The Duty Microbiologist had just got to the duty desk when the phone rang, 09:02 no time to even pour a cup of coffee… this was going to be a bad day!
 
The ward doctor from Phlegming Ward was treating an unknown illness in a patient who had just returned from a holiday from the Indian Subcontinent.
 
It sounded bad… they were septic, with low blood pressure and a very high lactate. The Critical Care Outreach Team were on their way but the team were worried the normal IV Amoxicillin, Gentamicin and Metronidazole for sepsis wasn’t working!
 
“Change to Meropenem, give a dose of Amikacin stat and isolate the patient ASAP. Also send us a blood culture, sputum and urine and we’ll see what we can grow. As there is a risk of enteric fever, make sure you write High Risk on the request form please!”
 
However, at the same time the Sister from Phlegming Ward was calling the Infection Control Nurses to say she thought they might have an outbreak as they had a number of patients that had all been in the same bay who were now all suddenly septic!
 
The Infection Control Nurses told the Sister they’d drop everything and hurry along to assess the situation; so they brought forward elevenses to a 10am cake break and then off they went… which is pretty speedy for IC! (…I am going to be in so much trouble for writing that!!!)
                                                     
When they arrived on Phlegming Ward the corridor looked dark and gloomy. The overhead strip lights flickered on and off like a broken strobe light at an 80s disco. A trail of bright pink slime oozed its way across the broken floor tiles disappearing off into the distance. Nothing moved; everything was silent. The ICNs looked through the doors to see carnage. To be fair it was often a chaotic place where no one ever washed up their coffee cups, so mould outbreaks were common. They entered the ward. This seemed different; the patients looked terrible, emaciated and sunken eyed which, although food was being cut back to make hospital savings, shouldn’t be noticeable quiet yet. There was also blood and vomit everywhere, as well as some funny looking bright pink stains no one quite knew what to make of, and the over-worked staff looked like they had finally lost the plot! 

This may seem like a strange question for a Microbiologist to ask but it’s not as straight forward as many people think. I have blogged about this kind of thing before, but recent conversations with other healthcare workers have shown me that many still do not understand the effect that antimicrobial resistance is going to have on the wider scope of medicine. Well, it’s my blog so I’m going to blog about it again… 😊
 
Most people, including healthcare workers, think that antimicrobial resistance’s biggest threat is related to our ability to treat common infections such as pneumonia, urinary tract infections or cellulitis, but I think that is incorrect. Don’t get me wrong, it’s still important, but for me it’s not the most important threat from antimicrobial resistance.
 
Before I tell you what I think the biggest threats are, let me tell why treating common infections isn’t the biggest threat…

​Sack the Microbiologists and just employ computer geeks! Whoa! Hold on!! Where did that come from I hear you say…?
 
A headline caught my eye last week… well other than the normal coronavirus shenanigans anyway; “A powerful antibiotic that kills some of the most dangerous drug-resistant bacteria in the world has been discovered using artificial intelligence”.
 
Ignoring the sensationalised headlines I dug out the research paper, published in Cell last week, and had a look at what was going on, obviously it was a quiet day on the coronavirus front!

"Why do we give broad spectrum antibiotics like Benzylpeniciilin, Gentamicin and Metronidazole to babies with necrotising enterocolitis [NEC] when their gut is sterile?" asked the Neonatal Unit [NNU] Registrar.
 
It was the middle of the NNU multidisciplinary ward round.
 
"Pardon?" said the Microbiologist, caught red-handed reaching for a second chocolate biscuit and suddenly feeling self-conscious as everyone turned to stare at him.
 
"Babies are born with a sterile gut so when they develop NEC why do they need antibiotics; surely there are no bacteria to cause a problem". The Registrar restated his question again but with more clarity.
 
The Microbiologist recognised the question was being rephrased; he obviously looked like he did not understand what was being asked! It was actually a very good observation of the Microbiologist! But it was an even better question thought the Microbiologist…so it needed a good answer…
 
Fortunately the Microbiologist was on the ball, and in fact was armed with the latest research provided by the NNU Pharmacist only a few weeks earlier.
 
Hopefully everyone knows where babies come from... but do you know where babies gut bacteria come from? Read on...

On his way to review a ward patient the Microbiologist was stopped by one of the Consultant Physicians and asked about a different patient. These “corridor consultations” are fairly frequent in medicine and often lead to significant decisions about patient care, it’s important to document them though; remember, “if it isn’t written down then you didn’t do it”.
 
“I have a patient who I have been seeing in clinic who I think might have tuberculosis, but the sputum and bronchoalveolar lavage cultures are negative. Is there anything else that can present in the same way that I might be missing?” the Physician asked.
 
“Why do you think they have TB?” asked the Microbiologist, thinking is this related to those pesky Tabby Cats!?

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.

Maggots are fly larvae. Their life cycle goes like this: flies are attracted to food and other rubbish on which they lay their eggs; later the eggs hatch into maggots, which turn into flies. You may be wondering if you have eaten that picnic sandwich which a fly had just landed on (and possibly laid its eggs), whether the eggs and maggots can survive!? Answer: larvae that might be accidentally ingested with food cannot usually survive in the gastrointestinal environment.

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

​One of the most common bacterial infections we see in the hospital setting is cellulitis; an infection of the skin and subcutaneous tissues. Most of these are caused by Gram-positive bacteria such as Staphylococcus aureus and the Beta-haemolytic streptococci. First line antibiotic treatment is usually Flucloxacillin, or Teicoplanin or Vancomycin (if the patient is allergic to beta-lactams such as Flucloxacillin). I have recently got to thinking about new antibiotics that might be useful in the treatment of cellulitis and in particular a new cephalosporin called Ceftaroline, which is supposedly active against all S. aureus including MRSA and the Beta-haemolytic streptococci.
 
So what have I found out about Ceftaroline? How does it work? Why is it active against MRSA? Read on to discover the answers to these questions and many more about this new antibiotic…

Antibiotic resistance is a major threat to public health. This isn’t just my opinion but also that of Dame Sally Davies, the Chief Medical Officer for England, as well as the World Health Organisation and other numerous national and international groups. It is not only the treatment of infections that will become impossible but perhaps an even greater threat is that surgery will no longer be possible without an unacceptable risk that the patient will die from a postoperative infection; who would want a surgeon to operate on their bowel without the availability of antibiotics to stop bowel bacteria causing peritonitis afterwards?