DST for fluoroquinolones is strongly encouraged in people with MDR/RR-TB, and although it should not delay initiation of the BPaLM, results of the test should guide the decision on whether moxifloxacin can be retained or should be dropped from the regimen – in cases of documented resistance to fluoroquinolones, BPaL without moxifloxacin would be initiated or continued. The BPaLM/BPaL regimen may be offered to patients with MDR/RR-TB in the following situations:
- pulmonary TB or all forms of extrapulmonary TB, except TB involving the CNS, osteoarticular TB and disseminated (miliary) TB;
- patient is aged 14 years or older;
- no known allergy to any of the BPaLM component drugs;
- no evidence of resistance to bedaquiline, linezolid, delamanid or pretomanid, or patient has not been previously exposed to any of the component drugs for 4 weeks or longer; when exposure to the component drugs is greater than 4 weeks in duration, the patient may receive the BPaLM regimens if resistance to the specific medicines with such exposure has definitively been ruled out;
- all people regardless of HIV status;
- no XDR-TB according to the 2021 WHO definitions (21); and
- patient is not pregnant or breastfeeding or, if the patient is a premenopausal woman, is willing to use effective contraception.
In cases of possible fluoroquinolone resistance (e.g. a history of >4 weeks of fluoroquinolone use or close contact with a person infected with a fluoroquinolone-resistant strain), it is best to initiate a BPaLM regimen until DST for fluoroquinolones is available, to decide whether moxifloxacin should be continued. If the result of fluoroquinolone DST is never determined or not done, the BPaLM regimen should be used throughout. This is often done even if fluoroquinolone resistance is suspected, because the toxicity of adding moxifloxacin is low and some patients with past use of a fluoroquinolone or contact cases may still be infected with susceptible strains. If resistance is highly likely (i.e. a treatment with a fluoroquinolone failed or the patient is a close contact of a fluoroquinolone-resistant case and was unlikely to get TB from another source, or in a setting with a high prevalence of fluoroquinolone resistance and in the absence of DST) it is reasonable to omit the moxifloxacin and use the BPaL regimen for treatment.
Several groups of patients were excluded from the ZeNix and TB-PRACTECAL trials. Inclusion of such patients should be considered with caution because no data are available regarding the safety of BPaLM/BPaL in such populations.
Caution should be taken in patients with a known history of cardiac disease. Populations of concern include those with a baseline corrected QT interval by Fridericia (QTcF) of more than 450 ms, history of cardiac disease with syncopal episodes, significant arrythmias, personal or family history of congenital QTc prolongation, torsade de pointes (tdP), bradyarrhythmia or cardiomyopathy. Although bedaquiline and moxifloxacin can prolong QTc, reports of serious adverse events and mortality are rare.
DST for fluoroquinolones is strongly encouraged to determine whether moxifloxacin should be retained in the regimen; however, results from DST should not delay treatment initiation. For patients with confirmed MDR/RR-TB, a WHO-recommended rapid molecular test should be used as an initial rapid test, in preference to culture and phenotypic DST, to detect resistance to fluoroquinolones (22). Although not readily accessible, if DST is available for bedaquiline or linezolid, it is highly desirable that this is also carried out at baseline. DST for pretomanid is being developed. Patients with strains resistant to bedaquiline, pretomanid or linezolid should commence treatment with a longer, individualized MDR-TB regimen. For patients who submit a sputum sample for culture-based second-line DST at the beginning of treatment, results may not be available until after treatment has started. If resistance to any of the regimen component drugs (except moxifloxacin) is discovered after treatment is initiated, the regimen needs to be discontinued.
Other considerations when initiating the BPaLM/BPaL regimen include the following:
- Linezolid is associated with anaemia and thrombocytopenia, and care should be taken in patients with anaemia. Care should also be taken for patients who have a haemoglobin level of less than 8 g/dL or a platelet count less than 75 000/mm3. Consideration of a linezolid-sparing 9-month or longer regimen may be a safe option.
- Patients with a very low body mass index (BMI) (<17 kg/m2) should be monitored. Although the ZeNix-TB trial excluded those with a BMI of less than 17 kg/m2, TB-PRACTECAL had no such exclusion criteria and 167 (40%) of those in TB-PRACTECAL had a BMI of less than 17 kg/m2. Low BMI should not be an absolute contraindication in commencing the BPaLM/BPaL regimen, but patients should be monitored closely.
- Patients with liver enzymes at levels three times greater than the upper limit of normal were excluded from both the ZeNix and TB-PRACTECAL trials because bedaquiline and pretomanid are both associated with increases in liver enzymes.
- Linezolid is associated with peripheral neuropathy; therefore, those with pre-existing peripheral neuropathy of Grade 3–4 should be treated with caution when commencing the BPaLM/BPaL regimen. Alternatively, to decrease the risk of peripheral neuropathy exacerbation, the 9-month regimen with ethionamide (and no linezolid) could be used.
- Patients who are moribund or with advanced disease should have considerations made for symptoms control and palliative care over initiation of treatment. Decisions should be guided by clinical judgement and the patient’s preferences.
Vigilance or, preferably, drug substitution should be considered when certain medications are prescribed concurrently with the BPaLM/BPaL regimen; for example:
- efavirenz may induce the metabolism of bedaquiline and alternative antiretroviral therapy (ART) should be considered for patients who are prescribed efavirenz;
- linezolid is known to be associated with serotonin syndrome; therefore, caution should be taken with other serotonergic drugs (e.g. sertraline and fluoxetine);
- concomitant drugs that prolong QTc should be avoided if possible – such drugs require extra vigilance and monitoring with electrocardiography (ECG) if prescribed with bedaquiline and moxifloxacin; for example, ondansetron, methadone, amitriptyline and clarithromycin, neuroleptics-phenothiazines (e.g. thioridazine, haloperidol, chlorpromazine, trifluoperazine, pericycline, prochlorperazine, fluphenazine, sertindole and pimozide), quinoline antimalarials (e.g. halofantrine, chloroquine, hydroxychloroquine and quinacrine) and anti-arrhythmic drugs (e.g. quinidine, procainamide, encainide, disopyramide, amiodarone, flecainide and sotalol);
- CYP3A4 inhibitors and CYP3A4 inducers can interact with bedaquiline:
- CYP3A4 inhibitors include the azole antifungals (ketoconazole, voriconazole and itraconazole), ketolides such as telithromycin and macrolide antibiotics other than azithromycin; the azole antifungals in general can safely be used for less than 2 weeks whereas fluconazole could potentially be used for more than 2 weeks;
- CYP3A4 inducers include phenytoin, carbamazepine, phenobarbital, St. John’s wort (Hypericum perforatum), rifamycins and glucocorticoids; and
- drugs inducing myelosuppression should also be used with caution (e.g. azathioprine and cytotoxic agents).
In each of the above situations, if the clinician judges that the potential benefits outweigh the potential risk (also considering alternative treatment options), then treatment may proceed with caution. However, patients who are not eligible for the BPaLM/BPaL regimen can benefit from the 9-month regimen if eligible (Chapter 5) or the individualized longer treatment regimen (Chapter 6).