Should we re-learn how to treat MDR TB?

Lancet. 2018 Sep 8;392(10150):821-834

Contributed by Dr Abi Manesh

This seminal paper summarises the clinical outcomes of individual from 50 studies across 25 countries. This individual patient data meta-analysis included potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016.

Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died.

Compared with failure or relapse, treatment success was positively associated with the use of:

  1. linezolid (adjusted risk difference 0·15, 95% CI 0·11 to 0·18)
  2. levofloxacin (0·15, 0·13 to 0·18), moxifloxacin (0·11, 0·08 to 0·14)
  3. carbapenems (0·14, 0·06 to 0·21)
  4. bedaquiline (0·10, 0·05 to 0·14)
  5. clofazimine (0·06, 0·01 to 0·10)

There was a significant association between reduced mortality and use of

  1. linezolid (–0·20, –0·23 to –0·16)
  2. levofloxacin (–0·06, –0·09 to –0·04), moxifloxacin (–0·07, –0·10 to –0·04)
  3. bedaquiline (–0·14, –0·19 to –0·10)

For the drugs that are commonly used in the Indian scenario:

  1. Amikacin in people with susceptible strains was associated with greater success (adjusted risk difference 0·06, 95% CI 0·04 to 0·08) but no difference in death
  2. Kanamycin was associated with significantly lower success (–0·07, –0·08 to –0·05) but no difference in death (0·01, –0·01 to 0·02)
  3. Capreomycin use with lower success (–0·03, –0·06 to 0·00) and more deaths (0·04, 0·01 to 0·07)
  4. Use of ethambutol, ethionamide and protionamide, or para-aminosalicylic acid were associated with no benefit in patients with susceptible isolates, and worse outcomes in patients with resistant isolates
  5. Use of pyrazinamide was associated with lower mortality (adjusted risk difference −0·03, 95% CI −0·05 to −0·01) if isolates were susceptible, but significantly less success (−0·05, −0·08 to −0·03) and higher mortality (0·05, 0·02 to 0·07) if isolates were resistant
  6. Use of cycloserine was beneficial in patients with susceptible isolates contributing to treatment success and protection from death

This study is the basis of the recent WHO MDR-TB update. While this is the largest summary of clinical data we have, the following points merit special attention.

  • The high baseline FQ resistance in many parts of India should be borne in mind
  • Bedaquiline availability is an issue in India
  • The paper did not look at toxicity data – prolonged use of linezolid requires close monitoring for bone marrow toxicity and neuropathy
  • Probably, amikacin should be our aminoglycoside of choice for MDR TB