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  • Longer Oral M/XDR-TB: Regimen and Duration

    Content

    Longer oral Multi (M)/ Extensive Drug-resistant (XDR) -TB treatment is specified with a definite regime and duration.

     

    Regimen: (18-20) Levofloxacin (Lfx), Bedaquiline (Bdq) (6 months or longer), Linezolid# (Lzd), Clofazimine (Cfz), Cycloserine (Cs)​​ (# dose of Lzd will be tapered to 300 mg after the initial 6–8 months of treatment)​

     

    • Duration: 18-20 months
    • No separate Intensive Phase (IP) and Continuation Phase (CP).
    • Bdq will be given for 6 months and extended beyond 6 months as an exception.
    • Pyridoxine should be given to all Drug-resistant TB (DR-TB) patients as per the weight bands.
    • For Extensively Drug-resistant TB (XDR-TB) patients, the duration of a longer oral XDR-TB regimen would be for 20 months.

     

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  • Pre-treatment Evaluation [PTE] in Longer Oral M/XDR-TB Regimen

    Content

    Pre-treatment evaluation for patients on a longer oral Multi/ Extensively Drug-resistant TB (M/XDR-TB) regimen requires both clinical evaluation and laboratory-based evaluation as given below.

     

     

    Clinical Evaluation

     

    • Physical examination​
    • Height​
    • Weight​
    • Psychiatric evaluation if required​
    • Ophthalmologist opinion (for Linezolid)​
    • Surgical evaluation for consideration after culture conversion is achieved​

    ​

    Laboratory-based Evaluation​

     

    • Random Blood Sugar (RBS)​
    • HIV-testing following counselling​
    • Complete blood count (Hb, TLC, DLC, platelet count)​
    • Liver function tests (including serum proteins)​
    • Thyroid Stimulating Hormone (TSH)​ levels
    • BUN and Sr Creatinine- If Amikacin needs to be added​
    • Urine examination- routine and microscopic​
    • Serum electrolytes (Na, K, Mg, Ca)​
    • Urine pregnancy test (in women of reproductive age)​
    • Chest X-ray​
    • Electrocardiogram (ECG)​

     

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  • Treatment Extension in Longer Oral M/XDR-TB Regimen

    Content

    The total duration of a longer oral Multidrug/ Extensively drug-resistant TB (M/XDR-TB) regimen is 18–20 months. ​

     

    Process overview

    Figure: Protocol for Treatment Extension in Longer Oral M/XDR-TB Treatment Regimen

     

     

    Extension of Bedaquiline (Bdq) beyond 6 months is to be considered in patients in whom an effective regimen cannot otherwise be designed.

    • If any additional resistance to Group A, B or C drugs in use is detected, the patient needs to be reassessed at the Nodal/ District Drug-resistant Tuberculosis Centre (N/DDR-TBC) for modification of a longer oral M/XDR-TB regimen immediately on receiving the report.
    • A treatment duration of 15–17 months after culture conversion is suggested for most patients. The duration may be modified according to the patient’s response to treatment.

     

     

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  • Dosages of M/XDR-TB Drugs for Adult in Longer Oral M/XDR-TB Regimen​

    Content

    It is important to know the dosages of Multi (M)/ Extensively Drug-resistant TB (XDR-TB) drugs for adults on a longer oral M/XDR-TB regimen.​

     

     

    The table below shows the M/XDR-TB regimen drugs for adults weight band-wise, used in longer oral M/XDR-TB regimen customized for India by national experts.

     

     

    Table: Dosages of M/XDR-TB Drugs for Adults in Longer Oral M/XDR-TB Regimen

    Sr.No

    Drugs

    16-29 kg

    30-45 kg

    46-70 kg

    >70 kg

    1

    Levofloxacin (Lfx)

    250 mg

    750 mg

    1000 mg

    1000 mg

    2

    Moxifloxacin (Mfx)

    200 mg

    400 mg

    400 mg

    400 mg

    3

    High dose Mfx (Mfxh)

    400 mg

    600 mg

    600 mg

    600 mg

    4

    Bedaquiline (Bdq)

    Week 0–2: Bdq 400 mg daily 

    Week 3–24: Bdq 200 mg 3 times per week

    5

    Clofazimine (Cfz)

    50 mg

    100 mg

    100 mg

    200 mg

    6

    Cycloserine (Cs)3

    250 mg

    500 mg

    750 mg

    1000 mg

    7

    Linezolid (Lzd)

    300 mg

    600 mg

    600 mg

    600 mg

    8

    Delamanid (Dlm)

    50 mg twice daily (100 mg) for 24 weeks in 6-11 years of age

     100 mg twice daily (200 mg) for 24 weeks for ≥12 years of age

    9

    Amikacin (Am)1

    500 mg

    750 mg

    750 mg

    1000 mg

    10

    Pyrazinamide (Z)

    750 mg

    1250 mg

    1750 mg

    2000 mg

    11

    Ethionamide (Eto)3

    375 mg

    500 mg

    750 mg

    1000 mg

    12

    Na - PAS (60% weight/ vol)2,3 

    10 gm

    14 gm

    16 gm

    22 gm

    13

    Ethambutol (E)

    400 mg

    800 mg

    1200 mg

    1600 mg

    14

    Imipenem-Cilastatin (Imp-Cln)3

    2 vials (1g + 1g) bd (to be used with Clavulanic acid)

    15

    Meropenems (Mpm)3

    1000 mg three times daily (alternative dosing is 2000 mg twice daily) (to be used with Clavulanic acid)

    16

    Amoxicillin-Clavulanate (Amx-Clv) (to be given with Carbapenems only)

    875/125 mg bd

    875/125 mg bd

    875/125 mg bd

    875/125 mg bd

    17

    Pyridoxine (Pdx)

    50 mg

    100 mg

    100 mg

    100 mg

     

    1For adults more than 60 years of age, the dose of Second-line Injectable (SLI) should be reduced to 10 mg/kg (max up to 750 mg).

    2In patients of Para Amino Salicylic Acid (PAS) with 80% weight/ volume the dose will be changed to 7.5 gm (16-29 kg); 10 gm (30-45 Kg); 12 gm (46-70 kg) and 16 gm (>70 kg).

    3Drugs can be given in divided doses in a day in the event of intolerance.

     

     

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  • Adverse Drug Reactions due to Longer oral M/XDR-TB Regimen

    Content

    The table below showcases the adverse drug events that may be caused by drugs used for longer oral Multi (M)/ Extensively Drug-resistant TB (XDR-TB) regimen. In these situations, replacement drugs are used instead of these drugs.

     

    Table: Possible Adverse Drug Events in the Longer Oral M/XDR-TB Regimen

    ADVERSE DRUG EVENTS

    DRUGS

    QT prolongation

    		  Bedaquiline (Bdq), Fluoroquinolone (FQ), Clofazimine (Cfz)
    Rash, allergic reaction and anaphylaxis

    Any drug

    Gastrointestinal symptoms

    		 Ethionamide (Eto), P-Aminosalicylic Acid (PAS), Pyrazinamide (Z), Ethambutol (E), Bdq, Cfz, Linezolid (Lzd), FQs

    Diarrhoea and/or flatulence

    PAS, Eto

    Hepatitis

    Z, Eto, PAS, Bdq

    Giddiness

    Amikacin (Am), Eto, FQ and/or Z

    Haematological abnormalities

    Lzd

    Hypothyroidism

    Eto, PAS

    Arthralgia

    Z, FQ, Bdq

    Peripheral neuropathy

    Lzd, Cycloserine (Cs), Am, FQ, rarely Eto, E

    Headache

    Bdq, Cs

    Depression

    Cs, FQ, Eto

    Psychotic symptoms

    Cs, Isoniazid (H), FQ

    Suicidal ideation

    Cs, Eto

    Seizures

    Cs, H, FQ

    Tendonitis and tendon rupture

    FQ

    Nephrotoxicity (renal toxicity)

    Am

    Vestibular toxicity (tinnitus and dizziness

    Am, Cs, FQs, Eto, Lzd

    Hearing loss

    		 Am

    Optic neuritis

    E, Lzd, Eto, Cfz

    Metallic taste

    Eto, FQs

    Electrolyte disturbances (Hypokalaemia and Hypomagnesaemia

    Am

    Gynaecomastia

    Eto

    Alopecia

    Eto

    Superficial fungal infection and thrush

    FQ

    Lactic acidosis

    Lzd

    Dysglycaemia and Hyperglycaemia

    Eto

     

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  • Details of Replacement Sequence of Drugs in Longer Oral M/XDR-TB Regimen

    Content

    Replacement of component(s) drug(s) is required in conditions like adverse drug reaction, poor tolerance, contraindication and resistance detected on baseline Liquid Culture (LC) Drug Susceptibility Testing (DST). 

     

    The replacement sequence of drugs is prepared according to their efficacy, no demonstrable resistance, prior use, side-effect profile and background resistance to replacement drug in the country.

    ​

    In case of the need for replacement of any of the component(s) in the longer oral Multi (M)/ Extensively Drug-resistant TB (XDR-TB) regimen, the following broad principles apply:​

     

    • The regimen should preferably be fully oral. However, in certain circumstances, injectables may have to be used.​
    • At least 4-5 drugs are to be used in the initial 6 to 8 months and at least 3-4 drugs in the last 12 months. ​
    • Replacement sequence of Group C drugs for longer oral M/XDR-TB regimen was recommended in the order of – Delamanid (Dlm), Amikacin (Am), Pyrazinamide (Z), Ethionamide (Eto), P-aminosalicylic acid (PAS), Ethambutol (E), Penems.​​​​
    • The combined use of Bedaquiline (Bdq) and Dlm in the regimen is recommended in whom an appropriate regimen cannot be designed using all 5 drugs from Group A and B.​
    • Dlm and Am will not be initiated in the final 12 months of treatment.​
    • The duration of new drugs (Bdq or Dlm) is limited to 6 months. Extension beyond 6 months to be considered in patients with whom an effective regimen cannot be otherwise designed
    • Imipenem-Cilastatin (Imp-Cln) will only be used as a last resort.
    • In individual patients for whom the design of an effective regimen is not possible as per recommendations, BPaL regimen (Bedaquiline, Pretomanid, Linezolid regimen) can be considered as a last resort under prevailing ethical standards.​

     

    To modify the regimen, the Nodal and District Drug-resistant TB Centre (N/DDR-TBC) physician must review DST and patient profile and then suitable regimen to be designed based on the replacement sequence table given in the Programmatic Management of Drug-resistant TB (PMDT) guideline.

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