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 December 2018 the World Health Organisation (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 (2018 update)", WHO, Geneva, 2018 https://www.who.int/tb/features_archive/updated-treatment-guidelines-multigrug-rifampicin-resistant-TB/en/ As the treatment provided for many patients will lag behind the guidelines produced by WHO, the 2016 recommendations are also provided here for reference.

The guidelines published by WHO provide extensive information, so the information provided here is just a summary.

Second line drugs, recommendations after December 2018

The second line drugs to be used for the treatment of drug resistant TB after 2018 are shown in the table below.

The new guidelines mark a major change in the recommended treatment to be provided for those on "longer regimens". Longer MDR-TB regimens are treatments for MDR/RR-TB which last 18 months or more and which may be standardized or individualized. These regimens are usually designed to include a minimum number of second line TB medicines considered to be effective based on patient history or drug resistance patterns. The term "conventional" was previously used to refer to such regimens but was discontinued in 2016 when WHO first issed a recommendation for the use of a shorter MDR-TB regimen.

Injectable agents are no longer among the priority medicines to be used when designing longer MDR-TB regimens and WHO recommends that oral regimens should become the preferred option for most patients. It is a major step forward in the treatment of patients with drug resistant TB that patients are no longer required to have injectable drugs.

Fluoroquinolones (levofloxacin or moxifloxacin), bedaquiline and and linezolid are strongly recommended for use in longer regimens, which are completed with other drugs ranked by their relative balance of effectiveness to potential toxicity.

Second line drugs used to treat rifampicin resistant and multi drug resistant TB after December 2018
Group A : Group B : Group C :
Levofloxacin (Lfx) or
Moxifloxacin (Mfx)
Clofazimine (Cfz) Ethambutol (E)
Bedaquiline (Bdq) Cycloserine (Cs)
or Terizidone (Trd)
Delamanid (Dlm)
Linezolid (Lzd) Pyrazinamide (Z)
Imipenem-cilastatin (Ipm-Cln) or
Meropenem (Mpm)
Amikacin (Am) (or Streptomycin)
Ethionamide (Eto) or Prothionamide (Pto)
p-aminosalicylic acid (PAS)

If a plus sign is shown, clicking on it will show more columns.

All three medicines in Group A should be included.
In group B one or both medicines should be included
Group C medicines should be included to complete the regimen when medicines from Groups A and B cannot be used.

There will shortly be further information about this on the page on the Treatment of Drug Resistant TB, and there is extensive information which should be consulted in the WHO guidelines document.

Second line drugs, recommendations after 2016 and before 2018

In 2016 WHO changed their recommendations on the second line drugs to be used for the treatment of drug resistant TB.2“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 were 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.

If a plus sign is shown, clicking on it will show more columns.

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

The 2016 regrouping was intended to guide the design of longer 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 longer & 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 were 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. (This was changed in the 2018 guidelines)

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. The 2018 WHO guidelines marked a major change in the recommendations on the use of these 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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Major Source for Second Line Drugs