The treatment of drug resistant TB has always been more difficult than the treatment of drug susceptible TB. It has required the use of second line or reserve drugs that are more costly and cause more side effects. Also the drugs must be taken for up to two years. The following is the type of problem that patients taking the drugs were and indeed still are faced with.
“These drugs are so horrible to eat every day. After nearly a year and a half, I thought it was just too much; I couldn’t keep taking all those pills. I thought it would be OK if I stopped taking them. But they told me if I didn’t keep going I might get sick again and then I would have to start again from the beginning with all the injections. So I kept going with the pills and now I am cured. It was such a long time.”
Drug resistant TB patient1Keshavjee, S., Farmer, P.E. “Time to put boots on the ground: making universal access to MDR-TB treatment a reality”, Int J Tuberc Lung Dis, 14(10), October 2010, 1222-1225 http://www.ingentaconnect.com
And so the search began for shorter regimens for the treatment of drug resistant TB, that were also easier to take.
This led to the development of the Bangladesh regimen which appears to have much higher cure rates and the drugs only need to be taken for eight or nine months. There are also other shorter regimens that are now being tested. The results of randomised control trials of these new regimens, are only just now starting to be available.
The Bangladesh regimen does not solve all the problems, as it still requires patients to have injections as part of their TB treatment. For some patients these can be extremely painful and difficult as Zolelwa Sifumba explains below.
“The injection was like nothing I’d ever felt before. It burns from the second it starts – it is quite a thick serum so you can’t inject it in fast. It takes some time. The pain went down my legs and up to my back. It is so painful. No injection should be that painful. It is intense pain that never stops.”
The pain lasts after the patient walks out of the doctor’s room.
“It is painful to get up. It is painful to go shower. It is painful to eat. It is painful to go to school. Everything is so difficult all day. And the next day when you go for your injection, you’re still in pain from the last injection”2“Frightening injection sends never-ending pain throughout your body”, www.health24.com
Not every patient will suffer in this way, but the fact that some do, means that the search must continue for TB treatments that don’t involve this type of injectable drug.
Not all patients with drug resistant TB are eligible for treatment with a shorter regimen. A shorter regimen is usually considered suitable for patients with rifampicin resistant or multi drug resistant TB who have not been previously treated with second line drugs and in whom resistance to fluoroquinolones and second line injectables has been excluded or is considered highly unlikely.
There needs to be a careful selection of patients to be enrolled in any shorter regimen. There also needs to be effective patient support to enable full adherence to treatment. It is recommended that patients are tested for susceptibility or resistance to fluoroquinolones and to the second line injectable agents used in the regimen before starting on a shorter MDR-TB regimen.
Patients with strains resistant to any of the two groups of medicines should be transferred to treatment with a conventional MDR-TB regimen. This is to ensure that patients are not being treated with drugs that they are already resistant to.
The availability of rapid and reliable TB tests can be very valuable in deciding within a few days which patients are eligible for shorter MDR TB regimens. It can also provide information about what modifications to conventional MDR-TB regimens are necessary based on the resistance detected. The Line Probe Assay test can be used as an initial direct test, rather than tests such as the culture test to detect resistance to fluoroquinolones and to the second line injectable drugs.
In settings where drug susceptibility testing (DST) for fluoroquinolones and injectable agents is not yet available, treatment decisions need to be guided by the likelihood of resistance to these medicines. This needs to take into account the patient’s clinical history and recent surveillance data.
In 2016 WHO changed their recommendations on the second line drugs to be used for the treatment of drug resistant TB.3“WHO treatment guidelines for drug-resistant tuberculosis (2016 update)”, WHO, Geneva, 2016 www.who.int/tb/areas-of-work/drug-resistant-tb/ The second line drugs to be used for the treatment of drug resistant TB after 2016 are as follows.
|Group A : Fluoroquinolones||Group B : Second line injectable agents||Group C : Other core second line Agents||Group D : Add-on agents (not part of the core MDR-TB regimen)|
|Levofloxacin (Lfx)||Amikacin (Am)||Ethionamide/Prothionamide (Eto/Pto)||D1 Pyrazinamide|
|Moxifloxacin (Mfx)||Capreomycin (Cm)||Cycloserine / Terizidone (Cs Trd)||D1 Ethambutol (E)|
|Gatifloxacin (Gfx)||Kanamycin (Km)||Linezolid (Lzd)||D1 High-dose isoniazid (Hh)|
|(Streptomycin)||Clofazimine (Cfz)||D2 Bedaquiline (Bdq)|
|D2 Delamanid (Dlm)|
|D3 p-aminosalicylic acid PAS)|
|D3 lmipenem-cilastatin (lpm)|
|D3 Meropenem (Mpm)|
|D3 Amoxicillin-clavulanate (Amx-Clv)|
|D3 Thioacetazone (T)|
Groups A, B & C are the core second line drugs.
This regrouping is intended to guide the design of conventional length regimens. For shorter regimens of eight or nine months the drug regimen is usually standardized. Medicines in Groups A and C are shown by decreasing order of usual preference for use. The carbapenems (which include meropenem and imipenem and ertapenem) and clavulanate are meant to be used together. Clavulanate is only available in formulations combined with amoxicillin. HIV status must be tested and confirmed to be negative before thioacetazone is started.
A conventional treatment regimen for any patient with rifampicin resistant TB, is always going to be complex. A number of different second line drugs need to be used on the basis of the drugs that the patient is already known, or likely to be resistant to.
These recommendations cover rifampicin resistant forms of TB, including patients with strains susceptible to isoniazid, or with additional resistance to isoniazid (i.e. multi drug resistant TB; MDR-TB). It also includes patients with strains also resistant to other medicines from the first line group (poly-resistant) or from the second line group (e.g. extremely drug resistant TB (XDR-TB)).
In patients with rifampicin resistant or multi drug resistant TB, a regimen with at least five effective TB medicines is recommended during the intensive phase. This includes pyrazinamide and four core second line medicines, one chosen from Group A, one from Group B, and at least two from Group C. If the minimum of effective TB medicines cannot be composed, an agent from Group D2 and other agents from D3 may be added to bring the total to five.
Group D2 consists of the drugs bedaquiline and delamanid. WHO has produced a “best practice” statement on the use of these two drugs.4“WHO best practice statement on the off-label use of bedaquiline and delamanid for the treatment of multidrug-resistant tuberculosis”, WHO, 2017, apps.who.int/iris/handle/10665/258941
In patients with rifampicin-resistant or multi-drug resistant TB, it is recommended that the regimen be further strengthened with high dose isoniazid and/or ethambutol.
Treatment with later generation fluoroquinolones (defined here as high dose levofloxacin, moxifloxacin, and gatifloxacin) has been shown to significantly improve treatment outcomes in adults with rifampicin resistant or multi drug resistant TB. This group of second line drugs is therefore considered to be the most important component of the core MDR-TB regimen. The benefits from their use outweighs the potential risks. So they should always be included unless there is an absolute contra-indication for their use.
The order of preference for the inclusion of the later generation fluoroquinolones in MDR-TB regimens is:
It is recommended that ofloxacin is phased out from MDR-TB regimens and that ciprofloxacin is never used due to the limited evidence for their effectiveness.
Adults with rifampicin resistant or multi drug resistant TB should always receive a second line injectable agent as part of their regimen, unless there is an important reason for not doing so.
The choice of which of the three standard agents to use, amikacin, capreomycin or kanamycin should be determined by the likelihood of effectiveness and by implementation considerations. Patients need to be carefully monitored for side effects while using second line injectable agents. Hearing loss and nephrotoxicity are among the most frequent and most severe side effects.
For the treatment of RR-TB and MDR-TB streptomycin can be used as a substitute for second line injectable agents when aminoglycosides or capreomycin cannot be used and susceptibility is highly likely. It needs to be remembered that streptomycin has severe side effects and can frequently result in a loss of hearing.`
Two or more of the following four medicines should be included. Ethionamide (or prothionamide) cycloserine (or terizidone) linezolid and clofazimine. Group C agents are included to bring the total of effective second line TB medicines in the core regimen to at least four during the intensive phase of the regimen.
Group D1 consists of pyrazinamide, ethambutol and high dose isoniazid. These agents are usually added to the core second line medications unless the risks from confirmed resistance, pill burden, intolerance or drug drug interactions outweigh the potential benefits.
Group D3 consists of p-aminosalicylic acid (PAS), imipenem-cilastatin, meropenem, clavulanate and thioacetazone. These drugs are only to be used when an MDR-TB regimen with at least 5 effective drugs ( i.e. primarily 4 core second line medicines plus pyrazinamide) cannot otherwise be composed.
Surgery for the treatment of drug resistant TB is now recommended in some circumstances. In patients with RR-TB or MDR-TB elective partial lung resection (lobectomy or wedge resection) may be used alongside a recommended MDR-TB regimen.
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WHO treatment guidelines for drug resistant tuberculosis 2016 update http://apps.who.int/iris/handle/10665/250125/
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|1.||↑||Keshavjee, S., Farmer, P.E. “Time to put boots on the ground: making universal access to MDR-TB treatment a reality”, Int J Tuberc Lung Dis, 14(10), October 2010, 1222-1225 http://www.ingentaconnect.com|
|2.||↑||“Frightening injection sends never-ending pain throughout your body”, www.health24.com|
|3.||↑||“WHO treatment guidelines for drug-resistant tuberculosis (2016 update)”, WHO, Geneva, 2016 www.who.int/tb/areas-of-work/drug-resistant-tb/|
|4.||↑||“WHO best practice statement on the off-label use of bedaquiline and delamanid for the treatment of multidrug-resistant tuberculosis”, WHO, 2017, apps.who.int/iris/handle/10665/258941|