It was another dull and dreary afternoon giving advice when an excited Dermatologist phoned about a patient with funny skin lumps. (Microbiologists get excited about bugs, Dermatologists get excited about rashes, so lumps and bumps together… what can I say…we were very excited!!)
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Their patient was a keen gardener who had been clearing a large number of blackthorn trees (good for making sloe gin) and despite wearing thick gloves had managed to get pricked and scratched all the way up their arms. At the site of one of those puncture wounds they had developed a small red lump which had eventually turned into a small ulcer. The ulcer hadn’t got much better and over the next few weeks the patient had noticed a number of other lumps appearing up their arm and then hard swellings in their armpit.

Both the patient and their family Doctor thought they might have an aggressive skin cancer which had spread to the lymph nodes but the Dermatologist thought this might be something else.
 
“I think this might be sporotrichosis” said the Dermatologist.
 
The Microbiologist nearly fell off his chair! What a great piece of clinical acumen he thought; this could indeed be sporotrichosis.
 
“How the heck did you think of that?” the Microbiologist asked.
 
“Oh, I’ve seen it before when I worked in Brazil for a while” answered the Dermatologist. “But I can’t remember how to diagnose it or treat it…!”
 
Crikey, thought the Microbiologist, not sure I would even have thought of it…
 
So what is sporotrichosis?
Sporotrichosis is a sub-acute or chronic infection caused by the fungus Sporothrix schenkii. Laboratories tend to identify S. schenkii but in fact there are actually a group of at least six different fungi, the most common of which is S. schenkii. Others in the group include S. brasiliensis, S. globosa, S. mexicana, S luriei and S. pallida. Sporotrichosis is very rare in the UK with only 1 case report in the literature since the year 2000.
 
Where do you find S. schenkii?
Sporothrix schenkii occurs Worldwide, and is found in organic matter such as sphagnum moss, hay, soil and other vegetation. Most cases of sporotrichosis have occurred in Brazil, USA, India, Japan and Mexico. It occurs in people who have occupational exposure to these sources of fungi such as gardeners, farmers, landscapers and even Christmas tree sales people! Infection can occur when the fungal spores are inoculated through the skin or when a wound is contaminated with organic material.
 
An outbreak of 84 cases of sporotrichosis, in Wisconsin in the USA, occurred due to contaminated sphagnum moss used to pack conifer seedlings. In South Africa in the 1960s there were over 3000 cases due to exposure to splinters from contaminated timber used in gold mining.
 
In Rio de Janiero, Brazil, there is a very large on-going outbreak of sporotrichosis due to S. brasiliensis, where more than 2,000 cases have occurred since 1988 spread from infected domestic cats. The cats have had a mixture of skin and respiratory infections, which has spread to their owners mainly via facial and mucus membrane involvement (another reason not to kiss your cat!).
 
There have also been a few cases of laboratory acquired sporotrichosis described in the literature where lab workers have caught the infection from handling either cultures of the mould form or infected animals.
 
How does sporotrichosis present?
Most cases of sporotrichosis are lymphocutaenous and follow inoculation of spores into soft tissue in patients who are otherwise fit and healthy. A papule (a small lump up to 1cm in diameter) forms within days to weeks at the original point of entry and eventually ulcerates, develops surrounding redness (erythema) and discharges clear colourless and odourless fluid. Over the next few weeks further skin lesions develop along the line of lymphatic drainage in a process known as “sporotrichoid spread” with enlargement of the associated lymph nodes. Without treatment the lesions will persist indefinitely with periods of improvement followed by flare-ups; even without treatment this form of infection is not fatal.
 
Sporotrichosis can also occur as an opportunistic infection in patients with other underlying illnesses:

• Pulmonary infection can occur in patients with chronic obstructive pulmonary disease (COPD) and presents in a similar fashion to tuberculosis with fever, night sweats, weight loss, worsening shortness of breath and ultimately death if untreated.
• Bone and joint (osteoarticular) infection can occur in alcoholics as a result of haematogenous spread (although rarely it can also occur via direct inoculation); bone destruction is progressive causing substantial deformity.
• Meningitis and disseminated infection can very rarely occur in profoundly immunosuppressed patients with HIV or lymphoma.

 
How is sporotrichosis diagnosed?
A history of exposure to potentially contaminated organic material is the key to making the diagnosis along with the typical pattern of cutaneous sporotrichoid spread.
 
The gold standard way of diagnosing sporotrichosis is to grow the fungus from tissue or body fluid. Sporothrix spp. are dimorphic fungi; they have two different growth characteristics depending on the temperature at which they are growing. At environmental temperatures around 25-30oC they grow as a filamentous mould whereas at body temperature they grow as a yeast. The mould takes 1-2 weeks to become apparent and then grows to form cream coloured colonies which eventually turn grey and produce the typical fluffy mycelia of a mould. The yeast form produces colonies which are cream coloured and wrinkled. Once the organism is growing in the mould form it can be identified from the microscopic appearance of its mycelia, conidia and spores.

Yeast forms of the fungus can sometimes be seen on histopathological examination of tissue, especially if using specific fungal stains, although they are not distinctive in appearance.
 
How is sporotrichosis treated?
The treatment of sporotrichosis depends on the type of infection.

• For lymphocutaenous infection the treatment of choice is PO Itraconazole 200mg OD until 4 weeks after all of the lesions have resolved (usually 3-6 months).
• For pulmonary, osteoarticular and disseminated sporotrichosis treatment should be started with IV liposomal Amphotericin B 3-5mg/kg OD and when the patient has shown sustained improvement they can be changed to PO Itraconazole 200mg BD for 12 months.
• Meningitis is treated with 4-6 weeks of IV liposomal Amphotericin B 3-5mg/kg OD before changing to PO Itraconazole 200mg BD for 12 months.

 
IV liposomal Amphotericin B is incredibly expensive; in the UK AmBisome costs £575 per day to treat a 70kg patient (and many of our patients weigh much more than this!). Alternatively patients may be given the more toxic but cheaper Amphotericin B deoxycholate (Fungizone) at 0.7-1mg/kg costing just £3.88 per day for a 70kg patient… but it is very nephrotoxic!
 
So our patient had a biopsy taken and yeast like fungi were seen on histological examination. Two weeks later a fluffy mould was growing on culture and the laboratory was able to confirm sporotrichosis. In the meantime the patient had been empirically treated with Itraconazole and got much better; they had also decided not to do any more gardening without better protection… although a good homemade sloe gin made from the fruit of the vicious blackthorn could possibly be worth the risk!!

A tried and tested sloe gin recipe (it’s very good but please drink responsibly!!)

• 1.2Kg cleaned and frosted or pricked sloes (Blackthorn berries)
• 120g granulated sugar (more if you want it sweeter)
• 1.6L gin (cheap as you like!)

Put all into a 3L Kilner jar and shake, shake daily for 1 week then once a week for 3 months. Drain the sloes but keep the juice! Bottle (use the empty gin bottles) and leave as long as you can, minimum 3 months but the longer you leave it the better the sloe gin... try 18 months, that makes a great sloe gin.

I was recently asked about antibiotics to treat a difficult infection caused by an extremely resistant Gram-negative bacterium and so I thought it was time to go back and look at what antibiotics are being developed for these situations. One antibiotic caught my eye, Cefiderocol, and I thought I ought to read more about it and see why it might be useful in the future.
 
What is Cefiderocol?
Cefiderocol is a cephalosporin antibiotic currently in clinical trials. It is a hybrid of Ceftazidime and a siderophore side chain… but what the heck does that mean and why does this matter?
 
A siderophore, from the Greek for “iron carrier”, is a small molecule produced by bacteria to help them scavenge iron from their environment. Iron is essential for bacteria, they cannot survive without it, and so they have come up with mechanisms like siderophores to help them get as much iron as possible. Siderophores bind to iron molecules and these combined molecules are then detected and actively transported into the bacterial cell; it’s like the iron needs a ticket to get in and the siderophore is the ticket.

​By combining an antibiotic with a siderophore the bacterium can be tricked into actively taking the antibiotic into the it’s cell, a process Microbiologists have termed a “Trojan horse” strategy (remember in Greek mythology Greek warriors hid in a wooden horse that was taken into the city of Troy as a “gift” and then the Greeks snuck out at night, opened the gates and sacked the city). The siderophore is “hiding” the antibiotic allowing it to be taken into the bacterial cell where it can damage the bacterium. This clever strategy leads to much higher intracellular antibiotic concentration than would occur without the siderophore and cunningly it bypasses mechanisms of resistance that might stop the antibiotic from entering as well… very clever!
 
Laboratory studies
Cefiderocol is very active against Gram-negative bacteria such as the enterobacteriales (previously called the enterobacteriaceae) E. coli and Klebsiella spp. as well as Pseudomonas aeruginosa, Stenotrophomonas maltophilia and Acinetobacter baumannii including strains that showed resistance to the carbapenem antibiotics such as Meropenem and Imipenem.
 
It seems that the siderophore side chain also provides 10-100x more stability against breakdown by carbapenemases of Ambler classes A, B and D than for Ceftazidime without the siderophore, including those from the “big five” such as KPC, VIM, IMP, NDM and OXA. Cefiderocol is usually active (reported to be about 99%) against these bacteria but that’s not 100% and it doesn’t seem to be entirely predictable but remember no antibiotic is 100% reliable.
 
Recent studies have also shown potential for Cefiderocol in the treatment of AmpC producing Gram-negative bacteria. The siderophore seems to give a low affinity for AmpC enzymes as well as a low risk of inducing the production of AmpC in bacteria that have the ability, but do not always have the ability switched on, such as P. aeruginosa and Enterobacter cloacae. Over production of AmpC when combined with a loss of a porin (hole) in the cell membrane of Gram-negative bacteria can lead to carbapenem resistance so having less ability to induce AmpC and bypassing the porin as a way to get into the cell seems like a pretty good strategy for getting around this mechanism of carbapenem resistance as well.
 
Clinical studies
In clinical studies Cefiderocol was shown to be well tolerated at doses of 2g TDS intravenously; unfortunately there is no oral version of this antibiotic but then there is no oral version of Ceftazidime on its own either. Like other Cephalosporins it is mainly eliminated by renal excretion.
 
There is an on-going Phase 3 clinical trial using Cefiderocol openly to treat serious infections caused by carbapenem resistant Gram-negative bacteria and another randomised and blinded study comparing against Meropenem in the treatment of hospital or ventilator associated pneumonia with Gram-negative bacteria. Many of us are waiting to see how these go and hoping that Cefiderocol will “pass” these tests with shining colours!
 
Tissue penetration
Cefiderocol at 2g TDS IV has been shown to give good serum levels with a maximum concentration of 140mg/L. The serum half-life is about 2 hours.
 
Cefiderocol is 60-70% excreted unchanged via the kidneys and so has excellent levels in urine.
 
In studies looking at the ability of Cefiderocol to treat pneumonia it has been shown that bronchoalveolar fluid concentrations are about 10% of serum concentrations (maximum 14mg/L) with the same half-life.
 
Most bacterial MICs for Cefiderocol are <2mg/L so these pharmokinetic and pharmacodynamic studies show that Cefiderocol should be good at treating systemic, urinary tract and pulmonary infections.
 
Cefiderocol resistance
Cefiderocol resistance has unfortunately already been seen in laboratory studies, especially with P. aeruginosa isolates. It is not common and so far >99% of isolates are sensitive, but it is worrying none-the-less as this antibiotic hasn’t yet been used widely and resistance already occurs. The mechanism of Cefiderocol resistance isn’t completely understood but is thought to be due to mutation in the siderophore transport mechanism (no longer accepting wooden horses as gifts!) in combination with other mechanisms that traditionally give resistance to Ceftazidime when it is used in its normal form e.g. mutation of the penicillin-binding protein to which Ceftazidime normally binds.
 
Cefiderocol won’t be the only answer to all of our antibiotic problems. Resistance will develop; it’s inevitable, as bacteria evolve to overcome the next challenge for their survival. In addition, Cefiderocol is only active against Gram-negative bacteria so is no use against the Gram-positives such as Staphylococcus aureus or Enterococcus spp. and let’s not mention the increasing “popularity” of beta-lactam allergy; Cefiderocol is a beta-lactam and so if you are allergic then you won’t be able to have it anyway!
 
Having said all of that I am still excited about the possibilities of Cefiderocol, we need more anti-Gram-negative antibiotics and this one seems to have promise. Let’s see what happens in the clinical trials…
 
Another word of caution
Whilst I may want to get hysterical about the potential value of Cefiderocol it is important to note that all of the primary research into Cefiderocol so far has been done by Shionogi & Co. Ltd from Japan, who is the producer of Cefiderocol! Now this is the way it will be at first as it is their drug and they won’t want to disclose trade secrets but it does mean we’ll have to wait for further, more open and robust, clinical trials and experience of its use by those without potential conflicts of interest before we finally yell “hooray for Cefiderocol”… but fingers crossed this won’t be long.

Last weekend the Nuts & Bolts team (except cats!) went to the cinema to watch the new film about the early life of J.R.R Tolkien. I have been a fan of Tolkien since reading The Hobbit at the age of 5 years old and The Lord of the Rings when I was 6… okay this is early to read this book; I didn’t understand much of the dark bits but I was captured by the heroic story and have read it again many times since… the ECIC cannot understand this, she thinks it’s weird to read a book when you already know how it’s going to end… maybe she’s right, but that won’t stop me, where did I leave my copy, or my second copy or that third copy or…
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Surely you can’t connect Tolkien with microbiology!? Read on to find out more…

​Tolkien enlisted in the Lancashire Fusiliers and was sent to the Western Front in June 1916 to join the Somme offensive. He was assigned as a Lieutenant in the signal corps and put in charge of enlisted men; there is a great quote from him, "the most improper job of any man... is bossing other men, …not one in a million is fit for it, and least of all those who seek the opportunity”… a sentiment I share.

“We have a young child with a fever and a rash who isn’t very well and we want to test for measles” said the Junior Doctor working in Paediatrics.
 
“Have they been vaccinated?” asked the Microbiologist in reply.
 
“No, their Mum was worried about the vaccine and so they haven’t had it done” was the response.
 
“Do they have any spots in their mouth?” asked the Microbiologist.
 
“They don’t have any spots, it’s not Chicken Pox it’s more like measles…” replied the Doctor sounding confused.
 
“They’re called Koplik spots, maybe get a Consultant to have a look. Is the child isolated?”
 
“Errrmmmm…” replied the Doctor “I don’t think so…”
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​Yep, it’s coming up to that time of year. All of Microbiology is excited as there is about to be a holiday and eggs are likely to feature in a big way… no not Easter!!! Its holiday time and people will be going to exotic countries and bringing back souvenir parasites and their eggs will be involved in working out what is wrong with them. Yep us Microbiologists’ love eggs, not just the chocolate variety. I don’t know, you lot all have chocolate on the brain :-)

The patient is a young female who presented with a very high fever of 40.5oC, lethargy and not eating. The past medical history included dislocated knees due to a congenital problem requiring surgery to relocate and reconstruct the patella groove. She is not taking any regular medication, has not been in contact with anyone else who is unwell and has not travelled out of the UK.
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Essentially this is a case of pyrexia of unknown origin or PUO. What is PUO and what should you do about it?

“I think my patient has syphilis” said the GP.
 
“Why do you think that?” asked the Microbiologist.
 
“Well, they have a funny skin lump and I had read recently that syphilis can mimic any other type of infection and that it’s making a comeback and so I did the test and it’s positive!”
 
The Microbiologist groaned to himself.
 
“Let me have a look at the results as well” he said.
 
To the Microbiologists surprise the patient did have positive syphilis serology.

“Where is the patient from?” the Microbiologist asked.
 
“What do you mean? They live locally” answered the GP.
 
“I mean where were they born? Have they lived abroad?”
 
“Oh, I don’t know. Why does it matter?”
 
“Can you give them a call and find out then call me back. This could be Yaws, Pinta or Bejel” replied the Microbiologist.
 
“Sorry my what? …Your's a pint of what…and a bagel? What did you say? This line is really bad” said the GP getting increasingly confused.
 
“Find out where they have been and call me back and then I’ll explain further” answered the Microbiologist.

The Bug Blog has been on holiday; okay you know this because there have been no blogs for 4 weeks or so. Having finally finished the 3rd Edition of “Nuts & Bolts” we went on holiday to Costa Rica to see what wildlife we could see; although Costa Rica only represents 0.03% of the World’s land mass it contains 6% of its biodiversity!

​We were really lucky. We saw all sorts of creatures from coatis and kinkajous (possibly the cutest animal ever!) to red-eyed tree frogs, massive cane toads, scarlet macaws and even the resplendent quetzal.

The mother was frantic.
 
“I don’t know what happened” she cried to the Paediatrician, “he was just a bit irritable when I put him to sleep last night and had a bit of redness around his mouth, but this morning his skin is falling off!” She then dissolved into floods of tears.
 
The Paediatrician took one look at the blisters and broken skin around the baby’s umbilicus and nappy area and asked “could he have been scalded with hot water at all? He looks burnt!

“Can I discuss an unwell baby?” asked the Neonatal Registrar.
 
“Of course, what’s the story?” replied the Microbiologist.
 
“We have a baby who is just over 24 hours old. They were born at term in good condition but started to grunt and looked mottled by 4 hours. We brought them to the Neonatal Unit, did blood cultures and started IV Benzylpenicillin and Gentamicin as per guidelines but they’re not really improving. Do you think we need to change the antibiotics? Has anything grown in the blood culture?”
 
The Microbiologist chose to ignore the last question as blood cultures are incubated in an automated incubator which scans the bottles every 10 minutes. If the blood culture where positive then it would have been phoned already.
 
“Is the baby’s mother okay? Have there been any problems during the pregnancy. Was the mother fully vaccinated? Was the labour normal? Is there anything else you’ve noticed about the baby, any odd lumps, bumps or spots?” asked the Microbiologist.