|THE EVOLUTION - THE VILLAIN OVERRIDE
|Year : 2017 | Volume
| Issue : 1 | Page : 53-62
Drug-Resistant tuberculosis: Key strategies for a recalcitrant disease
Department of Tuberculosis and Respiratory Diseases, National Institute of Tuberculosis and Respiratory Disease, New Delhi, India
|Date of Web Publication||6-Nov-2017|
Department of Tuberculosis and Respiratory Diseases, National Institute of Tuberculosis and Respiratory Disease, New Delhi
Source of Support: None, Conflict of Interest: None
Over half million cases of multidrug-resistant (MDR) tuberculosis (TB) occur every year globally, and a significant number of them are affected by extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis. There is limited access to reliable diagnostic facilities to drug-resistant (DR) TB in most developing countries. The treatment of MDR/XDR-TB is unfortunately very expensive, long, and toxic and the success rate is largely unsatisfactory (<50% among MDR-TB and <20% among cases with resistance patterns beyond XDR).The aim of this review is to summarize the available evidence-based updated international recommendations to diagnostic methods and treatment of MDR/XDR-TB, and briefly discuss the shorter MDR-TB regimen and the role of newly developed drugs as well as repurposed drugs. This review will help the reader to formulate treatment regimen for DR-TB patients based on currently available newer rapid diagnostic tests.
Keywords: MDR-TB, new drugs for TB, tuberculosis, XDR-TB
|How to cite this article:|
Singla R. Drug-Resistant tuberculosis: Key strategies for a recalcitrant disease. Astrocyte 2017;4:53-62
| Introduction|| |
Multidrug resistance (MDR) tuberculosis (TB) is a form of TB caused by Mycobacterium tuberculosis that is resistant to isoniazid and rifampicin. The emergence of drug resistance is a major threat to global TB care and control. World Health Organization (WHO) has recently launched its innovative “End TB Strategy” with the vision of a TB-free world aiming at zero death, disease, and suffering due to TB. The new strategy supports universal access to high-quality MDR-TB diagnosis and treatment. Currently, most developing countries do not have easy access to rapid diagnostic methods for drug-resistant tuberculosis (DR-TB). Also, the treatment of DR-TB is unfortunately long and contains drugs which are expensive and frequently have adverse effects. There is a need for physicians to update themselves about the current international and national recommendations concerning the diagnosis and treatment of various forms of drug-resistant TB including newer drugs.
| Epidemiology|| |
As per the Global TB Report released in 2016, in 2015, there were an estimated 480,000 new cases of MDR-TB, and an additional 100,000 people with rifampicin-resistant TB (RR-TB) who were also newly eligible for MDR-TB treatment. India, China, and the Russian Federation accounted for 45% of the combined total of 580,000 cases. Although the number of TB deaths reduced by 22% between 2000 and 2015, TB remained one of the top 10 causes of death worldwide in 2015. The crisis of MDR-TB detection and treatment continues. In 2015, of the estimated 580,000 people newly eligible for MDR-TB treatment, only 125,000 (20%) were enrolled. Globally, the MDR-TB treatment success rate was 52% in 2013 cohort.
Regarding children, Dodd et al. used mathematical modeling and estimated that a median (IQR) of 9% (2.7–3.1) incident TB disease in children were MDR-TB. In India, the 2016 annual report of RNTCP  reported MDR-TB among new pulmonary cases and retreatment pulmonary cases to be 2.2% (95% CI: 1.9–2.6%) and 15% (11–19%), respectively. WHO has estimated that, in 2015 in India there were 130,000 estimated cases of MDR-TB.
As per the Global 2016 report  an estimated 9.7% of people with MDR-TB develop extensively drug-resistant TB (XDR-TB) [Box 1]. As of 2015, XDR-TB had been reported by 117 countries.
| Factors Associated With the Development of Drug Resistance|| |
Drug resistance in TB develops from the natural spontaneous mutation among the bacilli. The frequency of natural mutation occurrence is more with streptomycin and isoniazid and is around 1:100000 bacilli. For rifampicin, it is more uncommon with approximately 1 in 100 million bacilli. Therefore, the frequency of naturally occurring mutation leading the MDR-TB is very uncommon. However, some factors lead to the selection of naturally occurring resistant mutants leading to MDR or XDR-TB.
Factors associated with the development of drug resistance include misuse of anti-TB drugs, premature termination of the treatment by the patients, poor quality of drugs, poor bioavailability of anti-TB drugs when used in combinations (especially when isoniazid and rifampicin are combined), nonavailability of anti-TB drugs due to poor drug supply, poorly running TB control program in the country, and poor absorption of anti-TB drugs.
Misuse of anti-TB drugs refers to the prescription of inadequate treatment regimen which includes inappropriate combination of drugs, inappropriate dosages, inadequate duration, and adding a single drug to a failing regimen. This is among the most prominent preventable factors causing acquired drug resistance. Most of these factors can be taken care of by ensuring that the patients take proper regimen with adequate doses of the drugs regularly for the entire treatment duration. Each country needs to take adequate steps to prevent misuse of the first-line and second-line anti-TB drugs.
There is also evidence that in the community primary transmission of MDR-TB is occurring from index cases to the contacts, highlighting the need for infection control practices in health care facilities and in households besides early and adequate treatment of all drug-resistant TB patients.
Genetic basis of drug resistance to anti-tubercular drugs
In the past few years, mutation in some genes have been identified which are associated with the development of drug resistance against specific anti-TB drugs. The following are some of the known genes mutations for some commonly used anti-TB drugs:
- Isoniazid: katG (usually results in high level resistance), inhA (resulting in low level resistance), other genes are kasA, ndh, and the oxyR-ahpC,fadE24, Rv1592c, Rv1772, Rv0340, and iniBAC
- Rifampicin: rpoB – (responsible for >96% of rifampicin resistance, codes for the β-subunit of the RNA polymerase – decreases affinity of rifampicin to bind to the protein)
- Pyrazinamide: pncA – (mutations result in lost or reduced pyrazinamidase activity), other genes are rpsA and panD
- Ethambutol: embB (codon 306), embC-embA intergenic region
- Streptomycin: rpsL and rrs, gidB
- Fluoroquinolones: gyrA and gyrB, which code the α and β subunits of the bacterial enzyme Topoisomerase II
- Kanamycin/Amikacin: position 1400 and 1401 of the rrs gene, promoter region of the eis gene (low level resistance to kanamycin)
- Capreomycin: tlyA gene (rRNA methyltransferase)
- Ethionamide: etaA/ethA (monooxygenase required for activation of the prodrug), ethR and mutations in inhA, mshA (enzyme essential for mycothiol biosynthesis)
The identification of these genes has helped in the development of some genotypic tests which can rapidly identify drug resistance in patients within 2–3 days. The conventional tests usually take 1 month to 3 months.
Clinical conditions leading to suspicion of drug resistance
Drug resistance should be suspected in the following conditions:
- There is history of previous treatment with antitubercular drugs within the past 6–12 months
- Patient is taking the drugs irregularly
- There is history of contact with a person known to have DR-TB
- There is history of contact with any person who has died of TB or is nonadherent to TB treatment
- Failure to improve clinically after 2–3 months of first-line antituberculosis therapy, i.e. persistence of symptoms or failure to gain weight in children
- Persistence of AFB in smear or culture positivity at 2–3 months of ATT (if the patient was microbiologically confirmed to begin with)
- HIV-TB coinfection
The patients fulfilling any of the above conditions are labeled as “presumptive DR-TB” cases. Every attempt should be made to microbiologically confirm drug resistance in such patients so that the treatment can be guided as per the drug resistance pattern. Even under the Revised National Tuberculosis Control Programme in India, attempts are being made to offer DST-guided treatment. However, in many instances microbiological confirmation of drug resistance may not be available.
Clinical conditions leading to suspicion of XDR-TB
XDR-TB should be strongly suspected in the following conditions:
- Failure to improve clinically after 6 months of a MDR-TB treatment regimen containing fluoroquinolones and second-line injectables
- Persistence of sputum positivity after 6 months of MDR treatment regimen
- History of close contact with known case of XDR-TB
- History of close contact with any TB patient not responding to MDR treatment regimen
| Diagnostic Issues Related to Drug-Resistant Tuberculosis|| |
Whenever DR-TB is suspected, sputum should be sent for microbiological confirmation. In situ ations where a good sputum specimen is not available, other samples that can be sent include respiratory samples such as gastric aspirate/lavage in children, induced sputum, bronchoalveolar lavage; other site specific samples such as lymph node aspirate/biopsy, pus aspirate from cold abscess, CSF, ascetic fluid, and pleural fluid. The specimen should be examined by the investigations which include:
- Ziehl–Neelsen (Z-N) staining for AFB/fluorescence microscopy
- Phenotypic investigation methods which include conventional culture and drug sensitivity testing (DST)
- Genotypic investigation methods which include Xpert MTB/RIF or cartridge based nucleic acid amplification test (CBNAAT) and Line probe assay (LPA)
Phenotypic/conventional culture and drug sensitivity testing can be performed by using either solid culture or liquid culture.
- Solid culture – Lowenstein–Jensen and Middlebrook 7H10/11. The turnaround time for solid culture is long and can be up to 6–8 weeks and for DST it can be up to another 6–8 weeks.
- Liquid culture – MGIT960 (BD Diagnostics) and BacT/ALERT (BioMerieux SA, Marcy l'Etoile, France) systems. Another method of liquid culture i.e. BACTEC is used less often now. In liquid cultures, the turnaround time for culture and DST is less and is usually up to 3–4 weeks. Liquid cultures are preferred over solid cultures because of reduced turnaround time. However, liquid culture is more resource intensive and so very few laboratories have reliable liquid culture facility compared to solid culture
Genotypic/Molecular testing for resistance: Here, the information of known gene mutations association with drug resistance is utilized to diagnose drug resistance. The turnaround time for diagnosis may be only a few hours to 2–3 days only. Here another advantage is that the clinical specimen can be examined directly and there is no need for growth in culture medium. Commonly available genotypic methods include:
- Xpert MTB/RIF or cartridge based nucleic acid amplification test (CBNAAT) and
- Line probe assay (LPA)
Xpert MTB/RIF or cartridge based nucleic acid amplification test (CBNAAT) – Xpert® MTB/RIF (Cepheid). This test gives information whether M. tuberculosis is present or not and simultaneously regarding rifampicin resistance gene in rpoB region. Mutation at rpoB locus is approximately 95% sensitive and specific for true rifampicin resistance in M. tuberculosis. Another very important advantage of Xpert MTB/RIF is that it can detect up to 75% of smear negative pulmonary TB.
The turnaround time for results of Xpert RIF/MTB is only 2 hours. One disadvantage of Xpert RIF/MTB is that it cannot detect resistance against isoniazid. According to a systematic review published by WHO, for detection of rifampicin resistance in pulmonary TB, the pooled sensitivity of Xpert RIF/MTB was 95% (95% CI: 90–97%) and specificity was 98% (95% CI: 97–99%). In children, the sensitivity of Xpert RIF/MTB in detecting rifampicin resistance was 86% (95% CI: 53–98%). The sensitivity of Xpert RIF/MTB has been reported to be high for CSF, lymph node aspirates, and gastric aspirates. However, it is low for pleural fluid and other extrapulmonary specimens.
A new version, Xpert MTB/RIF ultra, is likely to increase sensitivity to smear positive cases to nearly 100% and to smear negative pulmonary TB to nearly 93% will be launched soon. Another version, GeneXpert Omni, is likely to hit the market soon which will be small, portable and operable by battery.
Line probe assay
(LPA) – LPA can be done on specimen directly (direct testing) or on M. tuberculosis culture isolates (indirect testing). Turnaround time is up to 72 hours. Its advantage is that, besides rifampicin resistance gene rpoB, this test gives information on isoniazid resistance genes inhA (low level resistance) and KatG (high level resistance). Two commercial LPAs endorsed by WHO  are:
- GenoType® MTBDRplus assay, Hain Lifescience
- Nipro Assay, Nipro Corporation
GenoType® MTBDRplus assay is commonly used in India. A meta-analysis  demonstrated that, for detecting rifampicin resistance, MTBDR plus assay has a sensitivity and specificity of 98.1% and 98.7%, respectively, and for detecting isoniazid resistance 88.7% and 99.2%, respectively. The version 2 of MTBDR plus assay can also be used on smear negative specimen and this is a great advantage.
In clinical practice, it is important to look for additional resistance against important second-line drugs such as injectables and fluoroquinolones before starting treatment for MDR-TB patients. WHO has approved  some second-line line probe assay (SL-LPA) such as Genotype® MTBDRsl assay, (Hain Lifescience, Nehren, Germany) for detecting resistance to second-line antitubercular drugs (fluoroquinolones) and second-line injectables. This test has very high specificity (98–99%) and is thus ideal for ruling in the presence of resistance against second line injectables and fluoroquinolones. However, due to their low sensitivity, absence of particular gene mutation does not rule out the presence of drug resistance, and these patients should be subjected to liquid culture for confirming the presence/absence of drug resistance.
Version 2 of Genotype® MTBDRsl assay has been approved by WHO  and has the advantage that it can be used in smear negative cases; the sensitivity for detection has been increased; and is more sensitive to the detection of kanamycin resistance as it can detect mutation for eis promotor gene.
WHO has recommended that for patients with confirmed rifampicin-resistant TB or MDR-TB, SL-LPA may be used as the initial test instead of phenotypic culture-based DST to detect resistance to fluoroquinolones and second-line injectables. Resistance conferring mutations detected by SL-LPA are highly correlated with phenotypic resistance to SLI, ofloxacin, and levofloxacin. However, correlation of mutations with phenotypic resistance to moxifloxacin and gatifloxacin is unclear, and the inclusion of moxifloxacin or gatifloxacin in a MDR-TB regimen is best guided by phenotypic DST results.
SL-LPA has been recommended by WHO to be used in children with confirmed rifampicin-resistant TB or MDR-TB based on the generalization of data obtained from adults.
Xpert MTB/RIF is a closed automated system which does not require highly skilled personnel or biosafety arrangements in the laboratory. It can be used in field conditions without the need of a sophisticated laboratory. However, LPAs require more training and safety precautions.
In retreatment cases, if rifampicin resistance is established by CBNAAT, the patient should be treated as DR-TB. However, as per the current recommendations in new cases of TB, another sample should be subjected to CBNAAT to confirm the resistance to rifampicin before starting the patient on MDR-TB regimen.
In all cases with suspected rifampicin resistance, liquid culture DST should also be performed at least for isoniazid, rifampicin, levofloxacin, and kanamycin and if feasible for other second-line injectables and moxifloxacin. If resistance is detected for any second-line injectable or fluoroquinolone, extended DST for other drugs such as high dose moxifloxacin, linezolid, and clofazimine should be performed. DST to INH can be known by LPA to decide about the inclusion of INH in the MDR-TB regimen. In case inhA mutation is detected, high dose INH can be given, and ethionamide (which is also associated with inhA mutation) may be replaced by drugs. If katG mutation is observed, then ethionamide can be retained in the MDR-TB regimen, with no role of high dose INH.
The concordance of molecular/genotypic testing and phenotypic drug testing is not 100%. Studies have demonstrated discordance between the two methods in the range of 4–10%. Rifampicin resistance detected by the molecular method need not be confirmed by the conventional phenotypic method. However, if rifampicin is reported to be sensitive by the genotypic method in a setting of high index of suspicion of DR-TB should be confirmed by phenotypic methods.
Diagnosis of drug resistance in extra-pulmonary TB and in children
Whenever drug resistant TB is suspected in extrapulmonary TB or in children, one should try to obtain appropriate specimen from the affected site. With the availability of radiological tools, such as CT scan and ultrasound, it has become easier to obtain specimen under guidance. The appropriate samples should be sent for MGIT culture and DST as well as molecular tests such as GeneXpert MTB/RIF assay and line probe assays before starting empiric second-line ATT.
| Principles of Designing a Mdr-Tb Regimen|| |
In August 2016, WHO released new guidelines for the management of MDR-TB/rifampicin resistant TB. Classification of drugs to be used in MDR-TB regimen has also been revised as per the new evidence and experience available [Table 1]. MDR-TB regimen should be designed based on the following principles:
|Table 1: New classification of drugs to be used in MDR-TB regimen as per WHO guidelines, 2016|
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- MDR-TB regimen should be composed of at least five drugs likely to be effective, including four core second-line drugs and pyrazinamide.
- An anti-TB drug is considered “likely to be effective” when:
- The drug has not been used in a regimen that failed to cure the individual patent
- DST performed on the patient's strain indicates that it is susceptible to the drug
- There is no known resistance to drugs with high cross-resistance
- There are no known close contacts with resistance to the drug
- Drug resistance surveys demonstrate that resistance is rare to the drug in patients with similar TB history
Among the four core drugs, one should be from group A, one from group B, and at least two from group C. Drugs in groups A to C are shown by decreasing order of usual preference for use [Table 1]If a minimum of four core second-line TB medicines cannot be reached by using agents from groups A to C alone [Box 1], drugs from group D2 or, if not possible, from group D3 are addedPyrazinamide is added routinely unless there is confirmed resistance from reliable DST or well-founded reasons to believe that the strain is resistant or there is risk of significant toxicity. If pyrazinamide is compromised or cannot be used, the regimen may be strengthened with an additional agent from group C or D (preferably D2, or if not possible, from D3)Agents from group D1 are added if they are considered to have added benefit (e.g., high-dose isoniazid in patients without high-level isoniazid resistance). High dose INH refers to a dose range of 15–20 mg/kg/dayThe regimen be further strengthened, if required, with high-dose isoniazid and/or ethambutol, although the evidence for the same is very low
Kanamycin and amikacin are cheaper than capreomycin. Moreover, capreomycin has been shown to have ototoxicity than the aminoglycosides. There is high cross-resistance between amikacin and kanamycin, less so with capreomycin. Hence, if there is documented resistance to kanamycin or amikacin, capreomycin can be used instead. Streptomycin is not considered as a second-line anti-TB drug, because of the high rate of resistance to it, and is not included in the MDR-TB regimens. However, as there is little cross-resistance between streptomycin and the other three group B drugs streptomycin may be considered if there is resistance to all three second-line injectables.
Among the fluroquinolones, ciprofloxacin has very weak anti-TB activity and should not be used. Ofloxacin has been found to have a weaker anti-TB activity and has now been removed from the standardized regimen for MDR-TB in many countries. It is advisable to use the later generation fluoroquinolones such as moxifloxacin and levofloxacin. Use of gatifloxacin is not advised because of the many serious side effects such as hyperglycemia. Though moxifloxacin has been proved to have the maximum anti-TB activity, the safety profile of moxifloxacin in children has not yet been established. There is evidence that patients showing resistance to normal dose moxifloxacin may respond to high-dose moxifloxacin. The cross-resistance between the fluoroquinolones is known. The culture and drug susceptibility testing should be done for individual quinolones including for high-dose moxifloxacin and then choice of quinolone to be used should be decided.
Ethionamide and prothionamide have similar safety and efficacy profile, and so only one of them can be used. In cases of mutation in inhA gene, there may be cross-resistance between isoniazid and ethionamide, and here ethionamide may need to be replaced with some other drug. Ethionamide and PAS can cause severe gastrointestinal disturbances and hypothyroidism. It is preferable to avoid using them together unless strongly indicated. Based on the review of the evidence, linezolid and clofazimine have been placed in group C. Linezolid is one of the most effective new drugs. Clofazimine has been shown to have good sterilizing action.
The dosage of the second-line antitubercular drugs are described in [Table 2].
|Table 2: Dosage of the second-line ATT as per programmatic management of drug-resistant TB in India|
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Vitamin B6 (pyridoxine) should be given to all MDR-TB patients receiving cycloserine, high dosage of isoniazid or linezolid to prevent neurological side effects. Usual dose used is 100 mg per day.
Whenever drug resistance is suspected, a detailed history of drugs taken and drugs not taken by the patient should be obtained. It should be confirmed that the DST results are from a reliable laboratory. One should also remember that DST against isoniazid, rifampicin, injectable second-line drugs and fluoroquinolones is reliable. However, DST against ethambutol, streptomycin, most of other second line drugs is less reliable. The physician should combine the information about the drug history and the laboratory information and try to construct a regimen based on the principles mentioned above. The cost, tolerability, availability, and drug-drug interactions should be considered while designing the regimen.
Standardized vs. individualized treatment
MDR-TB patients may receive standardized treatment or individualized treatment regimen.
- Standardized regimen for MDR-TB treatment is designed according to the drug resistance surveillance data of the region and can be used before the results of DST of the patient is available. Here the treatment can be started early, but in some cases, it may not be appropriate for the given patient. Under national program conditions it is more practical to use standardized regimen.
- Individualized regimen is prescribed based on the DST results. Here, the treatment is more likely to be more appropriate, but may be delayed. Second, from national programme perspective it is more resource intensive
Standardized MDR-TB regimen under current national program in India is given in [Box 2].
Based on the results of DST at the beginning of treatment, injectables or fluoroquinolones can be replaced with other drugs.
Duration of MDR-TB treatment
As per WHO guidelines, the usual duration of intensive phase with injectables is 8 months and total duration of treatment is 20 months. In India, the current national program is recommending intensive phase of minimum 6 months, extendable to 9 months in case culture conversion has not been achieved at the end of 6 months. The continuation phase under Indian national program is of 18 months duration. Patients who continue to have positive culture at the end of 6 months of treatment should be suspected for XDR-TB and accordingly need to be offered DST to second-line drugs for further management.
Currently, the national guidelines for the management of Drug-resistant TB are under review. As the laboratory facilities for SL-LPA and DST for second-line drugs will be available at more sites in the country, the guidelines for the treatment regimen for MDR/XDR-TB will be revised.
Shorter MDR-TB regimen
In May 2016, WHO issued a conditional recommendation on the use of the shorter MDR-TB regimen of 9–12 months duration for MDR-TB patients under specific conditions. This regimen is also called “Bangladesh Regimen” as it was tried in Bangladesh. Shorter MDR-TB regimen reported statistically significant higher likelihood of treatment success than those who received longer conventional regimens (89.9% vs. 78.3%, respectively).
This shorter regimen is not to be considered if there is confirmed resistance or suspected ineffectiveness to a medicine in the shorter MDR-TB regimen (except isoniazid resistance), exposure to more than one second-line medicines in the shorter MDR-TB regimen for >1 month or Intolerance to >1 medicines in the shorter MDR-TB regimen or risk of toxicity (e.g., drug-drug interactions). Shorter MDR-TB regimen is mentioned in [Box 3].
Monitoring of MDR-TB treatment
Once the treatment has been initiated, regular monitoring is required by doing sputum smear and culture examination. During intensive phases, sputum should be examined once every month 3rd month onwards. During continuation phase, sputum should be examined once every 3 months. Further, symptomatic assessment and weight recording at least once a month. X-ray examination once every 3–6 months should also be done. The frequency of tests can be increased if indicated clinically. For extrapulmonary TB, examination of the relevant system is required. In these cases, use of radiological investigations may help in obtaining specimen from the relevant sites.
Treatment of drug resistant tuberculosis in children
Essentially principles of treatment of drug resistant TB in children are same as in adults. However, there are some additional challenges compared to drug sensitive TB. These include lengthy course of treatment, high pill burden, difficult adherence, and frequent adverse effects of the medications. Most of the drugs used in treating MDR-TB are not available in child-friendly formulations; they need to be divided which is cumbersome and not always accurate.
Even in pediatric patients, ideally microbiological confirmation of drug resistance is desirable before initiating MDR-TB regime. However, in pediatric patients where microbiological confirmation is not available, but there is high index of suspicion for drug resistance as mentioned, a diagnosis of presumptive DR-TB may be made and empiric second-line ATT may be started while awaiting the culture and DST results. If the DST results are not available, empiric treatment may be followed for the whole duration.
Paradoxical reactions during treatment
Once the appropriate treatment has been initiated, paradoxical reaction may manifest as increase in size or number of lymph nodes or CNS tuberculoma or development of pleural effusion. Paradoxical reaction usually occurs within the first 3 months of therapy, and there is associated symptomatic improvement such as resolution of fever, weight gain, and improved general well-being. These paradoxical reactions are more common in HIV-associated TB. During treatment if patient is otherwise improving, before suspecting a nonresponse to treatment or an augmentation of resistance, paradoxical reactions should be kept in mind. Here, the treatment with same drugs should be continued. Some patients may need addition of steroids.
Use of steroids in MDR-TB
Steroids in TB should always be used only under the cover of adequate antitubercular drugs. Corticosteroids may be indicated in cases of CNS involvement, pericardial disease, and severe respiratory insufficiency. Steroids are also indicated in managing paradoxical response to anti-tuberculosis treatment.
| Newer Drugs for Mdr-Tb|| |
Almost after five decades of initial drug discovery, two new drugs have been approved by FDA and endorsed by WHO for treatment of MDR-TB. These have been approved in a select group of patients when the core regimen for MDR-TB with pyrazinamide and at least four second-line drugs deemed to be still effective cannot be completed either due to intolerance to drugs or resistance. These drugs are bedaquiline and delamanid.
Bedaquiline is a new class of anti-mycobacterial agents, the dairyquinoline, that act by inhibiting ATP synthase. The efficacy of bedaquiline was assessed in three phase IIb studies, two of which were randomized placebo-controlled trials.,, It has been approved by the FDA to be used on compassionate basis in a select group of patients. In 2015, it was approved for use under the national program in India for a select group of adult patients in six sites in India under strict pharmacovigilance. Now its use is being expanded to several other sites in the country.
The prescribed dose of bedaquiline is 400 mg once a day for 14 days followed by 200 mg on alternate days for a total duration of 6 months. Commonly observed adverse events are nausea, arthralgia, and headache. Another important adverse effect is QTc prolongation especially when co-administered with other anti-TB drugs such as fluoroquinolones and clofazimine. Bedaquiline is highly concentrated in tissues and has a terminal half-life of 5.5 months. As of now, bedaquiline is not recommended for use under 18 years of age.
Delamanid is a nitro-dihydro-imidazo-oxazole derivative. It can be given on a compassionate basis to children above 6 years of age. The drug is predominantly metabolized by albumin in plasma. It can also cause QTc prolongation. An open label study reported that patients who received delamanid along with optimized background regimen for 6 months had lower mortality compared to patients who received it only for 2 months.,, The recommended dose recommended for delamanid is 50 mg twice a day for age 6–11 years of age or 20–34 kg body weight and 100 mg twice a day for more than 12 years of age or >35 kg body weight for 6 months (intensive phase). Delamanid should be given after meals. A case series published in 2016 describes 19 children who were administered delamanid on compassionate basis, 5 form India; interim outcome in the form of culture conversion was favorable in all children. Serious adverse event requiring stopping of delamanid was reported in one child.
Other important repurposed drugs include linezolid and clofazimine which have been reclassified by WHO in 2016 as a core second-line agent for treatment of MDR or XDR-TB. Migliori et al. reported that linezolid can improve treatment success in most of difficult cases of MDR and XDR-TB., Singla et al. reported from India that linezolid is a cheap and effective drug for XDR and XDR-TB patients. The usual dose is 600 mg once a day. Some studies have reported good outcome with 300 mg per day also. However, linezolid has potential toxicity including anaemia, thrombocytopenia, peripheral neuropathy, and optic neuritis.
Clofazimine is riminophenazine dye compound and has been shown to have sterilizing action also. It is generally well tolerated. Commonly reported patient complaint is skin darkening which is reversible but can take several months after discontinuation of the drug. It can also cause gastrointestinal complaints.
Some of the other important newer drugs which are in advanced phases of clinical trials include pretomanid belonging to class nitroimidazole and sutezolid belonging to class oxazolidinone. Under the umbrella of “STREAM” trial, a trial is being carried out with 9 months of duration for MDR-TB patients with moxifloxacin replacing gatifloxacin in Bangladesh trial. The results will be compared with WHO recommended standard of care treatment for MDR-TB.
| Adjunct Immunotherapy|| |
Levomisole, IFN-ƴ (intramuscular, subcutaneous, aerosolized), and mesenchymal stromal cells, thalidomide and Immuvac (Mycobacterium W) are some of the immunomodulators that have been or are being experimented with to improve the immune response in patients with drug-resistant tuberculosis.
| Role of Surgery|| |
Lung resection surgery may be considered in carefully selected patients with destruction of a lobe or entire lung and those with extensive disease with large or persistent cavities. Adequate chemotherapy should be given along with surgery. A systematic review and meta-analysis of adjuvant surgery in MDR-TB reported estimated pooled treatment success rate of 84%, failure rate of 6%, death rate of only 3%, and relapse rate of only 3%. Adjuvant surgery also prevents relapses in MDR or XDR-TB patients.
In 2016, WHO recommended that elective partial lung resection may be used alongside a recommended MDR-TB regimen. However, availability of centers with adequate resources and expertise is a big challenge for such cases. Moreover, majority of patients requiring surgery are not fit for surgery.
| Management of Xdr-Tb|| |
The treatment of XDR-TB (with resistance to fluoroquinolones and second line injectable in addition to isoniazid and rifampicin) is very complex and should be treated at centers with experienced physicians available. With the availability of SL-LPA, it may become easier to diagnose XDR-TB early and is likely to help in early initiation of appropriate treatment. Reliable culture and DST against second line drugs are available in very few laboratories which poses a challenge in the management of XDR-TB.
The basic principles of treatment of XDR-TB remain the same as for MDR-TB patients. The regimen should have at least 4–5 new drugs which are likely to be effective. In the management of XDR-TB drugs from group C and D are usually required including newer drugs such as linezolid, clofazimine, bedaquiline and delamanid. However, the availability of newer drugs such as bedaquiline and delamanid is always a challenge.
Many patients may need injectable penems which are very expensive. Moreover, penems are to be given by intravenous infusions which increases treatment challenges. In children, meropenem is preferred over imipenem due to CNS adverse reactions. These patients may have resistance to one of the fluoroquinolones which may lead to limited choice for use of fluoroquinolones. Many patients may need high dose moxifloxacin as laboratory may report resistance to low dose Moxifloxacin and sensitive to high dose moxifloxacin. In XDR-TB intensive phase with injectables is recommended to be given for 6–12 months and continuation phase for 18 months.
| Management of Isoniazid Monoresistance|| |
There is no consensus for the treatment of INH monoresistance. Patients diagnosed with isoniazid monoresistance are often treated with 6–9 months of rifampicin, ethambutol, and pyrazinamide. If there is associated resistance to ethambutol or streptomycin, addition of quinolone may be required. The national program of India has recommended 3–6 months of injection kanamycin accompanied with levofloxacin, rifampicin, ethambutol, and pyrazinamide followed by levofloxacin, rifampicin, ethambutol, pyrazinamide, and INH for next 6 months. If LPA shows only inhA mutation, high-dose INH may be added.
| Therapeutic Drug Monitoring|| |
Therapeutic drug monitoring (TDM) refers to measurement of blood levels of drugs to guide and monitor treatment. In some patients, it is observed that patient continue to be sputum smear and culture positive despite adequate compliance to anti-TB medication and a reliable laboratory report that the sputum is still sensitive to anti-TB drugs which patient is taking. This could be due to poor absorption of anti-TB drugs.
Many publications from India and across the globe have shown that many patients have low serum levels of anti-TB drugs, especially rifampicin., It is more likely in TB-HIV co-infection and in malnourished patients. TDM is required in such cases. However the TDM results should always be correlated with clinical scenarios and bacteriological data. Nonavailability of facility of TDM across the country is a major challenge in India.
| Treatment Outcome Definitions|| |
Treatment outcome definitions are given in [Box 4].
As per the Global TB report of 2016 treatment outcome data for cohort of patients registered in 2013 show treatment success rate of only 52% for MDR/RR-TB and only 28% for XDR-TB.
| Prevention/chemoprophylaxis for Dr-Tb Patients|| |
For all children who are in close contact with confirmed cases of MDR-TB, the first step involved is to rule out active disease by a thorough clinical examination and other relevant investigations such as chest X-ray and tuberculin skin testing. If the contacts are symptomatic, they need to be investigated upfront by rapid genotypic and/or phenotypic tests to rule out active DR-TB and treated accordingly. Most of the national and international guidelines do not recommend any chemoprophylaxis treatment for the asymptomatic contacts. CDC has recommended regular follow-up for at least 24 months from the time of exposure. Several drug regimens which have been tried for asymptomatic contacts of MDR or XDR-TB contact include delamanid, or moxifloxacin/ofloxacin/levofloxacin with ethambutol for close contacts of MDR-TB cases who are <5 years of age or are HIV-infected.
| Conclusions|| |
Drug-resistant TB is a continuing public health problem. Limited availability of the rapid diagnostic facilities in most of the developing countries leads to delay in diagnosis and initiation of appropriate treatment. This may also be associated with increased mortality and further augmentation of drug resistance. The current global interest towards discovery and development of newer anti-TB drugs offers some hope for the management of these cases. Basic principles of using at least 4–5 drugs likely to be effective drugs in the management of MDR or XDR-TB patients should always be used for an effective outcome. The national programs, besides arranging for newer rapid diagnostics and newer anti-TB drugs, need to show commitments to improve the knowledge and skills of health care workers involved in the management of drug-resistant cases to achieve the goal of elimination of TB.
I acknowledge the support of Dr. Aparna Mukherjee and Dr. Abhishek Faye in preparation of the manuscript.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]