Individualized DR TB treatment regimen

Clinical description

The design of the individualized regimen will include new and repurposed drugs such as Bdq, Dlm, Lzd, and Cfz.

Principles for designing individualized DR-TB treatment regimens

• The treatment duration should be sufficient to cure the patient while preventing

relapse; at least 12 months after bacteriological conversion, around 13-15 months if regimen includes at least 2 or 3 sterilizing drugs.). The transition from intensive and continuation phase might not be clear if there is no injectable agent and will depend on drug tolerability and DST results.

The regimen should be designed based on the patient’s most recent DST results and history of previous drug use and/or exposure (see Table 10.44 below).

• Never add Bdq, Dlm, Cfz or Lzd as a single drug to a failing regimen.
• If the patient is culture negative and the new drugs are being SUBSTITUTED for toxicity

reasons, a single drug substitution can be made 22.

The regimen should consist of at least four drugs in the intensive phase never used before and likely to be effective, plus pyrazinamide (Table 10.44). In the continuation phase, at least 3 effective drugs should remain.

• The backbone regimen usually consists of a new drug (Bdq, Dlm or both), Lzd, Cfz and

PZA.

• There have been no studies comparing Bdq and Dlm; if one drug has been used in the

past, or there is documented drug allergy, then the other drug should be chosen.

• Dlm should be the new drug of choice for HIV co-infected patients, due to the lack of

drug-drug interactions with antiretroviral therapy.

• For patient with limited treatment options (MDR treatment failure, pre-XDR, and

XDR-TB), a regimen combining Bdq and Dlm should be designed and approved by the clinical expert committee. Ensure closer monitoring of the QT interval by performing an ECG at baseline, 2 weeks, and monthly until the end of treatment with Bdq or Dlm.

• Bdq or Dlm should be initially given for 6 months; the use of Bdq or Dlm can be extended

by the clinical expert committee in patients with highly resistant forms of DR-TB where the remaining regimen is insufficient (less than 3 effective drugs) without Bdq or Dlm and the drug is well tolerated.

• For patients enrolled for treatment with regimens containing new drugs (Bdq or Dlm)

informed consent policies should follow local practice for DR-TB in general [11].

22 Treatment of Drug-Resistant TB with New and Re-Purposed Medications: A Field Guide. Cleveland, USA. DR-TB STAT; July 2017.

National Tuberculosis Control Programme 85

• For HIV-infected patients, antiretroviral therapy (ART) should be prescribed within 2-8

weeks of DR-TB treatment initiation, and as soon as possible after DR-TB treatment is tolerated.

• The QT prolongation that may occur in patients receiving Bdq or Dlm can be monitored

in the outpatient setting. There is no reason to admit stable patients to initiate Bdq or Dlm only for cardiac monitoring; Dlm takes 8 weeks to reach its peak concentration, and Bdq up to 16 weeks.

• Dlm is recommended for use in children ≥ 6 years old [5] and is being tested for

pharmacokinetic and safety in children aged 5 years and under. There may be individual children less than 6 years of age requiring Dlm due to highly resistant forms of DR- TB (often the resistance pattern of the adult index patient). Regimen design for these children must be discussed and approved by the National DR -TB committee.

• Although Bdq is recommended for patients over the age of 18, there may be a need to

use Bdq in a DR-TB patients less than 18 years of age; each of these individual patients must be referred to the National Drug TB committee for approval of Bdq in this age category.

• All children less than 18 years of age need to be referred to the National level experts

for guidance and approval of DR-TB treatment regimen design, whether a shorter regimen or an individualized regimen with new drugs is used.

Table 10.4-4: Regimen design steps for RR-TB patients who are not eligible for the shorter DR-TB regimen and require an individualized regimen Step 1: Choose either Bedaquilline or Delamanid (Group D2). Patients with MDR-TB treatment failure, intolerance to ≥ 1 drug in the shorter regimen, pre-XDR, or XDR-TB should have either Bdq, Dlm, or both in their regimen. The choice of which drug (or potentially both drugs) is outlined in Section 4.3.2.2 on ‘additional considerations’ below.

Step 2: Choose a fluoroquinolone (Group A – Mfx or Lfx). If only ofloxacin resistance from DST is known, Mfx or Lfx high dose (Lfx is preferred due to less QT prolongation than Mfx) can still be added to the regimen but should not be counted as one of the effective drugs. Treatment with a later generation FQ (Mfx or Lfx) significantly improves RR-TB treatment outcomes; they should therefore always be included unless there is an absolute contra-indication for their use or confirmed high level resistance by SL LPA or phenotypic SL DST.

Step 3: Choose an injectable (Group B – Km, Cm, Am). If clinical history or DST suggests resistance to all SLID, or in case of a serious adverse event (hearing loss, nephrotoxicity), the injectable should not be used or should be promptly discontinued. If the patient’s strain is still susceptible to one of the injectable drugs, it can be included in the regimen only if consistent monitoring for adverse events is assured. In children with mild forms of DR-TB disease, the harms associated with an injectable may outweigh potential benefits and therefore injectable agents may be excluded in this group.

Step 4: Choose at least two or more Group C drugs (Lzd, Cfz, Eto, Cs) thought to be effective as and never used before additional core second line drugs. If efficacy is uncertain, the drug can be added to the regimen, but should not be counted as an effective drug.

Step 5: Choose D1 drugs (PZA, INHhd, EMB) as add-on agents. PZA is routinely added to most regimens. High dose INH may further strengthen the regimen if DST shows INH sensitivity (e.g. inhA mutation alone), or INH resistance is unknown. Do not use INH if the katG mutation is present. D1 drugs are usually added to the core second-line drugs, unless the risks from confirmed resistance, pill burden, intolerance or drug-drug interaction outweigh potential benefits.

Step 6: Only choose D3 drugs (PAS could be added there are no other options available but doesn’t count as main 4 effective drug, imipenem or meropenem + amoxicillin/clavulanic acid) (Bactericidal) can be one of the effective drugs of the regiment but have the challenges of IV administration (only use if highly resistance forms or multiple intolerance to other DR-TB drugs)

86 National Tuberculosis Control Programme Additional considerations on choice of new drug use (Bdq or Dlm) in individualized regimens:

• Bedaquilline, Delamanid, the fluoroquinolones (Mfx more than Lfx), and clofazimine

can all cause prolongation of the QT interval. Patients with DR-TB regimens that contain one of the new drugs, especially when used with additional QT prolonging drugs, should be carefully monitored for clinical signs of an irregular heartbeat, as well as checking regular ECGs.

• Bdq had drug-drug interactions with ART: EFV lowers Bdq serum levels; LPV/r

increases Bdq levels.

• When starting Bdq or Dlm, serum electrolytes should be checked and corrected

when feasible to reduce the risk of cardiac arrhythmias. Since Dlm is metabolized by albumin, patients with a low BMI and/or a low serum albumin should be provided with high protein dietary foods.

• There is potential cross resistance between Bdq and Cfz; use Dlm if there is a history

of prior Cfz use > 2 months for DR-TB (Bdq can be used if there is history of prior Cfz use for leprosy).

• It is not recommended to dose reduce either Bdq or Dlm in the event of adverse events;

linezolid, however, may be reduced from 600 mg daily to 300 mg daily if there is myelosuppression (pyridoxine 50 mg should be added as well). Lzd should be definitely stopped n care of peripheral neuropathy or optic neuritis adverse drug reaction.

• Patients that are highly likely to have second line drug (SLD) resistance - those failing

MDR-TB treatment, symptomatic close contacts of DR-TB patients with SLD resistance, or patients that have received SLDs for ≥ 1 month in the past - can be started on Bdq or Dlm in the absence of confirmed DST by LPA or culture.

Table 10.4-5 Weight-based daily dosages of DR-TB drugs for patients ≥30 kg Drugs Daily dose 30-35KG 36-45KG 46-55KG 56-70KG >70KG Isoniazid 4-6mg/kg once daily 150mg 200mg 300mg 300mg 300mg Rifampicin 8-12mg/kg once 300mg 450mg 450mg 600mg 600mg Pyrazinamide 20-30mg/kg once daily 800mg 1000mg 1200mg 1600mg 2000mg Ethambutol 15-25mg/kg once daily 600mg 800mg 1000mg 1200mg 1200mg Rifabutin 5-10mg/kg once daily 300mg 300mg 300mg 300mg 300mg Levofloxacin 750-1000mg once daily 750mg 750mg 1000mg 1000mg 1000mg Moxifloxacin 400mg once daily 400mg 400mg 400mg 400mg 400mg Ethionamide 500-759mg/day in 2 500mg 500mg 750mg 750mg 1000mg divided doses Prothionamide 500-750mg/day in 2 500mg 500mg 750mg 750mg 1000mg divided doses Cycloserine 500-750mg/day in 2 500mg 500mg 500mg 750mg 750mg divided does P-amino salicylic acid 8g/day in 2 divided doses 8g 8g 8g 8g 8-12g Bedaquilline 400mg once daily for 2 weeks then 200mg 3 times per week Delamanid 100mg twice daily (total daily dose =200mg)

Clofazimine 200-300mg daily (2 months) then reduce to 100mg daily (alternative dosing 100mg daily)

National Tuberculosis Control Programme 87 Linezolid 600mg once daily 600mg 600mg 600mg 600mg 600mg Drugs Daily dose 30-33kG 34-40KG 41-45KG 46-50KG 51-70KG >70KG Streptomycin 12-18mg/kg once daily 500mg 600mg 700mg 800mg 900mg 1000mg Kanamycin 15-20mg/kg once daily 500mg 625mg 750mg 875mg 1000mg 1000mg Amikacin 15-20mg/kg once daily 500mg 625mg 750mg 875mg 1000mg 1000mg Capreomycin 15-20mg/kg once daily 500mg 600mg 750mg 800mg 1000mg 1000mg Notes:

*High dose INH is 10-15 mg/kg daily, maximum 600 mg daily *High dose Lfx is 1000-1500 mg once daily *High dose Mfx for the shorter regimen is 600-800 mg once daily *Clofazimine in the shorter regimen is given 100 mg daily from the start of treatment *Linezolid can be reduced to 300 mg daily in the event of toxicity at 600 mg daily *Meropenem dosing is 1000 mg three times daily (alternative dosing is 2000 mg twice daily)

*Imipenem/cilastatin dosing is 1000 mg imipenem/1000 mg cilastatin twice daily *Meropenem and imipenem should be given with Clavulanic acid available as amoxicillin/ clavulanic (625 mg 1 tablet 30 minutes before the infusion)