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Second Line Drugs – Fluoroquinolones, second line injectable drugs

Second line drugs are the TB drugs that are used for the treatment of drug resistant TB.

WHO recommendations on the treatment of drug resistant TB

In 2016 the World Health Organistaiton (WHO) changed their recommendations on the second line drugs to be used for the treatment of drug resistant TB.1“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.

Second line drugs used to treat rifampicin resistant and multi drug resistant TB after May 2016
Group A : Fluoroquinolones Group B : Second line injectable drugs Group C : Other core second line drugs Group D : Add-on drugs (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 imipenem-cilastatin (lpm)
D3 Meropenem (Mpm)
D3 Amoxicillin-clavulanate (Amx-Clv)
D3 Thioacetazone (T)

Groups A, B & C are the core second line drugs.

Conventionally the treatment of drug resistant TB has involved taking TB drugs for up to two years.

This regrouping is intended to guide the design of conventional length regimens. For shorter regimens of eight or nine months, such as the Bangladesh regimen, the drug regimen is usually standardized. See the Treatment of drug resistant TB for the difference between conventional & shorter regimens. 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.

Fluoroquinolones

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:

  • high-dose levofloxacin
  • moxifloxacin
  • & gatifloxacin

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.

Second line injectable drugs

Amikacin, a second line injectable drug

Amikacin, a second line injectable drug

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 drugs 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 drugs. 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.

Other core second line drugs

Two or more of the following four medicines should be included. Ethionamide (or prothionamide) cycloserine (or terizidone) linezolid and clofazimine. Group C drugs 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.

Add on agents

Group D1 consists of pyrazinamide, ethambutol and high dose isoniazid. These drugs 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 D2 is made up of bedaquiline and delamanid. These are two new TB drugs.

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 drugs plus pyrazinamide) cannot otherwise be made.

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You can read more by looking at the:

Treatment of drug resistant TB

Multi drug resistant TB

Major source for second line drugs

Major source for WHO treatment guidelines for drug resistant tuberculosis 2016 update http://apps.who.int/iris/handle/10665/250125/

References

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1. “WHO treatment guidelines for drug-resistant tuberculosis (2016 update)”, WHO, Geneva, 2016 www.who.int/tb/areas-of-work/drug-resistant-tb/