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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 8  |  Issue : 1  |  Page : 79-82

Can a new nitroimidazole knockout the unconquered tuberculosis?


Department of Pharmacology, All India Institute of Medical Sciences, Raipur, Chhattisgarh, India

Date of Submission10-Mar-2020
Date of Decision19-Apr-2020
Date of Acceptance21-Apr-2020
Date of Web Publication20-Jun-2020

Correspondence Address:
Dr. Alok Singh
Department of Pharmacology, All India Institute of Medical Sciences, Raipur, Chhattisgarh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/amhs.amhs_33_20

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  Abstract 


Pretomanid (PA-824) is the latest drug to get approval from the United States Food and Drug Administration (FDA) for the treatment of tuberculosis (TB). The present article aims to review the efficacy, safety, and tolerability of pretomanid in the management of drug-resistant TB for which a PubMed search (from the year 2007 to 2019) was conducted using the keywords: TB, multidrug-resistant TB, extensively drug-resistant TB, pretomanid, and newly approved drugs by FDA and PA-824. We included English language articles related to efficacy, safety, and tolerability of pretomanid in drug-resistant TB. Pretomanid is active against both the actively multiplying and latent Mycobacterium tuberculosis bacilli. In nonmultiplying bacterial cell, it causes nitric oxide-mediated nonspecific cellular damages, and in dividing bacteria, it acts by blocking the mycolic acid synthesis, thus resulting in inhibition of cell wall production. Pretomanid has been approved recently for managing such cases, in combination with bedaquiline and linezolid. Current data demonstrate its efficacy, safety, and tolerability with improved outcomes. The advantages of this combination observed could prove beneficial in developing countries, where there is not only a high burden of drug-sensitive TB cases but also the incidence of drug-resistant cases are on the rise.

Keywords: Multidrug-resistant tuberculosis, PA-824, extensively drug-resistant tuberculosis


How to cite this article:
Gupta D, Sahoo AK, Singh A. Can a new nitroimidazole knockout the unconquered tuberculosis?. Arch Med Health Sci 2020;8:79-82

How to cite this URL:
Gupta D, Sahoo AK, Singh A. Can a new nitroimidazole knockout the unconquered tuberculosis?. Arch Med Health Sci [serial online] 2020 [cited 2020 Aug 9];8:79-82. Available from: http://www.amhsjournal.org/text.asp?2020/8/1/79/287358




  Introduction Top


Tuberculosis (TB), a global health emergency since 1993, is still among the top ten causes of deaths due to infectious diseases.[1] Although prevalent all over the world, the global burden of this disease is disproportionate, more being in the Southeast Asian region.[2] As per the global TB report, 2018 by the World Health Organisation, around 9–11 million people had TB in 2017, and the deaths accountable to it were 1.2–1.4 million. Among the people affected with TB all over the world, majority of patients were in India (27%) and China (9%) alone.[1] The incidence of TB in India in 2017, was around 2.8 million, accounting for approximately a quarter of global incidence.[3] Mycobacterium tuberculosis (M. tuberculosis), acid-fast bacilli, is known to cause both pulmonary and extrapulmonary TB, even though primarily it is a pulmonary pathogen.[4] Various classes of drugs are being utilized currently to provide cure from this disease, that is, first-line agents (isoniazid, rifampicin, ethambutol, and pyrazinamide); second-line agents (fluoroquinolones, injectable aminoglycosides; oral agents such as ethionamide, cycloserine, linezolid; and add-on agents such as bedaquiline, delaminid, and others).[5] Currently, fixed-dose combinations of first-line agents are available, which are used in drug-sensitive TB patients. The treatment regime for a newly diagnosed drug-sensitive TB case includes isoniazid, rifampicin, pyrazinamide, and ethambutol for 2 months, and then except pyrazinamide, all are to be continued for another 4 months. However, if a patient is either defaulter or has been previously treated, then the regime consists of isoniazid, rifampicin, pyrazinamide, ethambutol, and streptomycin for 1 month, then apart from streptomycin, all are to be continued for another 1 month, then followed by only isoniazid, rifampicin, and ethambutol for the next 5 months.[6]

Until a few decades, the combination therapy with first-line agents was proving to be fruitful until the cases of drug resistance came up with multidrug-resistant TB (MDR-TB) and extensively-drug resistance TB (XDR-TB). MDR-TB is defined as the cases of TB not responding to isoniazid and rifampicin, and among the rifampicin-resistant cases, 82% were reported to be cases of MDR-TB.[1],[7] While XDR-TB, which accounts for 8.5% among the MDR-TB cases, is defined as those TB cases which are resistant not only to isoniazid and rifampicin but also to any fluoroquinolones, and at least one of the three injectable second-line drugs (amikacin, capreomycin, or kanamycin).[1],[8] The treatment regime for drug-resistant cases is mainly based on the utilization of second-line agents, for an approximate duration of 24–30 months, depending on the type of resistance encountered.[6] To overcome this hindrance of resistance, new drugs are being launched and incorporated into regimes, so as to improve the patient care. Recently, the United States Food and Drug Administration (US-FDA) gave marketing approval to a new drug, pretomanid, to be used along with bedaquiline and linezolid in treatment-resistant cases of TB.[9]

Bedaquiline is a diarylquinoline, which acts by inhibiting mycobacterial ATP synthase, thus leading to mycobacterial death. The drug got approved way back in 2012 by US-FDA for the management of pulmonary MDR-TB in adults, but in India, it was launched in 2016 under conditional access program for a selective group of MDR-TB patients.[10],[11] The success of this drug was not only observed in the treatment of drug-resistant TB cases but also in the shortening of treatment duration. Attributing to this property, the drug is now a part of a regime for the management of drug-resistant TB.[12]

On the other hand, linezolid, an oxazolidinone, was approved by the US-FDA in the year 2000 but for the management of Gram-positive bacterial infection. It is a protein synthesis inhibitor and acts by binding to 23S r-RNA of 50S subunit, and thus preventing the formation of functional 70S initiation complex. Although the use of linezolid in drug-resistant TB cases has proven to be effective and well-tolerated, still this use is considered to be off label, as none of the regulatory authorities has approved it officially.[13],[14] The use of pretomanid has been advised in conjunction with bedaquiline and linezolid, but as the scope of this article is limited, the discussion will be focussed on the pharmacology, clinical trials, and safety data of pretomanid, to assess its role in the management of drug-resistant TB.

All the relevant articles indexed in PubMed complying with the timeline of January 2007– July 2019 were reviewed. For a similar timeline, National Institutes of Health Clinical Trials Registry (http://www. clinicaltrials. gov) and European Clinical Trials Register https://www.clinicaltrialsregister.eu/were also searched. The search terms included TB, MDR-TB, XDR-TB, pretomanid, newly approved drugs by FDA, and PA-824. Research articles in the English language and containing the search terms were included in the study.


  Pharmacology Top


Pretomanid (PA-824), a nitroimidazooxazine, is quite similar to delamanid. It has activity against both the actively multiplying and latent M. tuberculosis bacilli. Once it enters the nonmultiplying bacterial cell, it gets activated by the enzyme deazaflavin-dependent nitroreductase, which then results in the production of nitric oxide, thus leading to non-specific intracellular damages, while in the actively multiplying bacilli, it blocks the mycolic acid synthesis, thus inhibiting cell wall production.[15],[16] Important pharmacokinetic properties of pretomanid are enumerated in [Table 1]. Pretomanid achieves steady-state concentration in about 4–6 days, following multiple dosing of 200 mg once daily. With a high-fat, high-calorie meal, Cmax is observed to be increased. In vitro studies have demonstrated that 20% metabolism of this drug is by CYP3A4, and it is excreted both in urine (53%) and feces (38%). Significant drug interactions have been observed with rifampin and lopinavir. Coadministration of pretomanid 200 mg four times a day with rifampin 600 mg QID for 7 days, resulted in decreased Cmax of the former. On the other hand, when Pretomanid was co-administered with Lopinavir, the Cmax of the latter was found to be reduced.[17] In a preclinical study done with a series of in vitro and in vivo models, the efficacy of pretomanid was found to be comparable to that of other anti-TB drugs which are currently in use.[18] In a study with healthy individuals, pretomanid alone, had few adverse effects such as headache, elevated serum creatinine level, stomach discomfort (nausea, vomiting, flatulence, and diarrhea), and back pain.[19] However, when this drug was studied in combination with bedaquiline and linezolid, different adverse events were noticed, of which a few of the concern were hepatotoxicity, myelosuppression (including anemia), peripheral and optic neuropathy, lactic acidosis, and QT prolongation. It has been advised that the patients receiving this combination be counseled regarding the modifications in the dose of linezolid, which may be done during the course of therapy, to manage its known adverse reactions.[17]
Table 1: Pharmacokinetic properties of pretomanid[16],[17]

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  Clinical Trial Top


The US-FDA approval to pretomanid was based on an open-label, single-arm trial, Nix-TB trial, which was conducted at three centers in South Africa. The trial included those patients who had either XDR-TB, or treatment intolerant MDR-TB, or nonresponsive MDR-TB, irrespective of their HIV status. The 109 patients who were enrolled in this trial were given the following drug combination to assess its safety and efficacy – bedaquiline orally (400 mg once daily for 2 weeks, followed by 200 mg three times a week for next 24 weeks), pretomanid orally (200 mg once daily for 26 weeks), and linezolid orally (1200 mg once daily for 26 weeks). The assessment was done for around 6 months, following which the follow-up was done till 24 months. The primary endpoint defined for this trial was the incidence of unfavorable outcome (treatment failure or relapse), while the secondary outcomes were time to unfavorable outcome and time to sputum culture conversion through the treatment period. Based on the evaluation of enrolled patients, at the end of 6 months, overall, 10% of them had an unfavorable outcome, which included 11% from the patient group having XDR-TB, and 8% from the patient group having MDR-TB. Further, a clinically relevant finding of this trial was that almost every patient had at least one adverse event that either occurred or worsened during the treatment period. Regardless of the fact that whether the patient was HIV positive or negative, both the groups had a similar frequency (17%) of developing serious adverse events. Moreover, the most common adverse events observed in this trial were peripheral neuropathy (81%), myelosuppression (48%), and anemia (37%).[20] Meanwhile, a new route of administration (intranasal) for pretomanid was being explored in animals in targeting anatomical TB reservoirs, like the brain.[21] Pretomanid, available in tablet form, is to be administered in combination with bedaquiline and linezolid as a part of the regime. It is to be given daily as a single dose of 200 mg for 26 weeks, preferably with food in adults with pulmonary MDR/XDR TB, however, it should not be administered with other drugs, extrapulmonary TB, and latent TB.[17] Any contraindication to bedaquiline and linezolid makes the regimen unsuitable to a patient. A few adverse effects associated with this combination, which either contraindicates its use or require significant precautions have been enlisted in [Table 2].
Table 2: Significant adverse effects and precautions of combination regimen of pretomanid, linezolid, and bedaquiline

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  Relevance to Patient Care Top


Even though TB has been a global health concern for decades, a permanent cure for it has never been achieved. Already, there are multiple regimes with different drugs and combinations, but still, the new cases and drug-resistant cases pose a major threat. Since isoniazid and rifampicin cannot be used in cases of drug resistance; hence, it becomes imperative to utilize less powerful agents (second-line agents).[22] In developing countries like India, it is necessary to consider the cost of treatment and drug regime before initiating the therapy. Implementation of Revised National TB Control Program (RNTCP) has led to a reduction in the cost of therapy, still, there are two-third of patients registered in the program who would require financial aid.[23] Moreover, this cost of therapy would be high only for drug-resistant TB cases. In this lieu, new drugs with different mechanisms of action are obviously required, so as to not only control the disease burden but also to contain the increase of drug-resistant cases. Pretomanid, recently FDA approved, seems promising in managing the unmet need of the latter.


  Conclusion Top


Pretomanid has got its approval on August 14, 2019, by US-FDA, based on its effectiveness proved in various trials.[9] This effectiveness proven in combination with bedaquiline and linezolid is yet to be assessed for any new adverse events or new pharmacokinetic characters. However, based on the benefits, this combination showed in various trials, it can be assumed that the same benefits could be extrapolated and reaped in the general population who are affected with MDR-TB or XDR-TB. Although this combination has been approved, the use of pretomanid in different regimes, with different combinations, can still be explored and tested for improved efficacy and patient outcome. However still, more head-to-head trials with the existing regimes are warranted in lieu to ascertain their similarity in terms of efficacy, safety, and tolerability, especially in patients with other comorbidities (HIV, renal insufficiency, hepatic disease, and more).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Global Tuberculosis Report; 2018. Available from: https://www.who.int/tb/publications/global_report/en/. [Last accessed on 2020 Mar 23].  Back to cited text no. 1
    
2.
Arinaminpathy N, Mandal S, Bhatia V, McLeod R, Sharma M, Swaminathan S, et al. Strategies for ending tuberculosis in the South-East Asian Region: A modelling approach. Indian J Med Res 2019;149:517-27.  Back to cited text no. 2
[PUBMED]  [Full text]  
3.
India TB Report; 2018. Available from: http://www.tbcindia.gov.in. [Last accessed on 2020 Mar 22].  Back to cited text no. 3
    
4.
Bahuguna A, Rawat DS. An overview of new antitubercular drugs, drug candidates, and their targets. Med Res Rev 2020;40:263-92.  Back to cited text no. 4
    
5.
Raviglione MC. Tuberculosis. In: Jameson JL, Kasper DL, Longo DL, Fauci AS, Hauser LS, Loscalzo J, editors. Harrison's Principles of Internal Medicine. 20th ed. New York: McGraw Hill; 2018. p. 1250.  Back to cited text no. 5
    
6.
Treatment of TB. Available from: https://www.tbcindia.gov.in/WriteReadData/l892s/8337437943TOG-Chapter4-TreatmentofTB.pdf. [Last accessed on 2020 Mar 23].  Back to cited text no. 6
    
7.
WHO | What is Multidrug-Resistant Tuberculosis (MDR-TB) and How Do We Control It? World Health Organization; 2018. Available from: https://www.who.int/features/qa/79/en/. [Last accessed on 2020 Mar 23].  Back to cited text no. 7
    
8.
WHO | Drug-resistant TB: XDR-TB FAQ. World Health Organisation. World Health Organization; 2018. Available from: https://www.who.int/tb/areas-of-work/drug-resistant-tb/xdr-tb-faq/en/. [Last accessed on 2020 Mar 23].  Back to cited text no. 8
    
9.
FDA Approves New Drug for Treatment-Resistant Forms of Tuberculosis that Affects the Lungs. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-resistant-forms-tuberculosis-affects-lungs. [Last accessed on 2020 Mar 22].  Back to cited text no. 9
    
10.
Highlights of Prescribing Information for Bedaquiline; 2012. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/204384s000lbl.pdf. [Last accessed on 2020 Apr 05].  Back to cited text no. 10
    
11.
Multi Drug Resistant TB Population in India (2018). Press Information Bureau, Government of India, Ministry of Health and Family Welfare. Available from: https://pib.gov.in/newsite/PrintRelease.aspx? relid=181612. [Last accessed on 2020 Apr 05].  Back to cited text no. 11
    
12.
Wares DF. Report on the Review of Programmatic Management of Drug-Resistant Tuberculosis (PMDT) Component of the Revised National TB Control Programme, India. 11-22, November 2019. Available from: https://www.who.int/docs/default-source/searo/tuberculosis/rglc-mission-report-india-2019.pdf?sfvrsn=9e4cf828_2. [Last accessed on 2020 Apr 05].  Back to cited text no. 12
    
13.
Highlights of Prescribing Information for Linezolid; 2000. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021130s032,021131s026,021132s031lbl.pdf. [Last accessed on 2020 Apr 05].  Back to cited text no. 13
    
14.
Tomlinson C. Linezolid. TB Online 2011. Available from: http://www.tbonline.info/posts/2011/8/24/linezolid/. [Last accessed on 2020 Apr 05].  Back to cited text no. 14
    
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Alliance T, Committee ADA. Pretomanid and BPaL Regimen for Treatment of Highly-Resistant Tuberculosis; 2019. Available from: https://www.fda.gov/media/128001/download. [Last accessed on 2020 Mar 23].  Back to cited text no. 15
    
16.
Stover CK, Warrener P, VanDevanter DR, Sherman DR, Arain TM, Langhorne MH, et al. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature 2000;405:962-6.  Back to cited text no. 16
    
17.
Highlights of Prescribing Information for Pretomanid; 2019. Available from: http://tballiance.org/sites/default/files/assets/Pretomanid_FullPrescribingInformation.pdf. [Last accessed on 2020 Mar 24].  Back to cited text no. 17
    
18.
Lenaerts AJ, Gruppo V, Marietta KS, Johnson CM, Driscoll DK, Tompkins NM, et al. Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium tuberculosis in a series of in vitro and in vivo models. Antimicrob Agents Chemother 2005;49:2294-301.  Back to cited text no. 18
    
19.
Ginsberg AM, Laurenzi MW, Rouse DJ, Whitney KD, Spigelman MK. Safety, tolerability, and pharmacokinetics of PA-824 in healthy subjects. Antimicrob Agents Chemother 2009;53:3720-5.  Back to cited text no. 19
    
20.
Conradie F, Diacon AH, Ngubane N, Howell P, Everitt D, Crook AM, et al. Treatment of highly drug-resistant pulmonary tuberculosis. N Engl J Med 2020;382:893-902.  Back to cited text no. 20
    
21.
Shobo A, Pamreddy A, Kruger HG, Makatini MM, Naicker T, Govender T, et al. Enhanced brain penetration of pretomanid by intranasal administration of an oil-in-water nanoemulsion. Nanomedicine (Lond) 2018;13:997-1008.  Back to cited text no. 21
    
22.
Prasad R, Singh A, Balasubramanian V, Gupta N. Extensively drug-resistant tuberculosis in India: Current evidence on diagnosis and management. Indian J Med Res 2017;145:271-93.  Back to cited text no. 22
[PUBMED]  [Full text]  
23.
Ananthakrishnan R, Muniyandi M, Jeyaraj A, Palani G, Sathiyasekaran BW. Expenditure pattern for TB treatment among patients registered in an Urban Government DOTS Program in Chennai City, South India. Tuberc Res Treat 2012;2012:747924.  Back to cited text no. 23
    



 
 
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