“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!?
“What antibiotics have you tried?” asked the Microbiologist.
The Physician looked a bit irritated, wondering why the Microbiologist appeared to be asking about whether he knew how to treat pneumonia.
“The patients GP had tried Amoxicillin and Clarithromycin, and I’ve used both Co-amoxiclav and Levofloxacin but whilst there was a bit of improvement with the latter antibiotics the patient hasn’t really improved much”.
“When were the samples taken in relation to the antibiotics?”
“I can’t remember, but why does it matter? The drugs haven’t worked and the patient has never been treated for TB so it should still grow” replied the increasingly irate Physician.
“Ahhh, but you have been partially treating for TB, on at least two occasions now” stated the Microbiologist cryptically.
“What are you talking about?” asked the Physician, now thoroughly perplexed and wishing he hadn’t stopped the Microbiologist after all.
So what is the Microbiologist blithering about?
What is the treatment of tuberculosis?
Tuberculosis (TB) is a chronic bacterial infection which can affect almost any body system although the main site of infection is usually the lungs. The treatment of TB is difficult and prolonged. The normal first line regimen is:
- 2 months – Isoniazid PLUS Rifampicin PLUS Ethambutol PLUS Pyrazinamide
- 4 months – follow on treatment with Isoniazid PLUS Rifampicin
- Total duration 6 months
Combination treatment is used to try and prevent the development of resistance to the antibiotics. Isoniazid and Rifampicin are bactericidal against TB (they kill it) but Ethambutol and Pyrazinamide are bacteriostatic (they just stop it growing while the patient’s immune response eventually kills it).
“In 2017, 87% of new TB cases came from 30 countries; 8 of these countries account for 2/3 of the total, with India leading the count, followed by China, Indonesia, the Philippines, Pakistan, Nigeria, Bangladesh and South Africa”… “The MDR-TB burden largely falls on 3 countries – India, China and the Russian Federation – which together account for nearly half of the global cases.” WHO.
Antibiotic resistance in TB is an increasing and worrying situation. TB with resistance to Isoniazid and Rifampicin is known as Multidrug Resistant TB (MDR TB). In this situation only the bacteriostatic agents are left from the standard TB treatment regimen and these are not effective on their own for treating TB; bactericidal antibiotics are needed.
In 2015 the rate of MDR TB in the UK was 4% (1.4% of new TB and 5.7% of reactivated TB). Rates of MDR TB are much higher in other countries; in Eastern Europe and Asia 20% of new TB and 50% of reactivated TB is MDR TB. Although “new cases of tuberculosis (TB) have sharply decreased within the Europe region as a whole, the region contains 18 high-priority countries (Armenia, Azerbaijan*, Belarus*, Bulgaria, Estonia, Georgia, Kazakhstan*, Kyrgyzstan*, Latvia, Lithuania, the Republic of Moldova*, Romania, the Russian Federation*, Tajikistan*, Turkey, Turkmenistan, Ukraine* and Uzbekistan*). The region also has 9 of the 30 countries in the world with the highest burden of MDR-TB*” WHO.
How is MDR TB “normally” treated?
MDR TB is still treated with a combination of at least five active antibiotics. The original treatment regimen consisted of:
- An injectable aminoglycoside e.g. Amikacin or Streptomycin (or Gentamicin if that is the only aminoglycoside available)
- A fluoroquinolone e.g. Levofloxacin or Moxifloxacin
- Any first line drug still active e.g. Ethambutol or Pyrazinamide
- Ethionamide, Cycloserine or Para-aminosalicylic acid
- Any other drug active against TB to create a five drug regimen e.g. Co-amoxiclav, Linezolid, Meropenem, Imipenem/Cilastatin
The IV aminoglycoside is usually stopped after 2 months.
Earlier this year the World Health Organisation (WHO) published new guidance for the treated of MDR TB, however it appears this is not widely known amongst frontline clinicians!
It is also slightly concerning that even though the WHO have made it clear that “whilst there is strong theoretical evidence for this regimen there is, as of yet, no extensive clinical evidence, and …these drugs are being used off license”.
The reason for changing the regimen is the release of two new anti-TB drugs, Bedaquiline and Delamanid, as well as the re-invention of an old anti-TB drug, Clofazimine (I’ll write a blog about these in more detail in the future). The change means it is now possible to move to an entirely oral regimen and drop the IV agent.
The new regimen is:
- Levofloxacin OR Moxifloxacin PLUS Bedaquiline PLUS Linezolid (unless they cannot be used)
- PLUS Clofazimine AND/OR Cycloserine (unless they cannot be used)
- PLUS any of the following to complete a minimum 4 drug regimen: Ethambutol, Pyrazinamide, Delamanid, Imipenem/ Cilastatin OR Meropenem (co-administered with Co-amoxiclav for the beta-lactamase inhibitor effect), Amikacin, Streptomycin, Ethionamide, Para-aminosalicylic acid.
The 2 month initial phase should include 4 drugs and the 4 month continuation phase should include 3 drugs shown to be active by laboratory testing.
…Stick with me there is a point to this!
So what are the implications of these regimens on the diagnosis of TB?
If you look at the list of antibiotics used in the treatment of MDR TB (above) you’ll see some familiar antibiotics used in the routine treatment of common infections such as pneumonia and urinary tract infections. This includes antibiotics such as Levofloxacin, Gentamicin, Imipenem/Cilastatin, Meropenem, Co-amoxiclav and Linezolid. Given that many doctors do not consider TB as an initial diagnosis it is therefore common for patients to have been treated with these antibiotics before the TB diagnosis is considered.
TB is usually diagnosed by growing Mycobacterium tuberculosis from a clinical specimen such as a sputum, BAL or tissue biopsy. Any antibiotic with activity against this bacterium will prevent it growing in the laboratory and therefore stop the diagnosis being made.
“So…” said the Microbiologist to the Physician (honest my “corridor consultations” are shorter than this!!!) “Do you see… the antibiotic choice may have inhibited growth of Mycobacterium tuberculosis in your patient’s specimen?”
So what can be done to improve the diagnosis of TB?
The best way of improving the diagnosis of TB is to think about TB before starting antibiotics. When you see a patient with pneumonia, ask yourself the question, “TB or not TB?” Okay, I know that’s corny and is the limit of my Shakespeare … but this memory jogger does work. If the patient could have TB then try and at least get a sputum sample before you start treating them for pneumonia. TB culture usually takes 7-10 days to go positive, it’s not a quick diagnosis, so “common treatments” should not therefore be delayed awaiting the TB result! But if the patient has not responded to your initial treatment, at least you’ll not have “messed up” the diagnosis of TB by trying to take samples at a later date when the patient is already on antibiotics.
NB If the patient has been on antibiotics it is likely to take at least 1-2 weeks before their samples are sufficiently “free from the effects of the antibiotic” for the M. tuberculosis to grow.
The Microbiologist quickly realised that he had significantly wound up his colleague and gave a short swift summary “the reason for the negative cultures was probably the Co-amoxiclav and Levofloxacin the patient had been given, as these were part of the MDR TB treatment regimens”.
The Physician rapidly calmed down and realised they had learnt something useful after all. The antibiotics were stopped and further samples were taken 2 weeks later. These subsequently grew a fully sensitive M. tuberculosis and the patient was able to start standard TB treatment.
The Microbiologist reflected later …“I didn't have time to write a short blog, so I wrote a long one instead.” - Mark Twain