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review article

Indian Pediatr 2019;56:213-220

What is New in Management of Pediatric Tuberculosis?

 

Alkesh Kumar Khurana1 and Bhavna Dhingra2

From the Departments of 1Pulmonary Medicine and 2Pediatrics, AIIMS, Bhopal, Madhya Pradesh, India.

Correspondence to: Dr Bhavna Dhingra, Additional Professor, Department of Pediatrics, AIIMS, Bhopal,
Madhya Pradesh, India.
Email: [email protected]

 

 


Tuberculosis continues to haunt mankind since its discovery more than a century ago. Although commendable advancements have been made in the diagnosis as well as treatment, especially in the last couple of decades, the healthcare burden of this disease worldwide is immense. Continuously evolving medical science has provided recent changes in national guidelines along with discovery of newer anti-tubercular drugs after many decades. In view of WHO declaring tuberculosis as a global health emergency and strong commitment being reflected by Government of India whereby National Strategic Plan aims to eliminate tuberculosis by 2025, it is high time that we work collectively on the goal of tuberculosis elimination. This article sums up the updates on newer anti-tubercular drugs as well as the recent changes adopted in Revised National Tuberculosis Control Program.

Keywords: Anti-tubercular drugs, Mycobacterium tuberculosis, Treatment


Tuberculosis (TB) continues to have a significant impact on healthcare worldwide. Despite availability of anti-tubercular treatment (ATT) available for more than last five decades, approximately one-third of total world’s population continues to harbour tuberculosis infection. The emergence of multidrug resistant tuberculosis (MDR-TB) and extensively drug resistant tuberculosis (XDR-TB) in the last decade has raised a global concern [1,2].

As per WHO estimates of 2015, there were an estimated 10.4 million new cases of TB worldwide, which included 1 million children. In the same year, 1.8 million people are estimated to have died from tuberculosis, of which 0.2 million were children. This is despite the fact that the number of TB cases fell by 22% from 2000 to 2015. Inequality in diagnosis and treatment access is evident from the fact that the case fatality ratio varies from 5% in developed countries to 20% in low- and middle-income countries [1]. In 2015, there were an estimated 480,000 cases of MDR-TB and an additional 100,000 cases of Rifampicin Resistant Tuberculosis (RR-TB), which are also eligible for treatment for MDR-TB. Only 20% of such eligible patients were started on second line ATT in the same year. In pediatric age group, MDR-TB is underestimated, and primary MDR-TB is reported as well [3,4]. Also, cases of XDR-TB have been on the rise in the last few years. A cure rate of meager 52% for MDR-TB and 28% of XDR-TB has been the real cause of worry and there is need of urgent and definitive measures to control tuberculosis [1].

Based on the current evidence, this review aims to apprise the readers about the newer drugs and the updated strategies to combat tuberculosis.

Drugs for Tuberculosis

The continuous need of newer drugs and combinations has always been felt as the disease has refused to die down over the last five decades. Many drugs are being tested, and are in various phases of development [5] (Box 1). Efforts are being made to develop newer drugs, and also to develop newer regimens with the help of these drugs.

BOX 1: Clinical Pipeline of Newer Anti- tubercular Drugs in Various Stages of Development

Pre-Clinical                              Phase II

1. PTBZ 169                           1. SQ 109

2. BTZ-043                             2. Levofloxacin

3. Spectinamide 1810              3. Rifampicin (High Dose)

4. GSK 070                             4. Nitazoxanide

5. TBA 7371

Phase I                                    Phase III

1. TBI-166                               1. Delaminid

2. Q-203                                  2. Bedaquiline

3. OPC 167832                         3. Rifapentine

                                               4. Clofazimine
 

The newer drugs are broadly discussed as: (i) New application of existing drugs (Table I); and (ii) Newer drugs/research molecules (Table II).

TABLE I Newer Applications of Existing Drugs for Treatment of Tuberculosis
Drug Class Dose Mechanism of action Current indications Side effects
High doseRifampicin Rifamycins 15-35 mg/kg OD   Inhibition of RNAsynthesis   Not currently approved  in WHO/RNTCP guidelines Fever, thrombo-cytopenia, acute renal failure
Rifabutin Rifamycins 300 mg OD Inhibition of RNAsynthesis Not currently approved  in WHO/RNTCP guidelines, but widely recommended byexperts and CDC Nausea, vomiting Mayneed to modify dosage as 150 mg BD 
Rifapentine Rifamycins 900 mg/week Inhibition of RNA synthesis Approved by CDC for treat-ment of latent TB infection Nausea, vomiting, headache
Moxifloxacin Flouro-quinolones 400 mg OD Inhibition of DNA gyrase Approved as core drugby WHO for drug resistant tuberculosis QT prolongation,psychosis
Levofloxacin Flouro-quinolones 750 mg OD Inhibition of DNA gyrase Approved as core drug byWHO for drug resistanttuberculosis QT prolongation, psychosis
Cycloserine Oxazolidinone 250-500 mg OD Inhibition of RNAsynthesis Approved as core drug byWHO for drug resistanttuberculosis Seizures, depression, vertigo, GI upset 
Linezolid Oxazolidinone 300-600 mg OD Inhibition of RNAsynthesis Approved as core drug byWHO for drug resistanttuberculosis Myelosuppression, GI upset, neuropathy,  thrombocytopenia
Amoxicillin-Clavulanate Beta Lactams 500-1000 mgand 125-250 mgTDS Inhibition of cellwall synthesis Enlisted as add on agent byWHO for drug resistant  tuberculosis Nausea, diarrhea  
Meropenem Carbapenems 500-1000 mgTDS Inhibition of cellwall synthesis Enlisted as add on agent byWHO for drug resistant tuberculosis Intravenous injection   related complications
Imipenem-Cilastin Carbapenems 500 mg QID Inhibition of cell wallsynthesis Enlisted as add-on agent byWHO for drug resistant tuberculosis Intravenous injectionrelated complications
OD: once daily; BD: twice a day; TDS: thrice daily; QID: four time a day; CDC: Centers for Disease Control; RNTCP: Revised National Tuberculosis Control Program; WHO: World Health Organization. 
 
TABLE II Newer Drugs for Treatment of Tuberculosis
Drug Class Dose  Mechanism of action Current indications Side effects
Bedaquiline Diaryl-quinolines  400 mg OD for 2 wks200 mg TDS for 22 wks Inhibition of ATPsynthetase WHO- and RNTCP-approved for MDR-TBwhen standard 2nd lineregime cannot be used QTC prolongation,arthralgia,  myalgia,  dark colored urine  
Delaminid (OPC 67683) dihydro-nitroimidazo-oxazole 100 mg BD for 6 mo  Inhibition of myco-bacterial cell wallsynthesis WHO-approved withconditional recommendation only in select patients QTC prolongation, psychosis
Pretomanid(PA 824) nitroimidazo-oxazole 100-1200 mg OD Inhibition of myco-bacterial cell wallsynthesis Under trial only Not significant so far,    under trials
SQ-109 1,2 ethylene diamine Under trial - Under trial Under trial
OD: once daily; BD: twice a day; TDS: thrice daily; RNTCP: Revised National Tuberculosis Control Program; MDR-TB: multidrug resistant tuberculosis; WHO: World Health Organization. 

New Application of Existing Drugs

Rifamycins: The drugs in this group consist of Rifampicin, Rifabutin and Rifapentine.

It has been suggested that dosage of Rifampicin higher than routinely recommended 10 mg/kg may be needed to achieve reduction in treatment duration in new cases of tuberculosis. Some studies in mice models have yielded encouraging results to evaluate the role of high dose rifampicin (15-30 mg/day), especially in the intensive phase of ATT [6]. A phase II randomized trial comparing rifampicin in doses of 20 mg/kg/day and 15 mg/kg/day to the standard 10 mg/kg/day for first two months of ATT is ongoing [7]. Preliminary evidence suggests acceptable tolerance of higher dosage and proportionate increased serum concentration levels with increasing doses of Rifampicin [8]. Higher doses of Rifampicin have also been studied in adults as a part of standard ATT regime as well as when used in combination with other newer drugs such as Moxifloxacin and SQ-109 [9]. Current evidence suggests the potential for shortened treatment duration with such higher doses of rifampicin.

Instead of Rifampicin, Rifabutin is generally recommended for patients of TB co-infected with HIV as it has lesser drug interactions and side effects [10]. The dose is 5 mg/kg in children and 150-300 mg/day in adults [11].

Another drug from the same class is Rifapentine, which has a longer half life and has been studied more for latent tuberculosis infection (LTBI) than active tuberculosis. Once weekly prophylactic regimen of 300 mg Rifapentine and 900 mg Isoniazid for three months has been found to be equally effective as 9 months of 300 mg daily Isoniazid in adults [12]. In children, doses varying from 300-900 mg have been used with acceptable tolerance. Higher weight-adjusted doses are warranted in children to achieve systemic exposures that are associated with successful treatment of LTBI in adults [13].

Flouroquinolones: The key drugs in this group are Moxifloxacin and Levofloxacin, and their superiority over other quinolones is well proven [14]. There have been numerous trials with encouraging results to use quinolones along with other first line drugs with an aim to curtail the duration of ATT [15]. A standard ATT regimen was compared with a Gatifloxacin/Moxifloxacin- containing regimen in the intensive phase with an aim to reduce the treatment duration to four months but the latter resulted in higher relapse rates as compared to the former. Further, children less than five years of age are known to eliminate quinolones more rapidly in urine and achieve a lesser serum concentration than adults.There is lack of adequate pharmacokinetic data, especially in children less than five years of age. Hence it becomes more relevant to optimize their usage in children for prevention of drug resistance [14]. Traditionally, the use of quinolones has been restricted in children because of concerns about arthropathy but available data does not show any evidence of such side effects in either children or adults treated with long term quinolones.

Oxazolidinones: This class of drugs act via competitive inhibition of an enzyme involved in translation, and hence block protein synthesis [16]. Cycloserine was the first oxazolidinone that was used as an antitubercular drug but the most popular drug currently in use is linezolid. Two recent randomized control trials with linezolid showed improved rates of sputum conversion in patients of XDR-TB [17,18]. However, increased failure rates at lower range of dose (300 mg/day) and increased severity of adverse effects at higher range (600 mg/day) limit its long-term use. Peripheral neuropathy, gastrointestinal disorders and myelosuppression are common adverse effects [19]. As of now, both Cycloserine and linezolid are enlisted as core drugs by WHO for management of drug resistant tuberculosis. There is not much data available about their use in children as anti-tubercular agents.

BOX 2: Newer Classification for Medicines Used for Drug Resistant Tuberculosis

A. Flouroquinolones·

— Levofloxacin ( Lfx)

— Moxifloxacin (Mfx)

— Gatifloxacin (Gfx)

B. Second line injectable agents

— Amikacin (Am)

— Kanamycin (Km)

— Capreomycin (Cm)

C. Other core 2nd line agents

— Ethionamide/Prothionamide (Eto/Pto)

— Cycloserine/Terezidone (Cs/Trd)

— Linezolid (Lzd)

— Clofazimine (Cfz)

D. Add-on agents

(Not a core part of drug resistant anti-tubercular regimes)

— D1

¡ Pyrazinamide (Z)

¡ Ethambutol (E)

¡ High Dose Isoniazid (Hh)·

— D2

¡ Bedaquiline (Bdq)

¡ Delaminid (Dlm)

— D3

¡ Para-amino salicylic acid (PAS)

¡ Imipenem-Cilastatin (Ipm)

¡ Meropenem (Mpm)
¡ AmoxicillinClavulanate(AmxClv)

Beta-lactams and Macrolides: Amoxycillin-Clavulanate, Imipenem-Cilastin and Meropenem are the drugs enlisted in WHO group D of drugs for treatment of drug resistant tuberculosis (Box 2). Meropenem and Clavulanate have potent synergistic in vitro activity against M. tuberculosis as Clavulanate inhibits the â-lactamase and potentiates the antibacterial activity of Meropenem [20]. A recent paper published encouraging data about triple therapy consisting of Amoxicillin, Clavulanate and Meropenem showing potential in vitro activity against tuberculosis bacilli [21]. Macrolides, especially Clarithromycin have been successfully used to treat non-tubercular mycobacteria in the past but the results in M. tuberculosis have been disappointing because of development of rapid resistance [22].

Newer Drugs

Bedaquiline: This particular drug has been the first anti-tubercular agent approved by the Food and Drug Administration (FDA) recently, after almost four decades. It inhibits the proton pump required for ATP synthesis and inhibits the metabolism of the mycobacterium [22]. Bedaquiline should be used only when the standard MDR regimen cannot be designed because of reasons such as; in vitro resistance to these drugs, known adverse drug reaction, poor tolerance or contraindication to any component of the combination regimen. As per WHO guidelines, it can be used as a part of second line ATT only in patients older than 18 years. However, it has been found to be effective and safe in children and adolescents in the same dosage as recommended for adults [25]. The dose is 400 mg once a day for two weeks followed by 200 mg thrice a week for remaining 22 weeks to complete six months, maximum time period for which bedaquiline can be given. Revised National Tuberculosis Control Program (RNTCP) of India is introducing this drug via a conditional access program throughout the country. Known, adverse effects associated with bedaquiline include nausea, vomiting, dizziness, arthralgia, myalgia, increased serum amylase and transaminase levels, QT prolongation and dark urine. Drugs which inhibit liver function via CYP3A4 metabolism (e.g., ketoconazole, ritonavir) increase blood levels of bedaquiline, and hence its toxicity [26].

Delamanid and Pretomanid: Both these drugs belong to the class of nitroimidazoles, which act by inhibition of mycobacterial cell wall synthesis [27,28]. Delamanid has been much more extensively studied than pretomanid. WHO recommends the use of delamanid only for six months of intensive phase in a dose of 100 mg twice a day in patients with MDR-TB/XDR-TB having high baseline risk for poor outcomes [29]. Increased rates of sputum conversion as well as decreased mortality have been docmented when delamanid was used in addition to an optimized background regimen in patients with drug-resistant tuberculosis [30]. Pretomanid, however, is a prodrug that requires bio-reductive activation of an aromatic group to exert an anti-tubercular effect. It has also shown substantial bactericidal activity both during intensive and continuation phases of treatment in experimental mice model of tuberculosis [28]. In 2016, WHO issued guidelines for use of delamanid in children and adolescents, which mentioned that children with MDR-TB with resistance to quionolones or second line injectables (or both) should be the candidates for this drug. In children, this drug should be used as an add-on drug in longer MDR-TB regimens (18-24 months) rather than as a part of shorter MDR-TB regimens launched by WHO in 2016 [31]. Bedaquiline, delamanid and pretomanid have revolutionized the management of not only drug-resistant tuberculosis but also HIV-TB co-infection.

Other Drugs: SQ-109 is a 1, 2 ethylenediamine, an ethambutol analogue. After having shown significant results in both in vitro and in vivo mice model of tuberculosis, this compound is currently undergoing trials in humans [32]. SQ-109 has been shown to have synergistic action with isoniazid, rifampicin and streptomycin. SQ-109 lowers the Minimum inhibitory concentration (MIC) of Rifampicin and this synergy may have a significant role in patients with Rifampicin resistant tuberculosis [33].

There are some other drugs in the preclinical phase.

• Pyrroles: BM 212 and LL3858 are the most potent pyrroles described so far. Synergistic activity with other first line ATT drugs has been noted in murine model [34].

• Benzothiazinones: this new class of drugs acts by inhibition of mycobacterial cell wall synthesis [35]. Primary evidence suggests activity against both drug-susceptible and drug-resistant strains.

Recently, WHO has approved a 9-12 month short regimen for uncomplicated MDR-TB patients (Bangladeshi Regimen). It consists of 4-6 months of Intensive phase of Kanamycin,Moxifloxacin, Prothionamide, Clofaziminie, High dose Isoniazid, Pyrazinamide and Ethambutol followed by 5 months of continuation phase which consists of moxifloxacin, clofazimine, pyrazinamide and ethambutol [36].

RNTCP: Revised and Revisited

There have been numerous changes and updates in the new guidelines issued by the government of India [37,38]. Highlights are summed up in Table III. 

TABLE III Highlights of Changes Between New and Old RNTCP Guidelines for Management of Tuberculosis

Old RNTCP Guidelines

New RNTCP Guidelines

No role of Nucleic acid amplification assay (CBNAAT) in diagnosis, only for diagnosis of drug resistance

Upfront use of CBNAAT in smear negative PTB cases, extra pulmonary TB, pediatric TB and HIV patients for diagnosis of TB

Alternate day drug delivery

Daily drug delivery

Continuation phase of Category II only included ethambutol

Continuation phase of both Category I and Category II now includes ethambutol

Intensive phase extended by one month if sputum positive at end of intensive phase

No need of extension of intensive phase irrespective of sputum result at 2 months

No fixed dose combinations

 Fixed dose combinations available

Limited weight band options with no provision of dispersible tablets for children

Multiple weight band options with provision of dispersible tablets for children

No provision/importance on long term followup of DOTS patients after completion of treatment

Follow up of minimum two years required for DOTS patients after completion of treatment

New Definitions

‘Presumptive Pulmonary TB’ refers to condition in a person with any of these symtoms: cough and/or fever of >2 weeks, significant weight loss, hemoptysis or any chest radiograph abnormality. In pediatric patients, loss of body weight is defined as >5% weight loss in the last three months. ‘Presumptive Drug Resistant TB’ refers to in a condition any patient who has failed treatment with first line ATT, pediatric TB non-responders, contacts of drug-resistance TB, previously treated TB cases, TB patients with HIV co-infection or TB patients found positive on follow-up examination during treatment with first line ATT.

Changes in Diagnostic Algorithms

In a patient with presumptive pulmonary TB, smear examination and chest radiograph both have been given importance now. All these patients undergo two sputum smear examinations. If the first smear is positive for AFB, the patient is labelled as microbiologically confirmed TB. If the first smear is negative, the second sample is simultaneously subjected to smear and Cartridge Based Nucleic Acid Assay (CBNAAT). On the basis of CBNAAT, the patient is diagnosed either as drug sensitive TB or Rifampicin resistant TB. An indeterminate result calls for an additional CBNAAT for a valid result, and in case of a second inderterminate result, the specimen is to be sent to an accredited laboratory for culture and drug sensitivity testing.

In a patient with presumptive extrapulmonary TB, appropriate specimen from the involved site should be collected and subjected directly to CBNAAT (except for urine, stool and blood). Based on a positive CBNAAT or a positive culture (where CBNAAT is negative), the patient is classified as microbiologically confirmed extrapulmonary TB. If the patient is diagnosed as having extrapulmonary TB, based on clinical suspicion or other diagnostic tools, he/she can be classified as clinically diagnosed TB.

Similarly, for a presumptive pediatric pulmonary TB patient, CBNAAT should be straightaway performed on sputum sample or on gastric lavage if sputum is negative but chest radiograph is suggestive. If both these arms are not clinically relevant, further course of action should be based on the combination of chest radiograph and Mantoux test.

Changes in Treatment Approach

Principles of TB treatment have changed from intermittent to daily treatment with administration of daily fixed dose combinations (FDCs). The FDCs now consist of four weight bands in adults (25 kg to >70 kg) and six weight bands in children (4 to 39 kg) with dispersible tablets. This has created a lot of flexibility in drug dosages in both adults and children. For new TB cases, Intensive phase now consists of 8 weeks of Isoniazid, Rifampicin, Pyrazinamide and Ethambutol followed by 16 weeks of three drugs Isoniazid Rifampicin and Ethambutol. For previously treated cases, intensive phase is recommended to be of 12 weeks where streptomycin is stopped after 8 weeks and remaining four drugs are given in daily dosage as per weight band for another 4 weeks. At the start of Continuation Phase (CP), pyrazinamide is stopped and rest of the three drugs are given for 20 weeks. In both new and previously treated cases, Intensive Phase is not recommended to be extended now. In extra pulmonary tuberculosis, continuation phase can be extended for 3-6 months in certain scenarios based on clinical decision.

Changes in Follow-up

A clinical monthly follow-up should be done whereby either the patient may visit the clinical facility or the medical officer may visit the patient’s house. In the previous guidelines, sputum smear examination was done at 2, 4 and 6 months in new cases and at 3, 5 and 8 months in previously treated cases. In newer gidelines, sputum smear examination is recommended only at the end of intensive phase and at the end of treatment. Long-term follow-up is now recommended with evaluation at 6, 12, 18 and 24 months after completion of treatment, which was not recommended earlier.

Changes in Management of Drug-resistant TB

There is no major change in treatment of MDRTB/RRTB patients, which includes 6-9 months of intensive phase with Kanamycin, Levofloxacin, Ethambutol, Pyrazinamide, Ethionamide and Cycloserine, and 18 months of continuation phase with Levofloxacin, Ethambutol, Ethionamide and Cycloserine. However, the newer drugs for drug resistant tuberculosis have been reclassified into four different groups (Box 2). Bedaquiline is being introduced in the RNTCP program in proven pulmonary MDR-TB patients >18 years of age with an aim to improve culture conversion time. In cases of INH resistance, the use of INH depends on the results of Line Probe Assay (LPA) or culture and sensitivity testing. If LPA reports INH resistance by Kat G mutation, INH is omitted whereas if the culprit is INHA mutation, high dose INH is added. In cases of polydrug resistance pattern, regimen designing or modification will be the prerogative of drug-resistance TB center committee.

Challenges and Future Perspectives

Numerous challenges have been coming in way of development of newer ATT options. The socioeconomic factors that underlie the huge global burden of tuberculosis cannot be rectified in a short span of time. The unique ability of this organism to persist in the host environment and potential to acquire drug resistance is another daunting task needing urgent and effective addressal. Molecular mechanisms responsible for this dormancy and persistence are still not fully understood [39]. The funding for tuberculosis research, though has increased recently remains inadequate in proportion to the burden of this disease. The required timeline for clinical trials in developing these regimens is often very long, and there is a paucity of such expensive and specialized facilities [40]. There is an urgent need for widespread and fully committed involvement of governments, pharmaceutical industries and policy makers to deliver optimal future treatment options for tuberculosis [41]. An effective collaboration should ensure access to the best treatments for all those in need. It is of paramount importance to spend time and money for identifying more targets in this bacterium’s pathophysiology so as to develop better treatment options, including those for drug-resistant organisms.

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