Rifampicin-resistant Tuberculosis: A Global Health Dilemma

Tuberculosis (TB) remains a significant cause of high levels of global morbidity and mortality.[1] The World Health Organization (WHO) reported that 1.3 million global population passed away from TB in 2022. Internationally, TB is the 2nd leading infectious exterminator disease.[2] In addition, TB is the most common contagious disease in low- and middle-income countries ([LMICs] 30 countries around the globe), encompassing 87% of all recently diagnosed TB instances in 2022.[3-5] It has been reported that 66.67% of the total global TB burden belongs to eight countries of the globe. Those countries are India (27%), Indonesia (10%), China (7.1%), the Philippines (7.0%), Pakistan (5.7%), Nigeria (4.5%), Bangladesh (3.6%) and the Democratic Republic of the Congo (3.0%).[5] Consequently, globally, India endures the maximum TB encumbrance, coming up with almost 27% and 25% of TB cases and deaths, respectively.[6-8] However, antitubercular vaccines and antitubercular medications are available for over 90 and 60 years, respectively.[9] Antitubercular medication regimens require a minimum of 6–24 months of medication with rifampicin and three more drugs, such as isoniazid (INH), pyrazinamide and ethambutol, depending on individual clinical need.[10-12] The 6-month regimen for TB is only recommended for those individuals with no complications, and antitubercular medications are susceptible to Mycobacterium tuberculosis (Mtb).[13] Worldwide, antitubercular-resistant TB remains an extreme health menace.[14,15] Drug-resistant TB (DR-TB) increases both disease-related suffering and death rates, often causing treatment failure; raises multiple complications with complexity in therapeutic management and increases the cost of pharmacological intervention.[16-18] The WHO categorises DR-TB into five major classes: ‘INH-resistant TB, rifampicin-resistant TB (RR-TB), multidrug-resistant TB ([MDR-TB] resistant to INH and rifampicin), pre-extensively drug-resistant TB (pre-XDR-TB) which is MDR-TB with resistance to a fluoroquinolone and finally XDR-TB that is TB resistant to rifampicin, plus any fluoroquinolone, plus at least either bedaquiline or linezolid’.[19] Rifampicin-resistance (RR) raises considerable concern for the therapeutic intervention of TB and is an intimidation to halt the spread of TB around the globe.[20-22] One Chinese study was conducted to detect screening rates for RR-TB and RR-TB cases amongst laboratory-confirmed TB cases from 2016 to 2020. Rifampicin resistance cases were amplified year by year. This research revealed that the RR-TB screening rate and number of RR-TB patients identified in 2016–2020 were statistically significantly higher (χ2trend = 29.2, P < 0.001).[23] It has been reported that low quality and underdosing of rifampicin are principally responsible for developing resistance amongst Mtb.[24] Multiple studies said that RR evolves because of the RNA polymerase β subunit (rpoB) gene mutation, decreased penetrability antitubercular medication through the cell wall and development of outflow pumps by Mtb.[25,26] Multiple studies reported that imprudent prescribing, self-purchasing antimicrobials, defective dosages and nonconformity to the prescribed quantity of medicine promote antimicrobial resistance (AMR).[27-31] The current epidemic of antitubercular medication resistance is equally responsible for imprudent prescribing that includes incorrect doses.[32] It has been reported that resistant Mtb develops not because of poor prescribing quality (not following national or international guidelines) and imperfect adherence to antitubercular medicine. Nonetheless, it is also possible because of the biotransformation of the medicine before intake and the second-rate quality of antitubercular medication [Figure 1].[33]Figure 1: The various factors that may lead to antitubercular drug resistance. TB: Tuberculosis, Pre-XDR-TB: Pre-extensively drug-resistant TB, which is MDR-TB with resistance to a fluoroquinolone, XDR-TB that is TB resistant to rifampicin, plus any fluoroquinolone, plus at least either bedaquiline or linezolid dihydrofolate reductase. This figure has been drawn with the premium version of BioRender (https://biorender.com/Accessed on January 23rd), 2024 with license number AK267V4SEG. Image credit: Rahnuma Ahmad.Pharmacological intervention for RR-TB has been recommended with INH, a fluoroquinolone, e.g. levofloxacin or moxifloxacin (highly efficacious),[34,35] and ethambutol for 12–18 months.[34-36] The length of interventions is subject to clinical outcome.[28] Pyrazinamide must be included for an initial 2 months in drug-resistant TB to kill non-replicating semi-dormant bacilli in a low-pH environment.[34,37-40] Other potential drugs that are considered highly pharmacologically active are bedaquiline and linezolid for therapeutic intervention-resistant TB cases.[36] De Vos et al., 2021, conducted a study in South Africa and reported that out of 502 cases with RR-TB, only 8% accomplished the planned RR-TB care medication schedule. Amongst these patients, 64%, 20% and 16% had started an MDR-TB regimen, had first-line medication for some time and had not ever had an MDR-TB therapeutic regimen, respectively. Those cases never had medication principally because of death and did not ever return to the research group soon after the diagnosis was made.[41] Furthermore, medication adherence amongst study participants was inadequate, with considerable privation in following treatment regimens. Thereby, this study concluded that there is a requirement to espouse novel know-how in the healthcare system to combat RR-TB and save from atrocities of resistant TB.[40] One more Indonesian study reported that amongst 3415 suspected cases of RR-TB, they were identified by utilising the Xpert laboratory procedure.[42] Amongst RR-TB-positive cases, 14% were never return diagnoses. Amongst these suspected Indonesian cases, 10.5% (339) were detected as RR-TB positive. Out of 339 positive cases, 85% (288) commenced the initial second-line TB therapeutic regimen.[42] It was additionally noticed that a good proportion of cases did not ever commence the MDR-TB treatment regimen.[41] Patients residing in rural areas were statistically significantly associated with delays in diagnosis and treatment initiation.[41] This research finally recommended that further research be required for the realistic upgrading of ongoing RR-TB-related national health services.[42] Those TB patients diagnosed as RR-TB positive through the Xpert® MTB/RIF test are contemplated as the precise cases for MDR-TB therapeutic regimen.[43] Xpert® MTB/RIF is a novel laboratory investigation procedure that speedily identifies TB and RR concomitantly.[43] The second-line antitubercular medication includes fluoroquinolones (moxifloxacin and levofloxacin), diarylquinoline agent (bedaquiline fumarate), synthetic oxazolidinone (linezolid), a non-steroidal anti-inflammatory and anti-leprostatic medicine ([clofazimine], nevertheless, it equally possesses pharmacodynamic for several infective [typical TB, rhinoscleroma and severe acne] and non-infectious disorders [pyoderma gangrenosum, necrobiosis lipoidica, discoid lupus erythematosus and pustular psoriasis]),[44] antimicrobial (cycloserine, amikacin and para-aminosalicylic acid) and anti-hyperthyroidism (propylthiouracil).[43] Patients need to continue second-line agents for 18–20 months.[45] Those TB cases are spotted as RR-TB through the Xpert MTB/RIF evaluation and also required to confirm INH resistance by other approaches regarding sensitivity to ascertain the MDR-TB before starting this treatment regimen.[43] Imprudent and unprofessional antimicrobial prescribing and consumption that comprise self-purchasing or self-medication are measured as the principal charioteer of the mounting expansion and blowout of AMR, including antitubercular medication.[45-52] DR-TB considerably burdens public and private healthcare systems, communities and individuals worldwide.[53-55] Antimicrobial-resistant TB frequently devours an enormous amount of the public healthcare financing budget, increasing out-of-pocket expenses and concomitant funds in many LMICs.[53,56] It has been reported that to cease the universal TB epidemic spread, we need to ensure the prevention of first-hand TB infections and cases. Prevention of new cases of TB requires rapid spotting of TB patients, and timely effective medical intervention to quickly convert these open cases of TB to non-infectious is a fundamental mission.[54,57] Padayatchi et al., 2016, reported that there is a narrow pipeline for new drug research regarding TB. Consequently, to prevent rising rates of anti-TB medicine resistance, we need to be more prudent in the utilisation of new and old anti-TB medications. Padayatchi et al. further recommended no alternative to accepting antimicrobial stewardship to confirm persistent pharmacological efficiency and assuage imprudent or irrational utilisation of new antitubercular (linezolid, bedaquiline, delamanid, etc.) medications.[58] Delamanid, bedaquiline and linezolid have recently been approved by the US Food and Drug Administration and by the Medicines and Healthcare Products Regulatory Agency, UK,for the treatment of MDR and XDR-TB.[59,60] In this context, national and international policymakers’ medication-related issues should be more stringent regarding imprudent prescribing of antimicrobials, including antitubercular medication.[61,62] In addition, agencies controlling pharmacy outlets must be more rigorous regarding self-purchasing, self-medication and over-the-counter sales, especially scheduled (controlled or prescribed) medication [Figure 2].[63,64]Figure 2: Illustrates the Critical Findings of this Editorial. TB: Tuberculosis, Pre-XDR-TB: Pre-extensively drug-resistant TB, MDR-TB: Multidrug-resistant TB with resistance to a fluoroquinolone, XDR-TB: TB resistant to rifampicin, plus any fluoroquinolone, plus at least either bedaquiline or linezolid dihydrofolate reductase, Xpert MTB/RIF: Laboratory procedure for rapid identification of tuberculosis and rifampicin resistance concomitantly. This figure has been drawn with the premium version of BioRender (https://biorender.com/Accessed on January 22nd), 2024 with license number HQ267V2GAA. Image credit: Rahnuma Ahmad.Consent for publication The author reviewed and approved the final version and has agreed to be accountable for all aspects of the work, including any accuracy or integrity issues. Disclosure The author declares that they do not have any financial involvement or affiliations with any organisation, association or entity directly or indirectly with the subject matter or materials presented in this article. This includes honoraria, expert testimony, employment, ownership of stocks or options, patents or grants received or pending royalties. Data availability Information for this editorial is taken from freely available sources. Authorship contribution All authors contributed significantly to the work, whether in the conception, design, utilisation, collection, analysis and interpretation of data or all these areas. They also participated in the article’s drafting, revision or critical review, gave their final approval for the version that would be published, decided on the journal to which the paper would be submitted and made the responsible decision to be held accountable for all aspects of the work.