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 such recent problem involved a patient with:
So let me explain why this is difficult…
The patient is bacteraemic with a significant pathogen, a Gram-negative bacillus. This cannot be ignored and treatment cannot be delayed or the patient is going to come to harm. The ward doctors hadn’t known what to start so had chosen to use Teicoplanin PLUS Metronidazole, which is great for Gram-positives and anaerobes but is no good for Gram-negative cover. This is a common mistake! The patient was thought to have a severe biliary tract infection and in a penicillin allergic patient our local first line treatment is Teicoplanin PLUS Metronidazole PLUS Gentamicin… BUT… because Gentamicin is contraindicated in myasthenia gravis they had just chosen to “leave it out” even though the patient was not on adequate treatment! You simply cannot do this, there needs to be some form of Gram-negative cover.
The previous multiple antibiotic resistant E. coli was resistant to all of the normal anti-Gram-negative antibiotics such as Amoxicillin, Co-amoxiclav, Cephalosporins, Trimethoprim, as well as Gentamicin and Ciprofloxacin (although these two cannot be used in myasthenia gravis). The only antibiotics which the resistant E. coli appeared sensitive to were Amikacin and Meropenem. As the patient had had a recent infection with this resistant bacterium it is likely that this “new” infection is also due to the same bacterium; most infections are caused by your own bacterial flora going somewhere they shouldn’t go and this E. coli is likely to be part of this patient’s normal flora.
So can we use Amikacin or Meropenem?
No, because Amikacin is an aminoglycoside like Gentamicin and so contraindicated in myasthenia gravis, and Meropenem is a beta-lactam and cannot be used in severe beta-lactam allergy.
That’s the conundrum; the patient needs urgent treatment but all of the obvious treatments are either not going to be effective due to resistance or are contraindicated because of myasthenia gravis! So what would you do?
We chose to use intravenous (IV) Fosfomycin. It’s not often I use IV Fosfomycin, it’s not normally necessary, but in this case it was a neat solution.
What is Fosfomycin?
Fosfomycin is a derivative of phosphonic acid and is the only drug in this class available in the UK. It is actively taken up by the bacterial cell before having its effects. It works by preventing formation of the bacterial cell wall by blocking peptidoglycan synthesis thereby killing the bacterium. Fosfomycin is a broad-spectrum antibiotic with activity against Gram-positive, Gram-negative and anaerobic bacteria as below:
- Gram-negative bacilli in his blood culture
- Previous infection with a multiple antibiotic resistant E. coli
- Severe beta-lactam allergy
- Myasthenia gravis
So let me explain why this is difficult…
The patient is bacteraemic with a significant pathogen, a Gram-negative bacillus. This cannot be ignored and treatment cannot be delayed or the patient is going to come to harm. The ward doctors hadn’t known what to start so had chosen to use Teicoplanin PLUS Metronidazole, which is great for Gram-positives and anaerobes but is no good for Gram-negative cover. This is a common mistake! The patient was thought to have a severe biliary tract infection and in a penicillin allergic patient our local first line treatment is Teicoplanin PLUS Metronidazole PLUS Gentamicin… BUT… because Gentamicin is contraindicated in myasthenia gravis they had just chosen to “leave it out” even though the patient was not on adequate treatment! You simply cannot do this, there needs to be some form of Gram-negative cover.
The previous multiple antibiotic resistant E. coli was resistant to all of the normal anti-Gram-negative antibiotics such as Amoxicillin, Co-amoxiclav, Cephalosporins, Trimethoprim, as well as Gentamicin and Ciprofloxacin (although these two cannot be used in myasthenia gravis). The only antibiotics which the resistant E. coli appeared sensitive to were Amikacin and Meropenem. As the patient had had a recent infection with this resistant bacterium it is likely that this “new” infection is also due to the same bacterium; most infections are caused by your own bacterial flora going somewhere they shouldn’t go and this E. coli is likely to be part of this patient’s normal flora.
So can we use Amikacin or Meropenem?
No, because Amikacin is an aminoglycoside like Gentamicin and so contraindicated in myasthenia gravis, and Meropenem is a beta-lactam and cannot be used in severe beta-lactam allergy.
That’s the conundrum; the patient needs urgent treatment but all of the obvious treatments are either not going to be effective due to resistance or are contraindicated because of myasthenia gravis! So what would you do?
We chose to use intravenous (IV) Fosfomycin. It’s not often I use IV Fosfomycin, it’s not normally necessary, but in this case it was a neat solution.
What is Fosfomycin?
Fosfomycin is a derivative of phosphonic acid and is the only drug in this class available in the UK. It is actively taken up by the bacterial cell before having its effects. It works by preventing formation of the bacterial cell wall by blocking peptidoglycan synthesis thereby killing the bacterium. Fosfomycin is a broad-spectrum antibiotic with activity against Gram-positive, Gram-negative and anaerobic bacteria as below:
Gram stain |
Microorganism |
Gram-positive |
|
Gram-negative |
|
Fosfomycin resistance in bacteria is not very common but can occur in a number of different ways. Alteration of the active transport mechanisms can lead to reduced concentration inside the bacterial cell or the bacterium can produce either an inhibitor molecule, which prevents binding to the target site, or an enzyme that breaks down Fosfomycin before it can have any effect. Fosfomycin resistance can be chromosomal, plasmid or transposon mediated.
What about the boring stuff: pharmacology and pharmacodynamics?
Fosfomycin is available as oral and intravenous preparations, with up to 40% oral bioavailability. It is renally excreted as active compound without being metabolised first which gives it good activity in urine, but also means the dose needs reducing in renal failure. It also has good penetration into bone, muscle, eyes, lungs and bile.
What stops you giving Fosfomycin: cautions and contraindications?
Allergy to Fosfomycin is uncommon but can occur and is a contraindication; it presents in the same way as other allergies with rashes, shortness of breath, neck selling or anaphylaxis. Fosfomycin also contains high amounts of sodium therefore it should be used with caution in hypernatraemia, cardiac insufficiency, hypertension, pulmonary oedema and hyperaldosteronism. There is no evidence whether Fosfomycin is safe or not in pregnancy therefore it should only be used in pregnancy if the benefits outweigh the risks. There are no common drug interactions.
What are the main side effects of Fosfomycin?
Gastrointestinal disturbance (nausea and vomiting) are quite common with Fosfomycin as they are for many drugs, occurring in about 10% of people. Dizziness occurs in about 2% and skin rashes in 1%. Less common (<1%) but more severe side effects include hypersensitivity reactions, bone marrow suppression including aplastic anaemia, hepatitis, phlebitis at site of intravenous injection and shortness of breath. Fosfomycin is rarely associated with Clostridium difficile associated disease.
Patients on long term Fosfomycin should have baseline and weekly full blood count, urea and electrolytes and liver function tests in order to spot some of the side effects and toxicity issues before they become too severe.
So was Fosfomycin a good choice for our patient?
Yes, Fosfomycin was a good choice for our patient. It is active against the common Gram-negative bacilli including the antibiotic resistant E. coli. It is bactericidal and so will help a sick patient without their own immune system having to do all of the work. It is available IV so will have rapid activity. It is not a beta-lactam and so can be given to patients with severe beta-lactam allergy and it is not contraindicated in myasthenia gravis. It gets around all of the problems that normal conventional antibiotics presented in our patient’s situation; it was perfect for the job.
So our patient got his IV Fosfomycin. His temperature rapidly settled and he started to improve. Sure enough the bacterium in the blood culture was the multiple antibiotic resistant E. coli and the urinary tract turned out to be the source. The E. coli was sensitive to the Fosfomycin as expected. The patient made a full recovery and had no problems with the Fosfomycin exacerbating his myasthenia gravis. And on a cold December day, I got to use IV Frosty-mycin (Fosfomycin)… job done. Now when’s that warmer weather coming back….brrr chilly?
What about the boring stuff: pharmacology and pharmacodynamics?
Fosfomycin is available as oral and intravenous preparations, with up to 40% oral bioavailability. It is renally excreted as active compound without being metabolised first which gives it good activity in urine, but also means the dose needs reducing in renal failure. It also has good penetration into bone, muscle, eyes, lungs and bile.
What stops you giving Fosfomycin: cautions and contraindications?
Allergy to Fosfomycin is uncommon but can occur and is a contraindication; it presents in the same way as other allergies with rashes, shortness of breath, neck selling or anaphylaxis. Fosfomycin also contains high amounts of sodium therefore it should be used with caution in hypernatraemia, cardiac insufficiency, hypertension, pulmonary oedema and hyperaldosteronism. There is no evidence whether Fosfomycin is safe or not in pregnancy therefore it should only be used in pregnancy if the benefits outweigh the risks. There are no common drug interactions.
What are the main side effects of Fosfomycin?
Gastrointestinal disturbance (nausea and vomiting) are quite common with Fosfomycin as they are for many drugs, occurring in about 10% of people. Dizziness occurs in about 2% and skin rashes in 1%. Less common (<1%) but more severe side effects include hypersensitivity reactions, bone marrow suppression including aplastic anaemia, hepatitis, phlebitis at site of intravenous injection and shortness of breath. Fosfomycin is rarely associated with Clostridium difficile associated disease.
Patients on long term Fosfomycin should have baseline and weekly full blood count, urea and electrolytes and liver function tests in order to spot some of the side effects and toxicity issues before they become too severe.
So was Fosfomycin a good choice for our patient?
Yes, Fosfomycin was a good choice for our patient. It is active against the common Gram-negative bacilli including the antibiotic resistant E. coli. It is bactericidal and so will help a sick patient without their own immune system having to do all of the work. It is available IV so will have rapid activity. It is not a beta-lactam and so can be given to patients with severe beta-lactam allergy and it is not contraindicated in myasthenia gravis. It gets around all of the problems that normal conventional antibiotics presented in our patient’s situation; it was perfect for the job.
So our patient got his IV Fosfomycin. His temperature rapidly settled and he started to improve. Sure enough the bacterium in the blood culture was the multiple antibiotic resistant E. coli and the urinary tract turned out to be the source. The E. coli was sensitive to the Fosfomycin as expected. The patient made a full recovery and had no problems with the Fosfomycin exacerbating his myasthenia gravis. And on a cold December day, I got to use IV Frosty-mycin (Fosfomycin)… job done. Now when’s that warmer weather coming back….brrr chilly?
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