Drug-resistant tuberculosis treatment

Definitions
). 
Extrapulmonary TB and TB meningitis. The WHO recommendations on longer MDR-TB regimens 
apply also to patients with extrapulmonary disease. Adjustments may be required, depending on 
the specific location of the disease. Treatment of MDR/RR-TB meningitis is best guided by DST of 
the infecting strain and by knowledge of the properties of TB medicines that cross the blood–brain 
barrier. Levofloxacin and moxifloxacin penetrate the CNS well (76), as do ethionamide/prothionamide, 
cycloserine/terizidone, linezolid and imipenem–cilastatin (77, 78). Seizures may be more common in 
children with meningitis treated with imipenem–cilastatin; thus, meropenem is preferred for meningitis 
cases and in children. High-dose isoniazid and pyrazinamide can also reach therapeutic levels in 
the cerebrospinal fluid, and may be useful if the strains are susceptible. P-aminosalicylic acid and 
ethambutol do not penetrate the CNS well, and should not be counted on as effective agents 
for MDR/RR-TB meningitis. Amikacin and streptomycin penetrate the CNS only in the presence of 
meningeal inflammation. There are few data on the CNS penetration of clofazimine, bedaquiline or 
delamanid (79–81). In addition, cerebrospinal fluid concentrations may not mirror concentrations in 
the meninges or brain. 
Culture-negative TB. Other durations of treatment may be appropriate for persons with culture-
negative TB and Recommendation 3.16 does not apply. In such cases, if a longer regimen option 
is chosen, a total duration of 18–20 months of treatment is advised, and the response should be 
monitored by clinical parameters other than specimen bacteriology. A negative culture result may 
reflect poor laboratory performance rather than true sputum negativity, underscoring the importance 
of quality assurance in the
laboratory.
Pregnancy. Amikacin, streptomycin, prothionamide and ethionamide are usually contraindicated 
during pregnancy. Because of the potential for teratogenic effects from these medications, including 
the injectable agents, Recommendation 3.17 is of limited relevance in this subgroup. Following the 
changes made in the 2018 guidelines update, these agents are expected to be used less frequently 
in longer regimens. Knowledge about the safety of bedaquiline and delamanid in pregnancy and 
breastfeeding is sparse. However, new evidence from an observational study in South Africa was 
presented to the GDG in 2019; it included information on 58 mothers who received bedaquiline 
during pregnancy (74). The results of this study indicated that fetal exposure to bedaquiline in utero 
was associated with low birth weight
43
(45% of babies exposed to bedaquiline had a low birth 
weight compared to 26% of babies not exposed, P=0.034) (74). However, there were no other 
significant differences in infant outcomes, pregnancy outcomes or maternal treatment outcomes, 
including weight gain in the infants until 1 year of age (74). In such cases, it is recommended that a 
longer regimen be individualized to include components with a better established safety profile. The 
outcomes of treatment and pregnancy, including data from postpartum surveillance for congenital 
anomalies, should be documented to help inform future recommendations for MDR-TB treatment 
during
pregnancy.
HIV infection. The composition of the treatment regimen for MDR-TB does not usually differ 
substantially for PLHIV. With careful attention, it is possible to avoid certain drug–drug interactions 
(e.g. bedaquiline and efavirenz; see also the HIV drug interactions website of the University of 
Liverpool (36)).