Journal of Bacteriology & Parasitology

Recent Advances in Effective Management of Patients with Multidrug-Resistant Tuberculosis (MDR-TB)

Suhail Ahmad^* Department of Microbiology, Faculty of Medicine, Health Sciences Center, Kuwait University, Kuwait, Kuwait
^*Correspondence: Suhail Ahmad, Department of Microbiology, Faculty of Medicine, Health Sciences Center, Kuwait University, Kuwait, Kuwait, Tel: 00965-24636503, Email:

Received: 27-Mar-2020 Published: 06-Apr-2020, DOI: 10.35248/2155-9597.20.11.368

Editorial

Tuberculosis (TB) is a major infectious disease worldwide. Most active TB disease cases in humans are caused by Mycobacterium tuberculosis [1]. Some cases in Africa are caused by Mycobacterium africanum while Mycobacterium bovis (bovine bacillus) can also cause TB in individuals who consume unpasteurized milk [1,2]. The global burden of TB is still enormous. According to the World Health Organization (WHO), an estimated 10 million new active TB diseases cases and 1.451 million deaths occurred in 2018, making TB as one of the top 10 killers and the leading cause of death from a single infectious agent [3]. Near 87% of TB cases occurred in 30 high TB burden countries and two-third of all cases in only eight (India, China, Indonesia, Philippines, Pakistan, Nigeria, Bangladesh and South Africa) countries [3]. Most active TB disease cases in high TB burden countries occur as a result of recent infection/reinfection while in low TB incidence countries, they usually arise as a result of reactivation of latent infection, acquired few to several years earlier [2,4,5].

Most TB deaths recorded in recent years have been attributed to emergence of drug-resistant TB, particularly multidrug-resistant (MDR)-TB (defined as infection with M. tuberculosis strain resistant at least to rifampicin and isoniazid, the two most effective first-line drugs) [6]. Worldwide, 484000 people developed TB in 2018 that was resistant to rifampicin, and of these, nearly 378000 (78%) were MDR-TB cases [3]. Compared to drug-susceptible TB, treatment of MDR-TB in resourcelimited settings is difficult due to lengthy, more expensive and more toxic regimens and leads to higher rates of clinical failure or disease relapse [6,7]. MDR-TB is also a risk factor for the development of extensively drug-resistant TB (XDR-TB), infection with MDR-TB strains additionally resistant to a fluoroquinolone and an injectable anti-TB drug, which is even more difficult to treat than MDR-TB [6,7]. Treatment success rates for susceptible TB, MDR-TB and XDR-TB are estimated as nearly 85%, 56% and 39%, respectively [3]. Rapid accurate diagnosis and effective treatment are crucial for proper management, which will also limit further transmission of MDRTB and evolution of XDR-TB [6-10].

Recent availability of two anti-TB drugs, bedaquiline and delamanid, has resulted in re-classification of available drugs which are now categorized into four groups (Group A to Group D) specifically for the treatment of MDR-TB and to prevent development of XDR-TB [11]. Other first-line drugs (pyrazinamide, ethambutol and possibly high-dose isoniazid and rifampin and/or rifabutin) have a minor role as a subclass of Group D agents mainly due to problems associated with accurate phenotypic drug susceptibility testing (DST) for these drugs [11].

Group A includes fluoroquinoloes with bactericidal and sterilizing activity (moxifloxacin, gatifloxacin or high-dose levofloxacin). They are preferred over injectable agents since their use is associated with a favorable outcome [11]. Group B includes amikacin, kanamycin and capreomycin (injectable drugs) which are bactericidal but lack sterilizing activity. In future, Group B may include three oral drugs; linezolid (or their derivatives sutezolid or tedizolid), bedaquiline and delamanid, if their use is more effective and less toxic than injectables [11,12]. Group C currently includes second-line oral drugs; linezolid, clofazimine, ethionamide, prothionamide, cycloserine and terizidone [11]. Linezolid is bactericidal with sterilizing action and its toxicity can be mitigated by dose reduction [12]. Clofazimine has strerilizing activity while ethionamide/ prothionamide exhibit some bactericidal activity but are also toxic [11].

Group D drugs are divided into three sub-groups; D1, D2 and D3. Group D1 includes pyrazinamide and ethambutol provided they are likely to be effective [13,14]. High-dose isoniazid may be used for M. tuberculosis isolates with mutations that confer lowlevel resistance to isoniazid [6,15]. Similarly, rifabutin may be used if M. tuberculosis isolates are susceptible to rifabutin [11,16]. Group D2 includes bedaquiline and delamanid that are bactericidal with sterilizing activity and have also been used simultaneously [8,17]. Group D3 includes p-aminosalicylic acid, thiacetazone, amoxycillin-clavulanate, imipenem-clavulanate and meropenem-clavulanate some of which are toxic [11]. The meropenem/clavulanate is bactericidal and may be used as a core drug for pre-XDR/XDR-TB cases with resistance to injectable drugs [11,18].

Patients with MDR-TB should be treated with at least five effective drugs during the intensive phase and the regimens should include pyrazinamide and four core drugs including one each from Group A and B and at least 2 drugs from Group C [11]. Other first-line drugs (ethambutol, high-dose isoniazid and/or rifabutin) may be used based on drug resistance profile. An agent from Group D2 or other agents from Group D3 may be added if sufficient numbers of effective drugs are not available. If genotypic testing indicates resistance to pyrazinamide or if it cannot be used due to toxicity concerns, drug regimens may be reinforced with a drug from Group C or D2 or from Group D3 [11]. The drugs should be carefully chosen for maximum benefits and minimum risk of adverse reactions and non-adherence. Recognizing and promptly managing adverse drug reactions in the treatment of MDR-TB should be a priority [3,11]. Culture conversion within 6 months of treatment is achieved in 80% of MDR-TB patients receiving delamanid as part of a multidrug regimen [19].

A shorter and cheaper ‘ Bangladesh regimen ’ of 9-months duration was recommended for male and female (if not pregnant) MDR-TB patients who do not have extrapulmonary TB, previous exposure to second-line drugs or resistance to pyrazinamide, ethambutol, kanamycin, moxifloxacin, ethionamide, or clofazimine [11,20]. This regimen originally included 4-months intensive phase with high-dose gatifloxacin, pyrazinamide, ethambutol, clofazimine, kanamycin, prothionamide and isoniazid and 5-months continuation phase with high-dose gatifloxacin, pyrazinamide, ethambutol, clofazimine with treatment success rate of nearly 90% [11,20]. However, gatifloxacin which played a central role in its success was recently withdrawn from the market due to toxicity concerns (dysglycaemia). The regimen has now been revised (and recommended by WHO) with moxifloxacin replacing gatifloxacin. It includes an initial phase of 4-6 months of treatment with pyrazinamide, kanamycin, moxifloxacin, prothionamide, clofazimine, high-dose isoniazid and ethambutol followed by 5 months of continuation phase with pyrazinamide, kanamycin, moxifloxacin and ethambutol [11,21]. However, in the USA, only 59 (10%) of 586 MDR-TB cases were eligible for the shorter regimen as MDR-TB isolates from most patients for whom full DST profiles were available were resistant to ethambutol and pyrazinamide [22]. It is pertinent to mention here that gatifloxacin was recently shown to be superior to levofloxacin- or moxifloxacin-based shorter regimens renewing the call for reintroduction of this efficacious, effective and inexpensive drug [23].

Individualized MDR-TB treatment with carefully chosen (such as bedaquiline, linezolid, clofazimine or meropenem) drugs and guided by genotypic and phenotypic DST can improve treatment outcomes [7,8]. Treatment success rate for MDR-TB depends heavily on resistance to additional drugs and is lower for MDRTB strains with additional resistance to fluoroquinolones alone than for those with resistance to second-line injectable drugs only [7,8]. In fact, an injection-free MDR-TB treatment regimen is now recommended in which kanamycin and capreomycin are not recommended at all. These regimens are also based on safety and mortality benefits of bedaquiline, the observations that the 9-11 month injectable-based 'Bangladesh' regimen was noninferior to longer regimens, and promising interim results of a novel 6 month 3-drug regimen comprising bedaquiline, pretomanid, and linezolid [8,24].

Clinical trials are evaluating 6-month oral regimens to simplify management and improve outcome of patients with MDR-TB [7,8,11].Three oral medicines (levofloxacin or moxifloxacin, bedaquiline and linezolid) are strongly recommended to be used in a longer individualized regimen together with other medicines ranked by a relative balance of benefits to harms to complete the regimen [7,11]. Most individualized MDR-TB regimens would include at least four agents likely to be effective in the first 6 months and three thereafter for a total duration of 18-20 months, modified depending upon patient response. The standardised, shorter MDR-TB regimen lasting for 9-12 months may also be offered to eligible patients though it may be less effective than an individualized longer regimen and will require a daily injectable agent (amikacin or meropenem/clavulanate) for at least four months [7,11,24]. Also, monitoring MDR-TB regimens with monthly culture and sputum microscopy rather than smear microscopy alone offers the best option to detect a failing regimen in time for corrective action [7].

The selection and optimal number of drugs and their route of administration, duration of the regimen and other desirable standards of patient care including recognition and management of adverse drug reactions will improve treatment outcome for MDR-TB. Until the results of all-oral long and modified all-oral short regimens are available, the WHO-has recommended that short MDR-TB regimens remain a better treatment option for management of eligible MDR-TB patients in low-income and middle-income countries with monitoring for ototoxicity. Furthermore, National Tuberculosis Programs of high MDR-TB incidence countries are required to strengthen their capacity for detection and management of fluoroquinolone-resistant MDR-TB (pre-XDR-TB) to prevent development of XDR-TB [25].

Acknowledgements

Research support from Kuwait University Research Sector grant MI01/18 is gratefully acknowledged.

REFERENCES

1. Ahmad S. The New approaches in the diagnosis and treatment of latent tuberculosis infection. Resp Res. 2010;11(1):169-172.
2. Ahmad S. Pathogenesis, immunology and diagnosis of latent Mycobacterium tuberculosis infection. Clin Develop Immunol. 2011;2011(1): 814943.
3. Global tuberculosis report 2019. World Health Organization. 2019.
4. Mokaddas E, Ahmad S, Samir I. Secular trends in susceptibility patterns of Mycobacterium tuberculosis isolates in Kuwait, 1996-2005. Int J Tuberc Lung Dis. 2008;12(3):319-25.
5. Ahmad S, Mokaddas E, Al-Mutairi NM. Prevalence of tuberculosis and multidrug resistant tuberculosis in the Middle East Region. Expert Rev Anti Infect Ther. 2018;16(9):709-721.
6. Ahmad S, Mokaddas E. Current status and future trends in the diagnosis and treatment of drug-susceptible and multidrug-resistant tuberculosis. J Infect Public Health. 2014;7(2):75-91.
7. Lange C, Dheda K, Chesov D, Mandalakas AM, Udwadia Z, Horsburgh CR Jr. Management of drug-resistant tuberculosis. Lancet. 2019;394(10202):953-966.
8. Dheda K, Gumbo T, Maartens G, Dooley KE, Murray M, Furin J, et al. The Lancet Respiratory Medicine Commission: 2019 update: epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant and incurable tuberculosis. Lancet Respir Med. 2019;7(9):820-826.
9. Mokaddas E, Ahmad S, Eldeen HS, Al-Mutairi N. Discordance between Xpert MTB/RIF assay and Bactec MGIT 960 culture system for detection of rifampin-resistant Mycobacterium tuberculosis isolates in a country with a low tuberculosis (TB) incidence. J Clin Microbiol. 2015;53(4):1351–1354.
10. Al-Mutairi NM, Ahmad S, Mokaddas E, Eldeen HS, Joseph S. Occurrence of disputed rpoB mutations among Mycobacterium tuberculosis isolates phenotypically susceptible to rifampicin in a country with a low incidence of multidrug-resistant tuberculosis. BMC Infect Dis. 2019;19(1):3-6.
11. Ahmad S, Mokaddas E. Recent advances in proper management of multidrug-resistant tuberculosis Kuw Med J. 2018;50(2):146-160.
12. Sotgiu G, Pontali E, Migliori GB. Linezolid to treat MDR-/XDR-tuberculosis: available evidence and future scenarios. Eur Respir J. 2015;45(1):25-29.
13. Al-Mutairi NM, Ahmad S, Mokaddas E. Molecular characterization of multidrug-resistant Mycobacterium tuberculosis (MDR-TB) isolates identifies local transmission of infection in Kuwait, a country with a low incidence of TB and MDR-TB. Eur J Med Res. 2019;24(1):38.
14. Ahmad S, Mokaddas E, Al-Mutairi N, Eldeen HS, Mohammadi S. Discordance across phenotypic and molecular methods for drug susceptibility testing of drug-resistant Mycobacterium tuberculosis isolates in a low TB incidence country. PLoS One. 2016;11(4):e0153563.
15. Al-Mutairi NM, Ahmad S, Mokaddas E. Performance comparison of four methods for detecting multidrug-resistant Mycobacterium tuberculosis strains. Int J Tuberc Lung Dis. 2011;15(1):110-115.
16. Farhat MR, Sixsmith J, Calderon R, Hicks ND, Fortune SM, Murray M. Rifampicin and rifabutin resistance in 1003 Mycobacterium tuberculosis clinical isolates. J Antimicrob Chemother. 2019;74(6):1477-1483.
17. Tadolini M, Lingtsang RD, Tiberi S, Enwerem M, D'Ambrosio L, Sadutshang TD, et al. First case of extensively drug-resistant tuberculosis treated with both delamanid and bedaquiline. Eur Respir J. 2016;48(3):935–938.
18. Tiberi S, Sotgiu G, D’Ambrosio L, Centis R, Abdo Arbex M, Alarcon Arrascue E, et al. Comparison of effectiveness and safety of imipenem/clavalunate-versus meropenem/clavalunate-containing regimens in the treatment of multidrug and extensively drug-resistant tuberculosis. Eur Respir J. 2016;47(6):1758-1766.
19. Seung KJ, Khan P, Franke MF, Ahmed S, Aiylchiev S, Alam M, et al. Culture conversion at six months in patients receiving delamanid-containing regimens for the treatment of multidrug-resistant tuberculosis. Clin Infect Dis. 2019;19(1):1084.
20. Aung KJ, Van Deun A, Declercq E, Sarker MR, Das PK, Hossain MA,et al. Successful '9-month Bangladesh regimen' for multidrug-resistant tuberculosis among over 500 consecutive patients. Int J Tuberc Lung Dis. 2014;18(10):1180-1187.
21. Chiang CY, Van Deun A, Rieder HL. Gatifloxacin for short, effective treatment of multidrug-resistant tuberculosis. Int J Tuberc Lung Dis. 2016;20(9):1143-1147.
22. Tsang CA, Shah N, Armstrong LR, Marks SM. Eligibility for a shorter treatment regimen for multidrug-resistant tuberculosis in the United States, 2011-2016. Clin Infect Dis. 2020;70(5):907-916.
23. Van Deun A, Decroo T, Kuaban C, Noeske J, Piubello A, Aung KJM, et al. Gatifloxacin is superior to levofloxacin and moxifloxacin in shorter treatment regimens for multidrug-resistant TB. Int J Tuberc Lung Dis. 2019;23(9):965-971.
24. Abidi S, Achar J, Assao Neino MM, Bang D, Benedetti A, Brode S, et al. Standardised shorter regimens versus individualised longer regimens for rifampin- or multidrug-resistant tuberculosis. Eur Respir J. 2020;55(3):1901467.
25. Van Deun A, Decroo T, Tahseen S, Trébucq A, Schwoebel V, Ortuno-Gutierrez N, et al. World Health Organization 2018 treatment guidelines for rifampicin-resistant tuberculosis: uncertainty, potential risks and the way forward. Int J Antimicrob Agents. 2020;55(1):105822.