 
Examination
The first thing to do in the examination is confirm the history. If the patient says they have a red patch of skin, take a look at it. If they have a painful joint, look at it! If there back hurts, look at it…!! you get the point. Confirm the story and see if it is enough to make the patient unwell.
 
If the history gave you no clues, then systematically examine the patient paying particular attention to:

• Skin and soft tissue– look at ALL of the skin, even if that means having to ask the patient to remove all their clothes down to their underwear. Make sure they can flex their hips without pain to rule out a psoas muscle abscess.
• Bone and joint – test functional movement such as walking, putting on shoes or reaching behind their back, gently press on the spine to look for tenderness, look for any swelling of the joints. Be thorough.
• Heart – look for signs of heart failure such as a high jugular venous pulse in the neck, oedema of the ankles and legs, crackles in the chest. Listen to the heart for murmurs which might suggest an abnormal heart valve. Look for evidence of clots flying from the heart to other parts of the body such as splinter haemorrhages (black lines on the nails… these can be normal so stop looking at your own fingers!) and painful lumps on the hands and feet (Janeway lesions). Look for evidence of immune mediated damage to body tissues, painless lumps on the hands and feet (Osler’s nodes) and retinal haemorrhages (Roth’s spots).
• Intravascular devices – look at all IV devices that you can see; making sure they are clean, painless and not red.

 
If the source is still unclear, or if you have a strong suspicion of a focus and need to prove it, then “targeted investigations” may be required.
 
Investigations
The investigations can be split into three main groups: laboratory, cardiology, radiology.
 
Laboratory
Repeat the blood cultures at 24-48 hourly intervals to make sure the bacteraemia is being controlled. Not only is uncontrolled bacteraemia associated with much higher mortality, but ongoing bacteraemia can be a feature of infective endocarditis as the infection is in the blood stream itself and so the blood is hard to sterilise. Also do paired blood cultures from any lines plus a peripheral culture if a line is thought to be the source; if the line culture is positive >2 hours before the peripheral this proves the line is the source.
 
Get a urine sample and look for blood. This is a soft sign for renal damage due to glomerulonephritis and is a common finding in infective endocarditis.
 
Aspirate or biopsy any joints or bone that might be infected and culture the fluid to look for bacteria. Positive Gram films and cultures prove the diagnosis of septic arthritis or osteomyelitis.
 
Cardiology
Echocardiography is an ultrasound technique that looks at the structure and function of the heart. Every patient with S. aureus bacteraemia should really have an echo to rule out endocarditis, whatever the other possible focus of infection. This is because endocarditis in this group is relatively common, and without the correct treatment (prolonged antibiotics +/- surgery) it is almost always fatal; remember patients can have endocarditis in addition to their other focus of infection.
 
Radiology
If the patient has any symptoms or signs suggesting a pyomyositis, bone or joint infection then TALK to a radiologist about the best way to investigate. Radiologists are the experts in these types of investigations, and they will do the right test for your patient; DO NOT tell them what you want, ask them what is best.
 
The radiologist might suggest a CT scan, MRI scan or even a PET CT scan to look for a focus. Take their advice.
 
I’m not a Radiologist but in my experience the types of tests they might suggest are:

• CT scan – to look for evidence of emboli to the kidneys and spleen or brain in endocarditis
• MRI scan – to look for pyomyositis or bone infections including the spine
• PET CT – when all else fails and you can’t find a focus; this can be done to look at the heart as well as other parts of the body, however very few hospitals have them and the waiting times are long (we have to send our patients to another hospital and the waiting list is usually about 2 weeks!)

 
If at the end of all of this, you still haven’t found the source then you will have to treat “blind” with AT LEAST 2 weeks of antibiotics. Two weeks is the MINIMUM course, anything less is associated with high relapse rates and higher mortality. And after treatment make sure the patient knows to come back if they feel unwell again… if they do then repeat the above, hopefully something will be found second time around….
 
Now although I seemed to have discovered my “focus” again…I probably still need to book an eye test, I can’t keep looking under my glasses to read patient notes! What was that Editor Chief in Charge, “am I just getting old – presbyopia, you say!”…well… you are closer to 50 than me…!!!!

​Common infections
Common infections are common. Okay, that’s obvious, but look at it another way. Common infections are SO COMMON that if they had a tendency to kill people then the human race would have died out years ago! There are 15,000x more bacteria on 1 person than there are people on the planet… and that doesn’t even take into account all the other microorganisms in the environment or on other animals… if you don’t like viruses, bacteria, parasites and fungi you’re living on the wrong planet….
 
We have only had antibiotics for the past 100 years of our existence and yet we have managed to survive and multiply and spread around the World for 6-7 million years before this. The pre-antibiotic era will be essentially the same as an antibiotic resistance era in terms of the treatment of common infections. Common infections have had millions of years to wipe out the human race and yet they haven’t. In fact, the tendency of most infections is to get better without any antimicrobial treatment.
 
Most of the reduction in illness and death from common infections was down to improvements in public health, not antimicrobials. A good example of this is tuberculosis. Look at the graph below showing the mortality rate from TB in the 20th Century. Mortality came crashing down (with a couple of noticeable blips during wartime) during the first half of the century, and even though Streptomycin, the first drug active against tuberculosis, was discovered by Selman Waksman in the late 1940s, it didn’t become routinely available until the 1950s. By that stage the mortality from TB had already reduced dramatically, and all of this was due to improved public health.

​Now that isn’t to say that we won’t see illness and death due to antimicrobial resistant organisms causing common infections, but rather this will not be the “biggest problem” as we will still tend to recover without any antimicrobials.
 
The No. 1 threat from antimicrobial resistance - surgery
For me the number 1 threat from antimicrobial resistance is surgery… even though the Royal College of Surgeons refused to review our book “Microbiology Nuts and Bolts” when it was first published because “it didn’t affect them”… they are simply wrong.
 
Every time a surgeon cuts into a non-sterile body site such as the gastrointestinal, urogenital or respiratory tracts, antimicrobial prophylaxis is given to prevent any serious infections from developing. If a surgeon is putting in any prosthetic material such as a prosthetic joint, heart valve or even a device like a pacemaker, antimicrobial prophylaxis is given to prevent the prosthesis getting infected. Also, there will be no operations on sites where infection might be unlikely, but the consequences would be devastating such as the brain e.g. removing benign tumours, repairing aneurysms, or putting in ventriculoperitoneal shunts.
 
If there are no antimicrobials left, then there will be no surgery on non-sterile sites. There will be no surgery to implant prosthetic material. There will be no neurosurgery.
 
Antimicrobial resistance will pretty much wipe out the surgical disciplines, leaving behind a few brave souls willing to risk everything doing painstakingly slow operations to try and prevent any risk of infection, and only when there is absolutely no alternative. Discomfort, disabilities, deformities and deaths will be common.
 
The No. 2 threat from antimicrobial resistance - cancer
I think the number 2 threat from antimicrobial resistance is cancer. There are essentially two ways to treat cancer, cut out the tumour or kill it with chemotherapy.
 
We’ve already seen that antimicrobial resistance will prevent many surgical operations to remove tumours, but it will also affect the type of chemotherapy that can be given.
 
Most chemotherapy aims to selectively kill cancer cells, but the selectivity is often only partial. Many other cells are also killed as innocent bystanders, and the rapidly dividing cells, such as those that make up the immune system, are particularly prone to being affected by chemotherapy.
 
Once the immune system has been “knocked down” the patient is at risk of infection, both with common virulent microorganisms and also less virulent opportunistic microorganisms. In this situation antimicrobials are key because the patients’ own immune system is not able to fight the infection. In these cases even common infections that don’t normally cause deaths can be lethal.
 
If we don’t have any effective antimicrobials due to resistance, then we won’t be able to operate to remove cancers and we won’t be able to give chemotherapy because the subsequent infections will kill the patient.
 
We also give antimicrobial prophylaxis to patients being treated for cancer to try and prevent infections occurring but, you’ve guessed it, these won’t be able to be given as they will not be effective; antimicrobial prophylaxis just won’t work.
 
The net result of this will be that people will die from currently treatable cancers and the mortality from cancer will shoot up. It won’t necessarily be the cancer itself causing the problem but the infections.
 
The No. 3 threat from antimicrobial resistance – empirical treatments
The number 3 threat from antimicrobial resistance is empirical treatment of infections, or rather the failure of empirical treatment of infections.
 
If a patient has an infection the doctor looking after them usually starts what is known as empirical treatment; the best “educated” guess at what should work to treat the patient with their group of similar symptoms or disease. The doctor doesn’t know the exact cause, so they look at a guideline that tells them what to start to cover the most common causes of that type of infection. In the UK these guidelines are often written by Microbiologists, and they are based on the common causes, possible adverse effects of the treatment options (such as Clostridium difficile associated disease) and the local and national antimicrobial resistance rates (it might surprise you that we don’t just “make them up”!). If there is a lot of resistance to antimicrobials, then the empirical treatment needs to change.
 
As antimicrobial resistance increases, the available pool of antimicrobials reduce… currently the pool is getting shallower as drug companies are no longer making new antimicrobials. Eventually the pool will be empty and there will be no empirical antimicrobial options left.

Now if someone comes into hospital with septic shock the mortality increases by 6% for every hour they are not on an effective antimicrobial. We talk about the “golden hour” which is the first hour of the patients care when “effective” antimicrobials must be given to try and save the patient’s life. The initial choice of antimicrobial is empirical. Now if antimicrobial resistance means the initial antimicrobial isn’t effective against the cause of the patient’s septic shock, then the risk of that patient dying will increase dramatically (to over 40%) before the doctors are even aware that the empirical treatment isn’t going to work… it takes over 24 hours for the first Microbiology samples to grow bacteria and by then it will be too late.
 
So, the patient may have an otherwise treatable cause of their septic shock, such as a urinary tract infection or cholangitis, yet they will die because there were no effective antimicrobials available because of resistance.
 
So, there you have it. The Nuts & Bolts doom and gloom guide to the end of the antibiotic era… cheerful huh?! Well, looking on the bright side… if there are no antimicrobials left there will probably be no real need for Microbiologists and I can retire… just a thought… 😊
 
PS This retirement plan has not been approved by my financial advisor!

So, let’s look at this from a theoretical scenario.

​The patient
A patient is seen in a hectic Emergency Department with cough and shortness of breath on lying down and waking in the night short of breath. They have a chest X ray which is interpreted as showing bilateral pneumonia. They are given a course of Amoxicillin and sent home and told that they are going to feel unwell for quite a few weeks and not to be too concerned about this.
 
After a brief period of feeling a bit better the patient starts to feel worse again. They go to their family doctor who looks at the hospital summary and thinks that maybe they didn’t have a long enough course of the antibiotics and so prescribes a further week of Amoxicillin.
 
Again, the patient feels a bit better for a while, and then one morning they feel awful. Their partner notices that they are having trouble getting out of bed. They are slurring their speech and part of the face is drooping. The partner immediately realises that the patient is having a stroke and calls an ambulance.
 
In the hospital the patient is diagnosed with an embolic stroke and has a scan of their heart that shows a large clot on their aortic valve which has a big hole in it allowing blood to flow backwards into their lungs. As the patient has a low-grade fever a blood culture was done, and it grows an Enterococcus faecalis.
 
Now, you may look at this story and see an unfortunate series of infections in the patient, but I don’t, but then I’m suspicious like this. I see a number of missed opportunities to make an early diagnosis of infective endocarditis and prevent the stroke!
 
The story
The key to almost any diagnosis is the story. In this patient’s case there are alarm bells that there was more to his story than just pneumonia. If I was to be involved in an investigation into his care these are the basic points I would pick out to explore further:

• Shortness of breath on lying down or waking short of breath – these are called orthopnoea and paroxysmal nocturnal dyspnoea respectively. Basically, they tell you that when you take away orthostatic pressure from gravity keeping the lungs empty of oedema, they fill up with fluid and the patient can’t breathe. Yikes…They are a sign of severe heart failure not pneumonia!
• Bilateral consolidation – bilateral pneumonia is uncommon, and having chest x-ray changes in both lungs is more in keeping with heart failure than pneumonia
• Clinical signs suggesting heart failure responding to antibiotics – if the patients’ symptoms were only due to heart failure the antibiotics shouldn’t make a difference. The fact that they do means an infection is making the heart failure worse… the question then would be, what or where is the infection?
• Why are two courses of antibiotics not enough to cure the patient – most cases of pneumonia will respond to a week of antibiotics (Amoxicillin), and yet this patient relapsed twice. This should raise an eyebrow or trigger inquisitiveness, if not an alarm “we’ve got something wrong here!” It implies it is not pneumonia but a much deeper source of infection.

 
When you combine the severe heart failure, bilateral chest X-ray changes, temporary response to Amoxicillin and the bacteria that would respond to this antibiotic it becomes likely that the patient actually has infective endocarditis causing heart valve destruction and pushing them into heart failure. The 3 most common bacterial causes of infective endocarditis are Viridans streptococci, Staphylococcus aureus and Enterococcus faecalis. Of these the Viridans streptococci and E. faecalis are sensitive to Amoxicillin.
 
So, even without the patient having a stroke and then positive blood cultures and a scan that shows a vegetation we can tell from the story what is going on, and even have a pretty good idea what the causative bacteria might be.
 
However, because we have failed to interpret the signs correctly the patient has gone on to have a stroke; a serious and life changing complication of the infection. And so, the question is “if we had intervened earlier and treated properly could we have prevented the stroke from happening?”
 
The investigation
Trust’s have something called incident reporting, where anyone within the organisation can report a situation where they believe something has gone wrong and that either it has “nearly” caused harm (known as a near miss) or has “actually” caused harm. It is imperative that everyone feels safe when incident reporting and that raising concerns will not result in the Trust taking any action against them. (This was also something that came out of the Francis Report where staff were targeted for reporting concerns).
 
If we were to do a Root Cause Analysis (RCA) on this incident and look to where things went wrong, we would identify a number of failure points:

• Incorrect interpretation of the symptoms
• Incorrect interpretation of the chest X-ray
• Wrong diagnosis
• Failure to recognise why the patient relapsed after initially responding to the antibiotics

 
There might be others. Did anyone examine the patient for signs of endocarditis like splinter haemorrhages or a heart murmur, was the patient febrile when they were seen in the Emergency Department and should they therefore have had blood cultures taken earlier which would have identified the bacterium prompting earlier scans, did the patient have other signs suggesting a more chronic infection such as weight loss or night sweats? The list could be long, and each is a potential missed opportunity to make the correct diagnosis.
 
The outcome
So, what would be the outcome of this investigation?
 
Firstly, there is a legal Duty of Candour on the Trust to explain what has happened to the patient and apologise. This isn’t an admission of any wrongdoing at this stage as the investigation may not be complete. It is a recognition that something bad has happened to the patient and that the Trust is going to investigate to see whether this could have been prevented.
 
After the investigation the patient should be told of the findings and what the outcome is going to be. They should also be given information for how they might proceed to a complaint if they want to do so. They should also be told what the Trust will do to try and prevent this from happening again; this might be in the form of further training for those involved.
 
At the end of the process a report should be written, and the Trust should demonstrate how it has learnt from the process.
 
So, at the end of the process the Trust must learn and make changes. If it doesn’t and the same thing keeps happening then the Trust will be held responsible for the harm it is allowing to happen. Incident reporting and investigating incidents is the process by which the healthcare service should learn and make changes to protect patient safety. It is not comfortable, it can be difficult and unpleasant to do, but it is very important, and a key part of healthcare.
 
The key question for us as healthcare professionals is how do you “see” incident reporting, how do you “feel” about investigating incidents and how can we all “foster” more openness, transparency and candour when patient safety concerns are raised. Are we all doing enough to create that “inquisitive atmosphere” so often needed to stop an incident occurring?

The two polio vaccines were developed in 1955 and 1960 in the USA by Jonas Salk and Albert Sabin in what was known as the “March of Dimes” where funds were raised by selling lapel pins for 10 cents each in 1938 in order to develop preventions or treatments for serious public health problems like polio. In that year 2,680,000 dimes or $268,000 were raised. This money was used to fund the development of the vaccines against polio. Polio vaccine is given to children in the UK as part of the primary course of immunisation. Since the vaccines were produced it is estimated they have prevented over 20 million cases of paralysis as a result of polio.
 
Polio can be a horrible infection causing paralysis of respiratory muscles and long-term neurological damage. Many people are familiar with pictures of the “iron lung” ventilators from the past used to try and keep children with polio alive.
 
So, the eradication of polio was the aim, and with a few bumps along the way the WHO did appear to be getting somewhere (even if not within the time frame they originally set). The last case of natural polio in the UK was in 1984. In 2019 polio was thought to have been eradicated from everywhere in the World except Pakistan and Afghanistan, from where only 175 cases were reported. We are a long way past the goal of the year 2000, and the new goal is 2026….
 
But then we had a global pandemic, and Russia’s war on Ukraine, and an energy crisis, and vaccines were no longer able to be moved around the World, and therefore the polio eradication program started to stall….
 
Heck, then there was even a report on the BBC news this week that 1 million children in London are going to be given booster doses of injectable (non-live) polio vaccine.
 
Back in May this year the Health Security Agency (HSA) sent an alert to healthcare professionals telling us that there was a possible risk of polio in the UK. This was based on the detection of genetically related Polio Virus isolates in three sewage samples collected from the London Beckton Sewage Treatment Works on the 8th February, 12th April and 26th April 2022. This sewage treatment plant covers a large catchment area across North and East London and a population of about 4 million. Since the beginning of the year the virus has been detected 116 times!
 
WHAT? IS POLIO BACK?
 
Before I answer that we need to discuss a little bit about vaccination against polio.
 
Polio vaccination in the UK
Now if you go back in time, it was very common to detect Polio Virus in sewerage in the UK. This was because we used the oral polio vaccine, known as the Sabin vaccine, a live attenuated virus vaccine which could replicate in the vaccinated person, normally without causing polio, and which then would be excreted in stool for a few weeks. I say normally not causing polio because the attenuated virus can occasionally recombine with other enteroviruses and become capable of causing polio; the incidence of polio after oral vaccination is about 1 in 2 million… much less than the risk of natural polio without any vaccines which causes paralysis in 1 in 100 to 1 in 1,000 unvaccinated people with infection.
 
The benefits of the oral polio vaccine are it is easy to use, no injections, it is easy to transport and manufacture, it is cheap, and it probably has less requirements to maintain a cold chain in order to vaccinate in remote places AND it came with a sugar lump to eat!!!!
 
Now eventually polio (and the sugar lump) disappeared from the UK and the risk of polio from the oral vaccine started to outweigh the risk of natural polio. The UK health service therefore decided it was time to move to the safer but more expensive Salk injectable vaccine as this is not a live attenuated vaccine and therefore doesn’t carry the risk of causing polio.
 
So why is polio back?
Firstly, is the Polio Virus in the sewerage samples from London, wild-type or oral vaccine polio?
 
Well, the three isolates from this year are all oral vaccine related Polio Virus. The genetic sequencing shows that the isolates are ORAL VACCINE STRAINS that have recombined with another enterovirus AND ALL THREE ISOLATES ARE THE SAME, so they have the same source as in an outbreak. This means there was someone who arrived in London who was excreting live polio virus (having had a recent oral vaccine). As the samples have been collected over a period of time, with the same isolate, there will have been transmission to others in the community in order to allow ongoing excretion into the sewerage system. It is very unlikely that a single person is responsible for all of the isolates over this period of time as the virus in this individual should have been cleared within a few weeks.
 
So, we have evidence from the stool samples of person-to-person transmission of an oral vaccine related strain of Polio Virus.
 
What else do we know about this situation?
Because this is an oral polio vaccine strain of virus, we know this is not someone vaccinated in the UK. Note: The UK stopped using oral polio vaccine in 2004 and the oral vaccine related virus is normally only detectable in stool for a few weeks after vaccination. So, as we haven’t used the vaccine for 18 years AND the vaccine virus is only detectable for a few weeks after vaccination the virus has to have come from someone who has recently entered the UK from overseas.
 
Now trying to find who the person excreting live virus is, is like looking for a needle in a haystack, and ultimately it would be futile. The people affected are going to be asymptomatic (remember vaccine related disease is incredibly rare) and so finding them to offer support and advice is pointless. Not only this but there has been huge amounts of political turmoil over recent years, and we have many refugees in the UK (legal and illegal) who are naturally going to be suspicious of authorities. It is critical that this isn’t seen as a punitive investigation to try and find “a culprit” but seen as a public health investigation to try and make sure we don’t see a re-emergence of polio cases.

Have there been any cases of polio?
So far in the UK there have not been any cases of polio associated with the current situation… and HSA want to keep it that way! However, in the USA there have been cases of polio and one unvaccinated person has been paralysed by the infection.
 
What is being done?
So, the HSA are going to try and vaccinate 1 million children in London against polio. This may seem like an overreaction given that all children in the UK should already have had their polio immunisation, but the reality is that the vaccine coverage rates aren’t great, on average 15% of children in London haven’t had all of their polio vaccines, and in some areas the rate is as high as 40%. This means there are large numbers of children unprotected against polio and all the other diseases primary vaccination covers. Primary childhood vaccination (injectable vaccine containing non-live Polio Virus) would prevent person-to-person transmission happening as the virus would be eradicated by the body’s immune system before it replicates or causes disease; it cannot be excreted as it is “zapped” before that stage! However with such low rates of vaccine uptake a lot of people are not immune to polio, and hence we have a problem.
 
So, the plan is to vaccinate all unvaccinated children between 1 and 9 years old in the Greater London area to try and interrupt the spread of the oral vaccine-related polio strain and prevent a possible outbreak of the infection.
 
Wow! This is a massive undertaking but it is not an overreaction, and I wish them good luck. I for one do not want to see a case of polio, I haven’t seen one yet and I’d really quite like to keep it that way!

Haemophilia is a genetic disease where the person affected is unable to produce certain blood clotting factors which results in them being at risk of spontaneous bleeding and life-threatening haemorrhages. It is estimated that about 1 in 10,000 people are affected and the majority are male as the genetic defect is within the clotting factor gene located on the X chromosome. Most cases occur when the abnormal gene is inherited however about a third of cases actually occur in utero due to new mutations in the X chromosome and are not inherited at all… so you don’t need a family history of haemophilia to be born with haemophilia!
 
Remember back to your GCSE or O-level biology days when you learnt that humans have pairs of chromosomes and the X and Y chromosomes determine if you are male or female; XX female, XY male. Now if you have a dodgy X chromosome and you are female, your other X chromosome usually takes over and you are fine. However, if you are male, you don’t have another X chromosome you have a Y and so you are affected. In the case of haemophilia, the gene for clotting factor production is on the X chromosome and so a female haemophiliac would have to have a fault on BOTH X chromosomes to be affected, and this is very rare.
 
There are two main types of haemophilia, A and B. Haemophilia A occurs when the clotting factor affected is Factor VIII, haemophilia B occurs with Factor IX. The normal treatment for both conditions is three times a week infusions of the missing clotting factor; about 130-150 infusions per year… every year… for the rest of your life…!
 
HOLD ON! This is a microbiology blog, not a haematology blog, what is going on?!
 
Okay, stay with me, this is where the microbiology comes in…
 
Roctavian, is a new treatment for haemophilia
Roctavian, or valoctocogene roxaparvovec (what a mouthful!), isn’t a Eurovision entry but a new treatment for haemophilia based upon microbiology related gene therapy.
 
Roctavian is a form of gene therapy that delivers a new gene for the production of the missing clotting factor directly into the patient’s cells which then produce the missing clotting factor stopping the patient being at risk of bleeding. Simple?!
 
Well, it’s not that simple really…
 
The original trial name of Roctavian was AAV5-hFVIII-SQ… I don’t know what the SQ stands for but the AAV5 stands for Adeno Associated Virus serotype 5 and the hFVIII stands for human Factor VIII. The AAV is the clever, and microbiology, bit.
 
AAV technology uses a genetically modified virus-like particle to carry a new piece of genetic material to a target cell. The AAV then enters the cell and releases the new genetic material into the cell’s nucleus. The new genetic material forms an episome, a separate piece of genetic material to the chromosome, which can then be used to produce new proteins. In the case of Roctavian, the new protein is Factor VIII.
 
There is an animated video showing how this technology works on the website of one of the companies who produce the vectored virus here.
 
Does Roctavian work?
Well, it appears that Roctavian works very well. From the Phase 2 and 3 studies reported so far (called GENEr8-1… “Generate”-1?), following a SINGLE infusion of Roctavian, spontaneous bleeding was prevented in 85-90% of 134 patients with severe haemophilia A for over 2 years (this is how long the study has been running). A continuation of the earlier and smaller phase 2 study has shown efficacy continuing for 6 years in 13 of 15 patients. For each of these individuals, 1 infusion of Roctavian has replaced >800 infusions of Factor VIII and allowed them to live a normal life… that is amazing!
 
But what about haemophilia B? Well, a more recent study of a varied formulation of the AAV technology where the gene replaced is that for producing Factor IX has shown similar results with 70% of patients being bleed free after infusion.
 
It can’t be all wonderful, what are the drawbacks?
Okay, let’s get the elephant in the room out into the open… Roctavian is expensive! And I mean REALLY EXPENSIVE!!!! I saw figures that suggest that a single treatment with Roctavian will cost $3million MORE than the current Factor VIII treatment. This is the cost the company BioMarin will charge in order to just breakeven from development in 5-8 years. BUT if you have haemophilia, you’d think this was worth every cent… and I would agree 100%!
 
Another potential problem is that a person might already have antibodies against AAV5, in which case their immune system will neutralise the treatment before it has an effect. At the moment patients are screened for these antibodies before receiving treatment. It may be that in the future, different viruses could be used to deliver the treatment to get around this as the antibodies do seem to be serotype dependent, i.e. if you have antibodies to AAV5 then maybe AAV3 would work?
 
There are some concerns about the oncogenic potential of gene therapy, but it seems the risk is pretty low with AAVs. The new genetic material isn’t incorporated into the genome of the cell, it sits outside of this, and so it is not passed on to daughter cells during cell division. As long as this remains the case, it is very unlikely that the new material could trigger a cell to become cancerous. However, because there is a concern there is a 7-year safety study that is 6 years in and hasn’t shown any problems with cancer risk or severe side effects (compare this amount of safety data to the Covid vaccines we all lined up for which only had a few months of safety data!).
 
The final issue is around duration. It is unclear how long an infusion of Roctavian will last. The manufacturers estimate a single infusion will last at least 8 years which is pretty good. It’s a shame it’s not permanent but a single infusion replacing >1000 infusions has got to be a good thing! If the patient has antibodies to AAV5 unfortunately they can’t have the treatment. Added to this, once a patient has been given the treatment it is not known if this treatment will trigger the development of antibodies thereby preventing them having further doses and they would relapse. It is also unclear how long it would take for someone to produce antibodies because of repeat Roctavian infusions, for that we’ll just have to wait and see.
 
So, what next? Well, Roctavian has just been recommended for approval by the European Medicines Agency so it may become available in the EU very soon. I suspect the UK will follow as well, especially given the public disgrace the Infected Blood Inquiry is uncovering. The US are being a little more cautious in that they are waiting until the 7-year safety study has finished, but I suspect they will move pretty fast after that as it is the first time we have had a good and safe treatment for this horrible condition.
 
And here’s some more food for thought… we’re only just starting with this technology with haemophilia… this technology could be used for ANY single gene defect where an AAV is used to insert a correct gene into a cell… research is ongoing for retinal diseases, Alpha-1-antitrypsin deficiency, muscular dystrophies, Parkinson’s disease, Batten disease, cystic fibrosis, Alzheimer’s, spinal muscular atrophy, etc, etc… just imagine the potential benefits! Isn’t microbiology great? :-)

​Unperturbed, and being used to this particular Microbiologist’s ways, the GP continued.
 
“This chap is in his 40s and I have been treating him for a skin infection, but it’s getting worse. He’s had courses of Flucloxacillin, Erythromycin and Doxycycline and nothing has made any real difference. I wonder what I should try next?”
 
The Microbiologist started to pay a bit more attention. This was a list of antibiotics usually good for treating skin infections so it sounded a bit more “interesting”… (yes ECIC, interesting!)
 
“What does it look like, this infection? Does he have cellulitis? Where on his body is it?” said the Microbiologist.
 
“It’s on his hand. It started as a slightly painful lump and then got bigger and now it looks like an infected ulcer. He also has new lumps up his arm. It looks a bit weird really,” replied the GP.
 
Hmmmmm, even more “interesting” thought the Microbiologist. This sounds like sporotrichosis, but I’ve already seen my one case in a lifetime so it can’t be that!
 
“Has there been any recent travel? What does he do for a living? Any hobbies or pastimes, pets, gardening?”
 
“Hold on, I’ll ask him” said the GP… the patient was clearly still in the room.
 
After a muffled conversation the GP came back on the line.
 
“No travel. He works in IT. No gardening and his only pets are a few fish… and before you ask…no, he hasn’t been bitten by them!” said the GP.
 
Bingo! Thought the Microbiologist… wondering if the GP really thought he thought the patient could have been bitten by a fish like Jaws. Deciding not to give the standard “detailed history is usually very relevant speech” he decided to let the GP off the hook… (pun intended!) and asked…
 
“What type of fish are they?”…and then to get his own back about the bite jibe, “and what are their names!?”
 
Another muffled conversation followed.
 
“He has a number of tropical fish tanks, but I forgot to ask their names” said the GP and then realised he’d fallen for a ruse. “You didn’t really need to know their names did you?!” he said accusingly.
 
“No” giggled the Microbiologist, “but on the bright side I think I know what’s wrong with your patient. I think he has fish tank granuloma, caused by Mycobacterium marinum. He’s going to need a biopsy and a long course of antibiotics. It might be best to let our Dermatology colleagues follow this up. To make up for the names thing I’ll have a chat with them and ask them to get him up to their clinic as soon as possible. Is that okay?”
 
Appeased that he wouldn’t have to try and get hold of the busy Dermatologists, the GP let the names joke slide… for now…
 
What is “fish tank granuloma”?
Fish tank granuloma is a skin infection caused by the bacterium Mycobacterium marinum which can be found in fresh or salt water, including the sea, swimming pools and fish tanks (any tanks… not just unclean ones!).
 
The bacterium enters the skin through punctures, abrasions and other wounds, usually occurring when someone is cleaning a tropical fish tank, where it sets up a chronic infection. Biopsy of a lesion shows granuloma formation like in tuberculosis (another mycobacterial disease); granulomas are a collection of macrophage white blood cells that occur in some types of chronic inflammation.
 
So, the name “fish tank granuloma” relates to where the bacterium is acquired from and the appearance of the lesion under the microscope… simple!
 
What does a fish tank granuloma look like?
Fish tank granulomas initially look like 0.5-1cm reddish purple lumps, usually on the hands (but if the exposure is from being in open water they can be anywhere). The incubation period is 2-3 weeks. The lesions usually enlarge before starting to collapse in the middle to form ulcers. The lesions often form scars unless treated early.
 
Occasionally the skin lesions spread along the lymphatics from the initial infection and new lumps and ulcers appear ascending up the limb. This is known as sporotrichoid spread as it is similar in appearance to the fungal infection called sporotrichosis.
 
How is it diagnosed?
The most important aspect to diagnosing fish tank granuloma is to take a full history. Other doctors regularly roll their eyes at Microbiologists who seem to want to know all sorts of obscure bits of information about patients, but in our defence, travel, occupation, animal exposure, and hobbies are often very important in determining what infections a patient might have been exposed to.
 
Once the infection is suspected the best sample to take is a biopsy both to try and grow the bacterium as well as histology to look for the granulomas.
 
Most laboratories in the UK use automated liquid TB culture incubators but these are not suitable for M. marinum as this bacterium requires a lower temperature to grow, 28-30oC rather than the 37oC body temperature of the automated incubator.
 
IF there is good clinical information on the request form such as “tropical fish tank” (yes, use that clinical info box on the form – it’s there for a reason!) the laboratory staff will put up an old-fashioned Lowenstein-Jensen media slope (often known as an LJ slope) and incubate it at 30oC for M. marinum. BUT ONLY IF THEY KNOW THE CLINICAL DETAILS!!! On Lowenstein-Jensen media the bacterium will normally grow within 7-10 days.
 
How is it treated?
There is no single recognised regimen for treating fish tank granuloma. However the bacterium is usually sensitive to Clarithromycin, Minocycline, Doxycycline and Co-trimoxazole, all of which are oral and can be used to treat the infection. If the infection is severe, especially if there is extensive sporotrichoid spread, then either Ethambutol or Rifampicin can be added.
 
I personally favour Clarithromycin as it is very familiar to doctors even if fish tank granuloma isn’t. In severe cases choosing between Ethambutol or Rifampicin would depend on whether the patient was on any other medications or had any co-morbidities that made one safer than the other.
 
Treatment should continue for 1-2 months after the lesions have resolved to prevent relapse. This usually means courses of 3-4 months.
 
It is also important to tell people who have tropical fish tanks to wear gloves when cleaning them… it’s the simplest way to avoid the infection in the first place!
 
So, for our patient he was seen the same day by the Dermatologists who took a biopsy and started the patient on PO Clarithromycin. The biopsy grew M. marinum confirming the diagnosis of fish tank granuloma, and after a few weeks the skin lesions had started to improve.
 
Oh, and if you’re wondering, the fish were called Bert, William, Tom, Doris, Mabel, Trevor… only kidding!