As some of you will be aware from reading previous New Year blogs (see Pandemic Legacy blog) I love board games and of course microbiology. This year Santa has brought me another brilliant bug board game combo… Plague Inc.
​
This is the opposite to the Pandemic games in which humans battle to eradicate bugs; here you are the bug and the aim is to infect cities of the world and kill off entire countries and continents! Now I feel this game lacks the shear panic that Pandemic Legacy gave me but it has meant I have slept over the two weeks of Christmas, which I did not when playing Pandemic Legacy (the ultimate, epic, scary and brilliant game for Microbiologists and all those interested in infection).

But back to Plague Inc, you start as a bacterium (all bacilli of various colours) with one country that you already infect and 5 Trait Cards. You gain DNA points (1 bonus point each round plus 1 for each country where your infection cubes are in control) that allow you to evolve by buying a trait from the Trait Cards you hold in your hand… At the start your bacterium has little potency (2 DNA points) so the game feels a bit slow, but it will grow on you!

Each round you select a new Country Card from 4 available (3 visible cards and 1 unknown, face down card). Then you may evolve using the Trait Cards in your hand (but only if you have enough DNA points for your new trait), like gaining the Waterborne trait (2 DNA points), “the ability to survive suspension in water” – your bacteria now has the ability to “ship” to another continent where there is a port, or gaining the Cold Resistance trait (4 DNA points) – “lowering the bacteria’s intracellular water volume and preventing it from freezing”, so your bacteria can now spread to colder climates, countries like Greenland, Russia and Norway.

Or you might evolve the Heat Resistance trait (5 DNA points) – “avoids cellular breakdown at high temperatures”, which allows your bacterium to spread to hot climate countries like Kenya, Brazil, Australia or India. Without the specific trait your bacterium cannot infect specific “trait requiring cities” e.g. a city accessible only by a port needs the bacterium to have evolved the Waterborne trait, or a hot climate city, Nairobi, needs the bacterium to have evolved the Heat Resistant trait. REMEMBER without the DNA points you cannot buy the trait!

Then you can infect cities with as many cubes as you have “Infectivity” traits, 2 at the start of the game. These can be placed on that new Country Card you have just selected or any other available city on an accessible Country Card (REMEMBER the traits). You can infect your original starting city or any other city(s) you can access, either because they are in the same country or continent, or because you have a trait that allows you to move (e.g. Waterborne or Airborne, Cold Resistant or Heat Resistant). You could also add them to your opponent’s countries as long as you have the traits to access them.

​At this initial stage you will not infect every city in a country and therefore will not be in “ultimate control” (all cities infected) of that country so the play transfers to your opponent who repeats these steps for themselves.

After a few rounds you realise your bacterium needs to be more “infectious”, so you’ll need to evolve “Infectivity” traits (2 DNA points), which allows you to take more germ cubes each turn and occupy more cities. You can even swap your evolution trait cards with a new hand as and when needed or tactically advantageous to do so, but beware this can have a DNA points cost!

This all seems fairly tame; your bugs are multiplying and evolving and your opponents bug is also multiplying and spreading contently. BUT then conflict arises! Your bacteria occupy Peru and another bug lands there by air as it has just evolved the Airborne trait (2 DNA points) and gained the ability to “survive suspended in air for a long time” (making it especially good at spreading via captive passengers on board an aircraft). Now only 3 cities in Peru remain uninfected and this new bacterium has the potential to control them, and therefore the country as a whole (NB that’s bad news for your bug’s ability to multiply and conquer the world!)

It is now a bug-fight to place infection cubes on the last 3 city spaces in Peru. If you win and have “ultimate control” of the country (have more cubes than your opponent bug) then you can roll the Death dice and try and eliminate the country and its population. Rolling the dice acts like the population fighting back against its total demise. Your bugs “Lethality” rating (something you can also develop by spending 2 DNA points and evolving) increases your chances of success.

If you win the dice roll, all infection cubes get returned so they can be spread again, DNA points go up according to numbers of infected cities, you get an “Event Card” as well as getting to keep the Country Card. Your fellow bug gets his cubes back, the equivalent points and an event card but NOT the Country Card. NB the countries you kill, and the overall number killed, may decide if you get powerful end game bonuses, so plan your strategy well.

Even though you both get an Event Card, it is still a big bonus! These add an element of “oh no!”… “oh, no, no, no!” to the game and can make your bug’s ability to spread or be eliminated more likely… or of course you can apply any elimination elements to competing bugs, not your own! If you are mean!!! (Note: my wife likes “take that” elements to games, I do not…it’s just mean).​

​By the way the 3rd edition of the book is now in the final stages of proofing and will be out for sale in bookshops as well as on Amazon in the next few weeks. It's 22% bigger with new sections and lots of updates following changes to policies and guidelines but we have managed to keep the cost the same by making it a little larger in format (4.5 inches by 7 inches) and publishing it with IngramSpark rather than CreateSpace. Hope you’ll like it!

P.S. Forgive me if I have missed a muddled up bacteria and bacterium in the book!

​The Microbiologist was sat at his desk Boxing Day morning authorising out results and waiting for some further work on the blood cultures before ringing them out when his oncall mobile phone went off.
 
“Hi, it’s the ED Registrar here; can I discuss a patient with you?”
 
“Of course, what have you got” answered the Microbiologist.
 
“We’ve got a chap who has recently been abroad and has presented with a fever and feeling unwell. The basic story is that he returned home from work in the early hours of this morning looking flushed and tired. His wife was worried about him, as his belly was rather distended, so persuaded him to come to the hospital. He insists this is how he normally feels at this time of year but his wife isn’t convinced.”

Sometimes you come across a patient who represents the perfect storm of allergies, resistance and contra-indications to antimicrobials that really make you scratch your head to come up with a way of treating them. I’m not complaining! These are the kind of clinical conundrums that stretch the brain cells and make Microbiologists earn their money

I was recently doing a ward round on the Critical Care Unit when a Doctor from overseas who was observing on the ward starting asking questions about how we give antibiotics in the UK and why we don’t use continuous infusions. This was a really good discussion, especially as we have recently been thinking about if we should be implementing this method of antibiotic administration locally.

The patient was a young man in his early 20s. He presented to the Emergency Department with pain in his neck and difficulty swallowing. He managed to tell the ED Doctor that he had had a bad toothache for over a week but had been putting off seeing a Dentist because “he had too many other things to do”.
 
On examination he was febrile and tachycardic and his respiratory rate was high. The ED Doctor could see that his neck was swollen even by looking from the end of the bed.

“I have a 3 year old patient with an infected ulcer on their leg which is proving particularly difficult to treat” was the opening statement from the Surgeon.
 
“What antibiotic are you giving?” asked the Microbiologist in a surly tone, thinking this was going to be a simple case of wrong antibiotic.
 
“I’ve been using Co-amoxiclav, but it doesn’t seem to be getting better” was the reply.
 
“Have you sent any samples to the lab?”
 
“I swabbed the wound and the result has come back showing a Coagulase-positive Staphylococcus; I wonder if this might be Staphylococcus pseudintermedius or possibly Staphylococcus aureus” said the Surgeon.
 
“Staphylococcus aureus is the most common bacterium we see in this situation” answered the Microbiologist, “why do you think it might be Staphylococcus pseudintermedius?”
 
“In our patients Staphylococcus pseudintermedius is often grown from these types of samples…oh, I forgot to mention, I’m a Veterinary Surgeon and the 3 year old patient is a Husky” was the reply…. “I should say too that the bacterium is resistant to beta-lactams… according to the report…

The phone started to vibrate at midnight and the Microbiologist groaned. Who would be ringing at the witching hour on Halloween? Then he started to worry… would it be safe to answer? Would there be some crazy person on the other end? Was it a vicious axe murderer? Then he remembered this was just the scary film he had watched before going to bed and he was actually on call for the hospital.
 
The person on the other end turned out to be the Emergency Department Registrar (certainly crazy for working Halloween in the ED…!)
 
“I’ve got a patient who has been bitten on their hand by a bat and I wondered what antibiotics we should start. We have guidelines for dog, cat and even human bites but nothing for bats.”

When I was a Registrar I was lucky enough to do an MSc in Clinical Microbiology at Queen Mary’s University of London. This involved a really early morning once a week to catch a train from Nottingham to London, a two hour journey, a day of practical work and lectures, and then a two hour journey home (it was a gruelling day, gosh I was so lucky!). I learnt a lot doing the MSc and met some great people, but it was during these long train journeys that I came up with an idea about how to pass essay and short note exams. This method became known as the Seven Pillars of Waffledom, but more on why later.
 
How do you help your examiner mark your essays and short notes?
Now this isn’t about cheating! It’s just a polite observation. During the MSc we had to write essays and short notes on various topics, it was good practice as this was also the standard format of the three hour exam papers in the “olde” FRCPath Part 1 exam; I  quickly realised I had to get better at writing essays and short notes. I spoke to my Consultant Supervisors who used to mark these exam papers and they all said the same thing, “make sure your answers are clear and easy to read”. “Is that it?” I replied grouchily. Simply put yes it is, because if you write clearly and legibly your examiner is more likely to look favourably on your essay and may give you the benefit of the doubt with some of your answers. If your answer is illegible and disorganised or if it takes too long to decipher your answer, then they will not be so kind and you won’t get the mark. How long do you think it takes to read an essay and how long extra should they allow to read a badly written one?! This may seem unfair but it is human nature… it’s also a good lesson for clinical work, good communication is really important and that includes your written communication.

​Another important lesson for me was that these essays and short notes usually involved closed marking; that is the examiner had a specific list of points they were looking for in the essay or short note. So you could wax lyrical about whatever you liked but if you didn’t put down the key points they were looking for you would get no marks.
 
So how do you write an essay or short note that hits those keys points and helps your examiner mark a question?
 
My solution was to write under headings in a report format rather than giving pages of prose. I would then use either short paragraphs or bullet points to make each individual point. In this way I was helping my examiner to see everything I knew without burying it in long paragraphs of text. I also didn’t waste time trying to work out how to beautifully structure my sentences or link my paragraphs into a long unnecessary story. It was purely factual. And if I did put down a piece of information they didn’t want to see they could go past it quickly and get to what they did want to see.
 
In order to do this I needed to know what my headings were for each essay before I wrote it; and this didn’t mean “acquiring the question” before the exam! What I needed was a clear essay plan that I could “learn” before I actually took the exam. But surely one size doesn’t fit all?! I hear you cry…

​Essay and short note plans
As you look at past exam papers you start to realise there are only a limited number of types of question you can be asked. The subject can vary but the types of essays repeat. This is a really important thing to realise as it means you only need to be able to remember a small number of “essay types” into which you slot your knowledge at the time of writing.

Let me explain with the original “seven pillars” I came up with which I could then write some knowledge or waffle about. For example, if you are asked to write an essay or short notes on a particular bacterium there are seven headings you should write under including the kind of things to write in each section:

1. Microbiology – describe the bacterium, Gram reaction, important biochemistry
2. Epidemiology – where do you find it, what infections does it cause?
3. Pathogenesis – how does it cause infection, what are its main virulence factors?
4. Laboratory Diagnosis – how is infection diagnosed, how is the bacterium identified?
5. Clinical Manifestations – how does infection with this bacterium present?
6. Treatment – how are the infections treated?
7. Prevention and Control – vaccination, prophylaxis, infection control procedures, public health

 
If you were to cover all of these aspects of a particular bacterium in an essay or short note then you would score very highly. Try it; using E. coli or Staphylococcus aureus apply what you know to this structure and see how it fits.

​Why seven headings?
​Because short lists are easier to remember than long lists and seven is often considered the optimum number of things we as humans can easily remember (although I did occasionally stretch the number to eight or nine if needed).
 
You can produce these types of plans for any infectious organism; bacteria, fungus, viruses and parasites. You can also then expand it out to antimicrobials, antimicrobial resistance and clinical scenarios.

So that’s the easy bit, what about other essay types?
I think the breakthrough for me came when I realised that what appeared to be more complicated essays were in fact all very similar, and standard essay plans could be adapted to help answer more difficult questions.
 
For example an essay might ask you to explain how you are going to investigate an outbreak of a specific infection such a Hepatitis C on a dialysis unit. Argh panic where to start!!! OK calm down… the essay plan might look like this:

1. Establish case definition
2. Confirm cases are real
3. Confirm outbreak and determine extent
4. Examine descriptive epidemiological features of the cases
5. Generate hypotheses
6. Test hypotheses
7. Collect and test environmental samples
8. Implement control measures
9. Interact with the press and write a report

A more detailed example of how this works for a specific essay on a Pseudomonas aeruginosa outbreak can be found here.
 
Now what if the essay said “you are a new consultant and the Chief Executive of your Hospital tells you the rate of Clostridium difficile is too high and he wants you to write a report saying how this should be tackled”. Argh! Don’t panic… On the face of it this might appear a different question but when you break it down your “outbreak” essay plan still applies:

1. Establish case definition – what is C. difficile and how are cases diagnosed, what constitutes a case?
2. Confirm cases are real – how will you test for C. difficile and confirm cases?
3. Confirm outbreak and determine extent – initiate a surveillance program to detect cases
4. Examine descriptive epidemiological features of the cases – look at surveillance data and undertake root cause analysis of cases to see if there are common factors
5. Generate hypotheses – based on common factors devise a plan to tackle those factors which appear to be driving C. difficile cases e.g. antimicrobial use, poor infection control practices, etc.
6. Test hypotheses – continue surveillance to look for reducing levels
7. Collect and test environmental samples – store patient samples for cross comparison if required
8. Implement control measures – factors shown to be successful should be expanded out through the hospital, and teaching and education undertaken to make this common practice
9. Interact with the press and write a report – present the findings of the new program to the Trust and ensure good practice becomes embedded in the Trust philosophy

 
So there you have my secret to writing essays and short notes. You still have to do the book work to know the facts to write down, but this method helps you make the best use of those facts. And I think it works.

​Whilst revising I read various books and papers to gain knowledge but I made sure every day that I read and learnt the essay and short note plans. I had them printed on post cards and in spare moments I would quickly read through them. The evening before and on the day of the exams when everyone was trying to cram in those last morsels of knowledge, I sat and read through my plans.
 
When I sat down with my exam papers I read all of the questions before starting and decided which questions I was going to answer. I then ordered them from easy to difficult and started with those I considered easiest to get some marks under my belt as well as give me more confidence and time to tackle the harder ones. I then picked my first “easy” question and jotted my “seven pillars” in the margin. I then started writing.
 
Here’s a big tip!
If I couldn’t think of anything to write under a heading the first time through I would just write the heading, leave at least half a page, and then come back to it at the end; I could usually by this point write something even if it was just “there is no vaccination against x, there is no role for prophylaxis and there are no specific infection control precautions”… it might be worth a mark or two?! On one occasion I was struggling to remember how we diagnose Cryptosporidium spp. infection, but I had time to come back to the blank space on the page, in my mind I went around the enteric lab “looking” at all of the equipment and “asking” why it was there. When I got to the UV microscope I remembered, Cryptosporidium spp. are acid fast and we used an auramine stain to detect it… Bingo! I filled in the space I’d left.
 
So finally why did this become known as the “Seven Pillars of Waffledom?” Well I was explaining my “original seven headings essay plan” approach to a friend on the MSc when she said, “oh like the 1922 book Seven Pillars of Wisdom by T.E. Lawrence (of Arabia)!” I said “kind of…but I think sometimes I may waffle more than provide wisdom!” She laughed “oh so you’re saying it’s the microbiological Seven Pillars of Waffledom, which will help me pass the MSc and my FRCPath exams!?” It wasn’t long before the “Seven Pillars of Wisdom” became permanently the “Seven Pillars of Waffledom” and the name stuck. (Editorial note: David can waffle on pretty much any topic, as long as he has a structured plan!)

Whatever you want to call them, here (these print to postcard size 4x6 inches) are the different types of essay and short note plans I came up with, and I hope they are as useful to you as they were to me. Incidentally, I also wrote Microbiology Nuts & Bolts in the same way using standard and consistent headings for each type of section (under editorial guidance!) so it is easier to remember the facts in the book.

1. Microorganism Essay Plans
2. Antimicrobial Essay Plans
3. Clinical Scenario Essay Plans
4. Diagnosis Essay Plans
5. Public Health Essay Plan – vaccination
6. Estates Essay Plan – department design
7. Outbreak Essay Plans

Looking down the blood cultures list whilst prioritising what needed phoning out first the Microbiologist noticed a blood culture positive on day 3 with a Gram-positive bacillus in the aerobic bottle only. Normally this wouldn’t provoke much interest as most pathogens grow within 12-24 hours and most Gram-positive bacilli are skin contaminants (Corynebacterium spp. and Cutibacterium spp.). However these were unlikely in this case: Corynebacterium spp. normally grow faster than this and would be in both bottles whereas Cutibacterium spp. although anaerobes tend to grow much slower. The clinical details just said “fever” (not overly helpful!) and considering the sample was 3 days old already, it didn’t seem that urgent, so the Microbiologist put it to the bottom of the list and got on busily calling out all of the Gram-negative bacilli and Gram-positive cocci, as these were more likely to be significant.

​Having cleared all the other positive blood cultures the Microbiologist came back to the Gram-positive bacillus. Looking up where the patient had been on this admission showed the blood culture had been taken in the Emergency Department, the patient had then briefly gone to the medical admissions unit before being discharged later the same day. Not much to go on there then. Maybe it wasn’t going to be significant after all.
 
Out of curiosity the Microbiologist then decided to check if the patient had been in before. This threw up something unexpected. The patient had had multiple attendances to the haematology ward as well as the outpatient clinic. Pulling up the clinic letters showed that the patient actually had chronic lymphoblastic leukaemia (CLL) and would therefore be immunosuppressed. This changed the situation; the blood culture could be an opportunistic pathogen and not a contaminant at all, muttering to himself, “chronic lymphoblastic anaemia is significant info for the specimen request card, when will they learn!” the Microbiologist decided to phone out the result straight away.
 
Still cursing healthcare staff who don’t fill out request forms with adequate clinical details, the Microbiologist bleeped the Haematology Registrar to find out more…
 
It turned out that the patient had presented to the Emergency Department with a fever and shortness of breath. The fever settled and the blood tests showed the patient wasn’t neutropaenic. The blood cultures had been taken before the blood test results came back. A dose of Piptazobactam had also been given in case the patient had febrile neutropaenia but this had been stopped when the neutrophil count was shown to be in the normal range. “As the patient was feeling better they were allowed to go home”, the Registrar said a little sheepishly knowing something was amiss if the Microbiologist was “showing concern”.
 
“Mmmmm…” said the Microbiologist to himself, “a blood culture positive on day 3 with a Gram-positive bacillus in the aerobic bottle only”… “Mmmmm…” he said again “this could be Nocardia”. The Microbiologist suggested getting the patient back in for a review whilst the laboratory tried to identify the microorganism. By the time the patient had been reassessed the organism had a name, Nocardia farcinica.

​What are the Nocardia spp.?
Nocardia spp. are a group of aerobic Gram-positive bacilli which do not take up Gram’s stain very well and so appear as long beaded Gram-positive bacilli. They have some mycolic acid in their cell wall, as a result they can be stained using a modified Ziehl-Neelsen (ZN) stain. The modified ZN stain uses 0.5-1% acid-alcohol as a decolouriser rather than the normal 3% used for Mycobacterium spp.  
 
Nocardia spp. live ubiquitously in soil, water and organic material within the environment. They are found worldwide.
 
On culture Nocardia spp. are slow growing, taking 2-3 days to produce typical colonies which look a bit like small fungi with hyphae. In fact early Microbiologists thought they were fungi and hence named all of the similar organisms to Nocardia spp. the Actinomycetes (a mycete is a fungus). They are bacteria though.
 
There are over 80 species within the Nocardia genus but the most common causing human disease include:

• Nocardia asteroides
• Nocardia farcinica
• Nocardia nova
• Nocardia camea
• Nocardia braziliensis
• Nocardia otitidiscaviarum
• Nocardia cyriacigeorgica
• Nocardia abscessus

 
How does infection with Nocardia spp. present?
The most common presentation of infection with Nocardia spp., known as nocardiosis, is with pneumonia, lung abscesses and lung cavitation. This is because the bacteria are most commonly acquired by inhalation. People with a normal immune system usually clear the bacteria but immunosuppression, especially defective cell mediated immunity, predisposes to this opportunistic pathogen. The most common immune problems include prolonged steroid use, haematological cancer, chemotherapy, organ transplantation and Human Immunodeficiency Virus infection.
 
Occasional infections occur in skin and soft tissue following contamination of wounds e.g. soil inoculation of a thorn injury or an animal or insect bite. In this case cellulitis or superficial abscesses are the most common presentations.
 
With pulmonary infections, infection spreads from the lungs via the blood stream to any body organ, but especially the brain where the bacteria cause abscesses; this is more common with N. farcinica than other species. Untreated pulmonary infections sometimes erode through the tissues of the thorax to discharge onto the chest wall through sinuses.

How is nocardiosis diagnosed?
Nocardiosis is diagnosed through the culture of Nocardia spp. from normally sterile sites. Identification of the bacterium used to be a bit of a nightmare and was based upon colonial appearance on agar, Gram appearance, modified ZN and unreliable biochemical methods. Nowadays MaldiTOF and PCR are excellent and reliable ways of identifying this bacterium.
 
If someone is suspected of having nocardiosis then further imaging is required, especially of the thorax. It is worth talking directly to the Radiologists to find the best modality for investigating. In my experience CT is often useful but I’m not a Radiologist. Confirmation of infection usually requires sticking a needle into the suspected site and aspirating pus for further laboratory testing; again this is often conducted by Radiologists.
 
Any immunocompromised patient with cutaneous or pulmonary infection should also have a brain scan to look for dissemination.
 
How is nocardiosis treated?
The treatment of nocardiosis can be difficult. It is important to test the individual bacteria for antimicrobial sensitivity as they are not always predictable. There is no national or international standard method for doing this but both Etests and broth dilution are suitable.
 
The species of bacterium is also important as some are more resistant than others e.g. N. farcinica is usually resistant to 3rd generation cephalosporins such as Ceftriaxone as well as Imipenem. Source control is also important, including drainage of abscesses and debridement of infected tissue wherever possible.
 
Trimethoprim-Sulfamethoxazole (Septrin) is the usual first line treatment with other agents added as required. Empirical first line treatments include:

Duration:

• Pulmonary 6-12 months
• Immunocompromised or disseminated ≥ 12 months
• For severe infection or disseminated disease IV antimicrobials should be continued for at least 6 weeks at which stage the patient can be converted to orals
• Cutaneous 3-6 months

 
Once sensitivities are known patients on three agent regimens can be converted to two agent regimens.
 
If there is no improvement within 2 weeks of starting treatment then the patient should be reviewed, further source control undertaken and consideration given to changing the antibiotics to alternative agents. Other antibiotics shown to have activity against some Nocardia spp. include: Co-amoxiclav, Ceftriaxone, Ciprofloxacin, Clarithromycin, Linezolid, Minocycline, Doxycycline and Tobramycin.
 
Monitoring
It is important to keep a close eye on these patients to look for disease progression as well as treatment toxicity. The most important toxicity is bone marrow suppression from the prolonged Trimethoprim-Sulfamethoxazole treatment. At least fortnightly full blood count, Urea and electrolytes and liver function tests should be checked. In addition further imaging is often required; some experts repeat imaging at 1, 3, 6 and 12 months of treatment and then 6 and 12 months after treatment to ensure there is no relapse.
 
With early diagnosis and targeted antimicrobial treatment the long term survival is 90%.
 
So our patient was brought back into hospital and reassessed. A CT scan of their chest showed a number of cavities however the scan of their head was normal. They were started on IV antimicrobials and by two weeks had started to improve. The patient was advised it was going to be a long course of treatment, the Microbiologist returned to the list of blood cultures to see if he could “intervene”, or more accurately “meddle”, with any other patient and their unsuspecting Registrar!

I am really fortunate to work with a great team of diagnostic cardiologists who have a keen interest in infective endocarditis. We have an endocarditis multidisciplinary team and do a ward round of all the endocarditis patients every week, regardless of where they reside in the hospital. One of the big problems for these patients is the long courses of IV antibiotics in the current treatment guidelines, be they British, American or European. As a result patients have long periods of time where they have central venous catheters (CVC) for administering the antibiotics and prolonged hospital stays; both predisposing to further infections.

​So when I saw an article in the New England Journal of Medicine from Denmark investigating whether oral antibiotics can be used in the treatment of this infection, my attention was stirred and I made the most of the present moment and ordered the paper from the library, “carpe diem”.