DR-TB refers to the presence of drug resistance to any of the first-line or second-line drugs. The definitions below explain the terminology used for various types of drug resistance. Resistance to some key drugs has more severe consequences than others, e.g. resistance to INH or Rifampicin clearly compromises the initial four-drug therapy. Likewise, additional resistance to Group A second line drugs like Fluoroquinolones (FQ) or newer drugs like Bedaquiline or Linezolid in a patient with MDR-TB seriously impacts therapy with second-line drugs.

Prevalence of MDR-TB, i.e. M. tuberculosis resistant to isoniazid and Rifampicin with or without resistance to other drugs, is estimated to be about 2.8% (2.3–3.5) among new cases and 14% (12–17) among the previously treated patients[1].

Minimal data is available regarding MDR-TB in children. In children, it primarily results from the transmission of drug-resistant bugs from the source case (usually adolescents and adults). Less commonly, it does also result from previous inadequate TB treatment. The prevalence of MDR-TB in children mirrors MDR-TB in adults. Thus, it is common in settings where the MDR-TB pool exists in adults and is associated with higher morbidity and mortality than the drug-sensitive disease.  

 

Based on the pattern of drug resistance, the cases may be further classified for treatment purposes as:

a. Mono-resistant TB (MR-TB). A TB patient whose biological specimen is resistant to one first-line anti-TB drug only.

b. Isoniazid-resistant TB (Hr-TB). A TB patient whose biological specimen is resistant to isoniazid and susceptibility to Rifampicin has been confirmed.

c. Poly-drug resistant TB (PDR-TB). A TB patient whose biological specimen is resistant to more than one first-line anti-TB drug, other than both H and R.

d. Rifampicin-resistant TB (RR-TB). A TB patient whose biological specimen is resistant to R detected via phenotypic or genotypic methods, with or without resistance to other anti-TB drugs. It includes any resistance to R in the form of mono-resistance, poly-resistance, MDR or XDR.

e. Multidrug-resistant TB (MDR-TB). A TB patient whose biological specimen is resistant to both H and R with or without resistance to other first-line anti-TB drugs. MDR-TB patients may have additional resistance to any/all FQ or any other anti-TB drug.

f. Pre-extensively drug-resistant TB (Pre-XDR-TB). TB is caused by Mycobacterium tuberculosis strains that fulfil the definition of MDR/RR-TB and are also resistant to any fluoroquinolone.

g. Extensively drug-resistant TB (XDR-TB). TB is caused by Mycobacterium tuberculosis strains that fulfil the definition of MDR/RR-TB and are also resistant to any fluoroquinolone (levofloxacin or moxifloxacin) and at least one additional Group A drug (presently to either bedaquiline or linezolid [or both]).

h. Extensive (or advanced) TB disease refers to the presence of bilateral cavitary disease or extensive parenchymal damage on chest radiography. 

i. Severe extrapulmonary TB refers to the presence of miliary TB or TB meningitis extrapulmonary forms of disease other than lymphadenopathy (peripheral nodes or isolated mediastinal mass without compression) are considered as severe (adapted from Wiseman et al., 2012 (7)).

 

A. Approach to Diagnosis of DR-TB in Children:

As there are no clinical disease patterns that can identify the presence of drug resistance in a given case, epidemiological markers, when present, can suggest possible DRTB. However, these markers are not always present. Moreover, first-line drug regimens fail and have an added risk of amplifying resistance to other companion drugs if resistance to Rifampicin and INH is present. Therefore, there has been a shift to identifying the presence of these key resistance in all TB patients at diagnosis (universal DST), replacing the earlier approach of targeted testing for DRTB among the patients more likely to harbour drug resistance strain (presumptive DR-TB cases). Universal DST (U-DST) refers to universal access to rapid DST for at least Rifampicin (and where possible INH). It also includes DST for fluoroquinolones among all TB patients with Rifampicin resistance (preferably before initiation of treatment or as soon as possible).

 

Epidemiological Markers for DR-TB:

Important epidemiological markers for DR-TB include: 

  • finding a history of contact with suspect MDR
  • details of previous poor treatment (inadequate drugs, dosage and duration) and lack of adherence
  • in a patient not responding to therapy, or those with recurrence of disease after previous treatment, as such cases could be harbouring a drug-resistant strain.  
  • it must be added that the causes of non-response to anti-TB therapy include incorrect diagnosis of TB, poor adherence, paradoxical upgrading reactions, and other untreated coexisting or inter-current co-infections.  
  • TB among Children living with HIV (CLHIV) or those in contact with someone dying of TB is also found to have a higher likelihood of DRTB. 

 

Confirmation of Drug Resistance:

Confirmation of drug resistance is always by microbiological methods (genotypic and phenotypic). Getting appropriate body fluid samples for pulmonary or EPTB patients is crucial for mandatory microbiological confirmation and drug susceptibility testing. For this, sputum (or other alternative respiratory specimens, e.g. gastric aspirate or lavage for swallowed sputum, induced sputum, bronchoscopic lavage) or other relevant specimens like lymph node aspirates, CSF analysis, pleural or pericardial or peritoneal fluid, tissue biopsies must be collected in all children with presumed DR-TB for NAAT (e.g. Truenat/ Xpert M.TB  RIF), LPA and culture and drug sensitivity testing. This may imply a referral to a higher centre to facilitate detailed and sometimes invasive testing.

In a presumptive DR-TB patient, if all efforts for microbiological confirmation have failed or confirmation is not possible due to inaccessible specimen, but the clinical probability of it being DRTB is high (failure of adequate first-line therapy and/or close contact of a proven MDR-TB case), and there is no alternative diagnosis or explanation for non-response the patient may be treated as a clinically diagnosed DR-TB (Probable MDR-TB).   In such situations, drug regimen can be decided based on the drug sensitivity pattern of the DRTB contact (likely source case), where available. Moreover, the patients considered to have 'probable' MDR-TB should be presented to and discussed with the DR-TBC Committee for confirming the decision to treat in consultation with a paediatrician. 

Furthermore, in children with a severe disease like central nervous system TB or other life-threatening manifestations who have substantial risk factors for DR-TB, treatment as probable MDR-TB can be initiated, pending confirmation, in consultation with the paediatrician in the Nodal DR-TB Centre (NDR-TBC) committee, given their high risk of mortality. Further treatment in such situations can be decided based on their test results as and when available.

 

 

 

 

 

Box 5. Probable MDR-TB Among Children

 

 

 

 

 

Box 6. Confirmed Drug-resistant TB cases

 

 

 

Additional Consideration:

Practitioners need to know which medicines have frequently been used in a given geographical setting or patient group. Moreover, practitioners should strive to test for drug resistance and limit empiric treatment to a minimum despite some uncertainties about DST. The patient's clinical response to treatment should constantly be carefully monitored. If there is poor treatment response, undiagnosed resistance should be considered, as should alternative explanations for failure to respond to treatment (e.g. poor or erratic adherence to treatment, immune reconstitution inflammatory syndrome (IRIS) or the presence of comorbidities.

 

B. Methods for Drug Susceptibility/Drug Resistance Testing:

I. Drug Resistance Tests Using Molecular Methods: 

This can be performed on sputum specimens (direct) or culture isolates (indirect) for diagnostic purposes. Presently the following technologies are available for diagnosis of DR-TB through rapid molecular diagnostic testing:

a. Nucleic Acid Amplification Test (NAAT) (viz. Xpert MTB RifTM test using the Gene-Xpert platform /TrueNatTM): These NTEP approved, cartridge / chip-based NAATs can be performed on smear-positive, smear-negative and extrapulmonary specimens as they can detect DNA even with few copies. The tests detect M. tb as well as resistance to Rifampicin in the MTB. The test time is about two hours.

b. Line Probe Assay (LPA) refers to molecular test(s) used for (a) detection of MTB complex and rapid diagnosis of R and H resistance (FL-LPA), (b) resistance to class FQ and class SLID (SL-LPA). LPA needs many DNA copies (over 10,000 per ml) for detection and thus can be used directly only on smear-positive specimens. The processing time is 72 hours each for both first- and second-line LPA. In addition, LPA can be used for genotypic drug sensitivity on an isolate from culture (like MGIT) from any specimen, including smear-negative samples. This mixed-method approach could decrease turnover as the phenotypic sensitivity testing would take weeks compared to a few days with LPA.

c. Xpert M.TB /XDR

This newer version of Cartridge Based NAAT can detect mutations associated with resistance towards H, FQ, SLI and Eto in a single test, using a semi-quantitative nested PCR followed by high-resolution melt technology. It requires GeneXpert platforms equipped with 10-colour modules. Test processing time is about 90 minutes.  

  • When endorsed, the test is suited to follow molecular tests that detect M. TB/Rifampicin resistance. 
  • It can potentially improve access to rapid drug susceptibility testing, especially for ruling out fluoroquinolone resistance, which is required before starting the shorter oral Bedaquiline-containing MDR/RR-TB regimen.

 

These methods are PCR-based and cannot be used for determining response to treatment, unlike a smear.

 

II. Growth-Based Phenotypic Drug Susceptibility Testing:

M. tb Culture, though a highly sensitive and specific method for TB diagnosis, requires 2-8 weeks to yield results and hence does not allow rapid confirmation, unlike molecular tests. Culture, however, needs to be used for long-term follow-up of patients on DR-TB treatment and help detect early recurrence in both drug-sensitive and drug-resistant TB. The growth-based phenotypic culture methods include automated Liquid culture systems, e.g., BACTEC MGIT 960, BacTAlert or Versatrek etc., and solid (Löwenstein Jensen) media. 

 

Mycobacteria growth indicator tube (MGIT) is currently the preferred method for DST under NTEP, and both first and second-line anti-TB drugs sensitivity can be tested by this method. Following drugs can be tested for susceptibility by liquid culture:

  • First-line drugs: R, H, E, Z
  • Second-line drugs: S, Lfx, Mfx, Km, Cm, Am, Lzd, Cfz*, Bdq*, Dlm etc.

 

Phenotypic testing also determines the critical inhibitory concentrations of various drugs to guide therapy. It could save time by running a molecular genotypic test (LPA) on a culture isolate if the initial specimen was unsuitable due to smear negativity. 

 

Important notes to microbiological testing and result interpretation:

  • Ideally, two specimens should be collected from every patient and sent to the NAAT facility, who shall run the NAAT and transmit or test the other aliquot for M. tb culture.
  • Samples must be transported immediately after collection to the linked laboratory for appropriate testing. Standard Operating procedure for triple-layer packaging must be strictly adhered to, and the sample must be transported in a cold chain. Samples must not be batched. 
  • EPTB samples should not be collected in Formalin for bacteriological tests (genotypic as well as phenotypic).
  • Airborne Infection Control (AIC) measures must be followed at all times. Biomedical Waste Management must be ensured.
  • If R resistance is detected on NAAT, the patient is offered First Line (FL) and Second Line (SL) LPA followed by LC DST as indicated in the algorithm.
  • If R resistance is detected with a very low level of M. tb in a patient with low clinical suspicion, it should be confirmed by a repeat specimen for NAAT.
  • Suppose R resistance is not detected on NAAT. In that case, the patient is offered FL LPA for detecting resistance to H. All H resistant patients are subsequently offered SLLPA followed by LC DST as indicated in the algorithm.
  • Treatment is initiated based on LPA results and modified based on the LC DST results, available later.
  • Phenotypic DST for ethambutol, ethionamide may be inaccurate and not reproducible. No agreed DST methods had been established for some other second-line drugs [e.g. cycloserine/terizidone, imipenem- cilastatin/meropenem and P-Aminosalicylic Acid (PAS)].

 

 

C. Integrated Drug Resistant TB Algorithms

 

 

 

 

 

 

Figure 5. Integrated diagnostic and treatment algorithm for drug resistant tuberculosis

 

 

 

 

 

Figure 6. Algorithm approach to diagnosis of DR-TB in children

 

 

 

 

  Figure 7. Specimen Flow and Operational Processes

 

 

5.1.  Treatment of Drug Resistant TB in Children

Compared to drug-susceptible TB (DS-TB) treatment, DR-TB regimens require a longer course, higher pill burden, and higher toxicity profile, resulting in lower adherence and poorer treatment outcomes, including deaths. The principles of designing a WHO-recommended regimen section also applies to the paediatric population. 

  • Include at least 4-5 effective medicines from Group A and B to which the Mycobacterium tuberculosis strain is known or likely to be susceptible.
  • Do not add a single drug to a failing regimen to avoid amplification of resistance.
  • Strict monitoring of treatment by clinical examination, radiology and culture response to be undertaken by paediatrician/ expert available/ linked to DR-TBC.

Children aged five to less than 18 years of age and weighing at least 15 kg are eligible for both Shorter or Longer oral MDR/RR-TB regimens. Furthermore, the pre-treatment evaluation carried out at the treatment initiation can be considered valid for one month from the test result. The patient can be re-initiated on a subsequent regimen based on this. In addition, long term follow-up will be done with six-monthly cultures among symptomatic patients till two years after completion of any DR-TB regimen, i.e. months 6, 12, 18 and 24 post-treatment. Lastly, Active Drug Safety Management and Monitoring (aDSM) treatment initiation form need to be completed for all DR-TB patients at the time of initiation of each new episode of treatment.

 

5.1.1. Grouping of Drugs

The anti-TB drugs recommended for MDR/RR-TB patients are grouped based on efficacy, the experience of use, drug class and aligned with revised classification as per WHO Consolidated Guidelines for TB Module 4: Treatment of Drug-Resistant TB (2020). 

 

 

 

 

 

 

Table 6. Grouping of anti-TB drugs and steps for designing a longer MDR-TB regimen

 

 

 

5.1.2. Standard DR-TB Regimens Available Under NTEP

The NTEP Treatment Expert group (Paediatric), India, has agreed to the following regimens for our country, keeping in view the WHO advice. 

 

 

 

 

 

 

 

Figure 8. Treatment Algorithm for DR-TB in Children

  • * As per the exclusion criteria (mentioned in details in this chapter and Annexure 6) for the shorter MDR-TB regimen, while considering the option of longer oral regimen, shortening the total treatment duration may be considered depending upon the response (12 to 18 months) but not less than 12 months in any case.
  • ** Can be given in all children with extensive disease.  However, for children under five years of age where neither Bdq nor Dlm is approved yet, the longer oral M/XDR-TB regimen is suitably modified with replacement of Group C drugs for longer oral M/XDR-TB regimen in the sequence of -  amikacin, pyrazinamide, ethionamide, PAS, ethambutol, penems.
  • ***In conditions like: extensive pulmonary disease; uncontrolled underlying morbidity; extrapulmonary TB (other than isolated pleural effusion or peripheral lymphadenopathy) or any change in the standardized regimen necessitated by drug resistance or intolerability to any drug of the regimen, the therapy is increased to 9 months. For cases with spinal and neuro TB, the total duration is 12 months.
  • #dose of Lzd will be tapered to 300 mg after the initial 6–8 months of treatment

 

5.1.3. Special Considerations for M/XDR-TB in Children
  • Always treat in consultation with an expert, preferably paediatrician available/ linked.
  • Bedaquiline(Bdq) will be given to children more than five years of age weighing 15kg or more.
  • Delaminid(Dlm) will be given to children six years onwards. Although WHO has approved the use of Dlm in the age group 3-5 years, the regulatory approval in India is awaited.
  • Delaminid(Dlm) will be considered only as a replacement in a longer oral M/XDR-TB regimen.
  • To modify the longer oral M/XDR-TB regimen, the N/DDR-TBC physician must review the resistance pattern, tolerability history, contraindications, and availability of first and second-line drugs to identify the number of drugs from Group A and Group B that need to be replaced.
  • In special situations, an extension of Bdq beyond six months and concomitant use of Bdq and Dlm can be done.
  • The regimen should preferably be entirely oral. However, injectables may have to be used for efficacy and side-effect profile in certain circumstances.
  • The avoidance of an injectable-containing regimen is particularly desirable in children. Given the profound impact that hearing loss can have on the acquisition of language and the ability to learn at school, the use of injectable agents in children should be exceptional under strict monitoring to ensure early detection of ototoxicity.
  • For paediatric patients, the drug dosage should be adjusted immediately once the patient's weight crosses the range of weight-band and counselling regarding the change in weight band and the change in the number of pills that need to be consumed.
  • Child-friendly (dispersible and palatable) formulations should be used whenever available.
  • Bedaquiline tablets suspended in water have been shown to have the same bioavailability as tablets swallowed whole and can therefore be used to treat drug-resistant TB in children until a child-friendly formulation becomes available.
  • Clavulanic acid should be included in MDR/RR-TB regimens only as a companion agent to the carbapenems (Imp-Cln and Mpm). When used in this way, it should be given with every dose of carbapenem and should not be counted as an additional effective TB agent.
  • Seizures may be more common in children with meningitis treated with imipenem, and meropenem is preferred for cases of TB meningitis and in children.
  • The monitoring of DR-TB treatment in children is the same as in adults. However, for probable MDR-TB patients, the paediatrician available at or linked to the N/DDR-TBC must regularly evaluate the child's progress on treatment and initiate any other investigations as deemed necessary.

 

5.2. (H) mono/poly DR-TB regimen in Children

(6) Lfx R E Z
  • Duration is of 6 or 9 months with no separate IP/CP.
  • The patient is initiated on (6) Lfx R E Z when found to be resistant to INH (but not Rifampicin) based on the First-line Line Probe Assay (FL-LPA) report. The regimen could be modified subsequently based on SL-LPA results.
  • If H mono/poly DR-TB is detected, the FL- LPA deposit is subjected to SL-LPA by the lab and LC-DST to Mfx, Z, Lzd, Cfz*(*Whenever DST is available).
  • If there are signs of non-response, the patient must be subjected to NAAT again to rule out amplification of Rifampicin resistance and further LPA and DST.
  • In conditions like - extensive disease, uncontrolled comorbidity, extrapulmonary TB or any change in drug of standardized regimen due to additional drug resistance or intolerability to any drug, the regimen is increased to 9 months.
  • In exceptional situations of unavailability of loose drug R or E or Z, the use of 4 FDC (HREZ) with Lfx loose tablets may be considered as an option rather than not starting the treatment.
  • The dosage of drugs would vary as per the weight of the patients.
  • All drugs in the regimen are to be given daily under observation.

 

 

5.2.1. Replacement Sequence

Replacement is done in case of additional resistance, intolerance, unavailability or contraindication of the component drugs of the regimen.

 

 

 

 

 

 

*whenever DST is available

Table 8. Standard Replacement sequence of drugs to modify H mono/poly DR-TB regimen

 

 

5.2.2 Follow up Monitoring

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 9. Follow up evaluation schedule of H mono/poly DR-TB patients

  • 1Lzd containing regimen to rule out bone marrow suppression
  • 2 HBsAG and other viral markers (Hepatitis A, C & E) to be done in case of Jaundice
  • 3 In case of baseline ECG abnormality or QTcF ≥450ms for regimen containing Mfx(h) or Cfz, ECG must be done on daily basis for initial 3 days or as suggested by cardiologist. Repeat ECG with long II lead after an hour to reconfirm abnormal ECG.
  • DST whenever available
  • Urine Pregnancy Test (UPT)

 

5.3. Shorter oral Bedaquiline-containing MDR/RR-TB Regimen

(4-6) Lfx, Cfz, Z, E, Hh, Eto (6) Bdq | (5) Lfx, Cfz, Z, E
Eligibility Criteria

Children, aged five years to less than 18 years of age and weighing at least 15 kg, in consultation with a paediatrician

A. Inclusion Criteria

I. DST based inclusion criteria

  • Rifampicin Resistance detected/inferred
  • MDR/RR-TB with H resistance detected/inferred based on InhA mutation only or based on KatG mutation only (not both)
  • MDR/RR-TB with FQ resistance not detected

II. Non-DST based inclusion criteria

  • No history of exposure to previous treatment with second-line medicines in the regimen (Bdq, Lfx, Eto or Cfz) for more than one month (unless susceptibility to these medicines is confirmed);
  • No extensive TB disease
  • No severe extrapulmonary TB
  •  

B. Exclusion criteria

I. DST based Exclusion Criteria

  • MDR/RR-TB patients with H resistance detected with both KatG and InhA mutation or MDR/RR-TB patients with FQ resistance detected

II. Other Exclusion Criteria

  • those with a history of exposure for > 1 month to Bdq, Lfx, Eto or Cfz. (If the result for FL-LPA, SL-LPA and DST to Z, BDQ & Cfz is not available)
  • Intolerance or risk of toxicity from a drug in shorter oral Bedaquiline-containing MDR/RR-TB regimen.
  • Extensive TB disease: bilateral cavitary disease or extensive parenchymal damage on chest radiography. 
  • In children aged under 15 years, presence of cavities or bilateral disease on chest radiography.
  • Severe EP-TB disease: the presence of miliary TB or TB meningitis or central nervous system (CNS) TB.
  • In children aged under 15 years, extrapulmonary forms of disease other than lymphadenopathy (peripheral nodes or isolated mediastinal mass without compression)
  • Children below five years 

 

C. Duration of Regimen

  • The regimen consists of an initial phase of 4 months that may be extended up to 6 months and a continuation phase of 5 months, giving a total duration of 9–11 months. Bdq is used for a duration of 6 months.
  • From start to the end of 4 months: Bdq, Lfx, Cfz, Z, E, Hh, Eto   
  • From the start of 5 months to end of 6 months – (If IP not extended) – Bdq, Lfx, 
  • From the start of 6 months to the end of 9 months – Lfx, Cfz, Z, E
  • If the IP is extended up to 6 months, then all three drugs Bdq, Hh and Eto, are stopped together.

 

D. Treatment Extension

 If sputum smear microscopy does not become negative by the fourth month of the treatment, subject the patient to FL-LPA, SL-LPA and culture & DST, and the IP should be extended. IP can be extended to the 5th or 6th month based on smear results at the end of the 4th and 5th months of treatment. T (total duration of IP is not more than six months). If any additional resistance to Z/Cfz on C&DST of the baseline sample is detected or to FQ/ inhA mutation of the 4th-month sample is detected, the patient needs to be reassessed at N/DDR-TBC for stopping shorter oral Bedaquiline-containing MDR/RR-TB regimen and initiation of longer oral M/XDR-TB regimen, immediately on receiving the report. The duration of CP is fixed for five months.

Details on erstwhile Shorter Injectable Containing Regimen could be found in Annexure 6.

 

E. Pre-Treatment Evaluation

 

 

 

 

 

 

Table 10.  Pre-Treatment Evaluation for Shorter oral Bedaquiline-containing MDR/RR-TB Regimen

 

 

F. Follow-up evaluation schedule during treatment

 

 

 

 

 

 

 

 

 

 

Table 11.  Follow-up evaluation schedule for Shorter oral Bedaquiline-containing MDR/RR-TB Regimen

 

  • If smear/ culture remains positive at the end of the third month or by the end of IP respectively or extended IP, a fresh specimen/culture isolate of that time will be subjected to FL-LPA and SL-LPA to check for amplification of resistance to FQ and H (both inhA and katG mutation).
  • If no additional resistance is detected, the IP is extended monthly up to a maximum of 6 months.
  • If bacteriological reversion is ascertained or if FL-LPA or SL-LPA detects any resistance or if found to be smear/culture positive at the end of six months or later, the patient will be declared as ‘treatment failed’ and re-evaluated for the longer oral M/XDR- TB regimen.
  • Once treated with the shorter oral Bedaquiline-containing MDR/RR-TB regimen for more than one month, a patient will never be reinitiated on it again.

 

 5.4. Longer oral M/XDR-TB Regimen

(18-20) Lfx, Lzd[2], Cfz, Cs (6)Bdq (6 m or longer)

 

A. Duration of Regimen                            

18-20 months with no separate IP or CP

 

B.  Eligibility Criteria

  • MDR/RR-TB patients who are excluded from shorter oral Bedaquiline-containing MDR/RR-TB regimen.
  • Additional resistance to any second-line drugs, especially Lfx, Mfx, Bdq* Lzd*, Cfz*, Dlm* and Z (*whenever available) or intolerance or non-availability of any drug in use.
  • Return after Lost-To-Follow Up (LTFU) or failed to shorter oral Bedaquiline-containing MDR/RR-TB regimen or any longer regimen.
  • However, as mentioned previously, for children under five years of age where neither Bdq nor Dlm is approved yet, the longer oral M/XDR-TB regimen is suitably modified as per the replacement sequence.

C. Pre-treatment evaluation (PTE)

The list of investigations enumerated for shorter oral Bedaquiline-containing MDR/RR-TB regimen will remain applicable to longer oral M/XDR-TB regimen. Additional investigations specific to group C drugs that may be required in situations where the longer oral M/XDR-TB regimen may need to be modified are as under:

  • Blood Urea & Serum Creatinine – if Am need to be added
  • Ophthalmologist opinion (for Linezolid)
  • Surgical evaluation for consideration after culture conversion is achieved

Once a patient is placed on the longer oral M/XDR-TB regimen for at least four weeks, such a patient can no longer be switched to the shorter oral Bedaquiline-containing MDR/RR-TB regimen because this 4-weeks treatment would represent exposure to second-line medicines.

D. Treatment Extension

  • Total duration of longer oral M/XDR-TB regimen is 18-20 months.
  • After month 6 of treatment, the patient is reviewed based on the month five culture result. If the month five culture result is not available at the end of month 6, the decision to taper the dose of Lzd from 15mg/kg body weight to 10 mg/kg body weight based on the month four culture result.
  • If the month 5 or 4 culture result (whichever applicable) remains positive, the dose of Lzd (15 mg/kg) and the regimen is extended by one month to month seven and for a maximum till month eight based on monthly culture results of month 6 and 7 respectively and clinical/radiographic response.
  • If the month eight culture is also positive, subject the culture isolate to FL-LPA and SL-LPA and Culture & DST.
  • If any additional resistance to Group A, B or C drugs in use is detected, the patient needs to be reassessed at N/DDR-TBC to modify the longer oral M/XDR-TB regimen.
  • The duration of Bedaquiline is limited to 6 months.
  • Extension of Bedaquiline beyond six months is considered in patients in whom an effective regimen cannot be designed, i.e. if only 2 of 5 drugs are available from Groups A & B and an adequate number of Group C drugs are not available due to high background resistance, non-availability or unreliability of DST.
  • The maximum duration of treatment is not more than 20 months.
  • A treatment duration of 15–17 months after culture conversion is suggested for most patients; the time may be modified according to the patient’s response to treatment.
  • In XDR-TB patients, the duration of all oral longer regimen is of 20 months.

 

E. Replacement Sequence:

As per the 2021 Guidelines for PMDT in India following principles apply to the replacement of any of the component(s) in the longer oral M/XDR-TB regimen:

  • The drugs replacement is based on efficacy, no demonstrable resistance, prior use, side-effects profile and background resistance to the replacement drug in the country as per the National Drug Resistance Survey (NDRS) report.
  • The regimen should preferably be entirely oral.
  • Sometimes injectables may be used based on efficacy and side-effect.
  • 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.
  • In situations where no drug replacement is required in the first 6 or 8 months of treatment in MDR-TB or XDR-TB patients, continue with at least three drugs after this depending upon resistance, tolerability, availability, contraindication etc. of any one of Group A or B drugs.
  • Replacement sequence of Group C drugs for longer oral M/XDR-TB regimen was recommended in the order of - Delamanid, Amikacin, Pyrazinamide, Ethionamide, PAS, Ethambutol, Penems.
  • Combined use of Bdq and Dlm in the regimen is recommended for those M/XDR-TB patients in whom an appropriate regimen cannot be designed using all five drugs from Group A and B.
  • Dlm and Am will not be started in the final 12 months of treatment.
  • Though Imp-Cln is 4th in the sequence of drugs of group C in WHO guidelines, it will only be used as the last resort for designing the regimens, operational issues of a Peripherally Inserted Central Catheter (PICC) placement for the entire duration of its use, need for admission.
  • Table for replacement sequence of using drugs to modify the longer oral M/XDR-TB regimen is placed as annexure (Annexure 5)

 

F. Follow-up Monitoring

 

 

 

 

 

 

 

 

 

 

 

Table 12.  Follow up evaluation schedule of longer oral M/XDR-TB regimen during treatment

  • ^ If Lzd is part of the regimen to rule out bone marrow suppression.
  • # HBsAG and other viral markers (Hepatitis A, C & E) to be done in case of Jaundice.
  • $ In case of baseline ECG abnormality or QTcF ≥450ms with longer oral M/XDR-TB regimen that contains Bdq, Mfx, Cfz or Dlm, ECG must be done on daily basis for initial 3 days or as suggested by cardiologist. Repeat ECG with long II lead after an hour to reconfirm abnormal ECG.
  • * DST whenever available.

 

G. Management of Treatment Interruptions and Lost to Follow-up

 

Patients Who Miss Doses:

All missed doses during IP must be completed before switching the patient to CP. Similarly, all missed doses during CP must be administered prior to ending treatment.

Patients who interrupt treatment for less than two months: The treatment will be continued, and the duration of treatment will be extended to complete the regimen. The follow-up cultures will be done as per the schedule. An additional culture may be considered if the patient returns between one to two months of treatment and has clinically deteriorated. 

  • If the culture is positive - repeat FL/SL LPA, and LC DST need to be done as per diagnostic algorithm. If additional resistance is detected to any component drugs, the patient will be switched to the longer oral M/XDR-TB regimen with a fresh PTE. 
  • If the interruption is in IP, the outcome will be accounted for this patient for the longer oral M/XDR-TB regimen only. If the interruption is in CP, the outcome for a shorter oral Bedaquiline-containing MDR/RR-TB regimen will be declared ‘treatment failed’.

Patients who are “lost to follow-up” (interrupt treatment continuously for two months or more) - give an outcome of “lost to follow-up”. 

  • Subject to repeat NAAT & FL/SL-LPA and LC-DST as per the diagnostic algorithm to restart with appropriate treatment. 
  • Suppose there are signs of impending treatment failure for any MDR/RR-TB patient with or without additional resistance to second-line drugs. In that case, the patient should be switched to the longer oral M/XDR-TB regimen and evaluated further to modify appropriately based on DST results.
  • If a patient has received the shorter oral Bedaquiline- containing MDR/RR-TB regimen for more than one month and returns for treatment after continuous interruption of two months or more, the patient is not restarted on a shorter oral Bedaquiline-containing MDR/RR-TB regimen.

 

H. Paediatric Drug Dosages

 

 

 

 

 

 

Table 13.  Paediatric Drug Dosages

 

 

[1] Central TB Division, MoHFW G of I. Report of the First National Anti-Tuberculosis Drug Resistance Survey India 2014-2016. Available at: https://tbcindia.gov.in/showfile.php?lid=3315

[2] dose of Lzd will be tapered to 300 mg after the initial 6–8 months of treatment