High-dose rifampicin in tuberculosis: Experiences from a Dutch tuberculosis centre

Charlotte Seijger, Wouter Hoefsloot, Inge Bergsma-de Guchteneire, Lindsey Te Brake, Jakko van Ingen, Saskia Kuipers, Reinout van Crevel, Rob Aarnoutse, Martin Boeree, Cecile Magis-Escurra, Charlotte Seijger, Wouter Hoefsloot, Inge Bergsma-de Guchteneire, Lindsey Te Brake, Jakko van Ingen, Saskia Kuipers, Reinout van Crevel, Rob Aarnoutse, Martin Boeree, Cecile Magis-Escurra

Abstract

Background: Recent evidence suggests that higher rifampicin doses may improve tuberculosis (TB) treatment outcome.

Methods: In this observational cohort study we evaluated all TB patients who were treated with high-dose rifampicin (> 10 mg/kg daily) in our reference centre, from January 2008 to May 2018. Indications, achieved plasma rifampicin exposures, safety and tolerability were evaluated.

Results: Eighty-eight patients were included. The main indications were low plasma concentrations (64.7%) and severe illness (29.5%), including central nervous system TB. Adjusted rifampicin dosages ranged from 900 mg to a maximum of 2400 mg (corresponding to 32 mg/kg) per day. Patients with severe illness received high-dose rifampicin immediately, the others had a higher dosage guided by therapeutic drug monitoring. Four patients developed hepatotoxicity, of which two were proven due to isoniazid. Re-introduction of high-dose rifampicin was successful in all four. Eighty-seven patients tolerated high-dose rifampicin well throughout treatment. Only one patient required a dose reduction due to gastro-intestinal disturbance.

Conclusion: High-dose rifampicin, used in specific groups of patients in our clinical setting, is safe and well-tolerated for the whole treatment duration. Measurement of drug exposures could be used as a tool/guide to increase rifampicin dosage if a reduced medication absorption or a poor treatment outcome is suspected. We suggest to administer high-dose rifampicin to patients with severe manifestations of TB or low rifampicin exposure to improve treatment outcome.

Conflict of interest statement

The authors have declared that no competing interests exist.

References

    1. van Ingen J, Aarnoutse RE, Donald PR, Diacon AH, Dawson R, Plemper van Balen G, et al. Why Do We Use 600 mg of Rifampicin in Tuberculosis Treatment? Clin Infect Dis. 2011;52(9):e194–9. 10.1093/cid/cir184
    1. Boeree MJ, Diacon AH, Dawson R, Narunsky K, du Bois J, Venter A, et al. A dose-ranging trial to optimize the dose of rifampin in the treatment of tuberculosis. Am J Respir Crit Care Med. 2015;191(9):1058–65. 10.1164/rccm.201407-1264OC
    1. Hu Y, Liu A, Ortega-Muro F, Alameda-Martin L, Mitchison D, Coates A. High-dose rifampicin kills persisters, shortens treatment duration, and reduces relapse rate in vitro and in vivo. Front Microbiol. 2015;6:641 10.3389/fmicb.2015.00641
    1. Gumbo T, Louie A, Deziel MR, Liu W, Parsons LM, Salfinger M, et al. Concentration-dependent Mycobacterium tuberculosis killing and prevention of resistance by rifampin. Antimicrob Agents Chemother. 2007;51(11):3781–8. 10.1128/AAC.01533-06
    1. Pasipanodya JG, McIlleron H, Burger A, Wash PA, Smith P, Gumbo T. Serum drug concentrations predictive of pulmonary tuberculosis outcomes. J Infect Dis. 2013;208(9):1464–73. 10.1093/infdis/jit352
    1. Dong Y, Zhao X, Kreiswirth BN, Drlica K. Mutant prevention concentration as a measure of antibiotic potency: studies with clinical isolates of Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2000;44(9):2581–4.
    1. Drlica K, Zhao X. Mutant selection window hypothesis updated. Clin Infect Dis. 2007;44(5):681–8. 10.1086/511642
    1. Svensson EM, Svensson RJ, Te Brake LHM, Boeree MJ, Heinrich N, Konsten S, et al. The Potential for Treatment Shortening With Higher Rifampicin Doses: Relating Drug Exposure to Treatment Response in Patients With Pulmonary Tuberculosis. Clin Infect Dis. 2018;67(1):34–41. 10.1093/cid/ciy026
    1. Aarnoutse RE, Kibiki GS, Reither K, Semvua HH, Haraka F, Mtabho CM, et al. Pharmacokinetics, Tolerability, and Bacteriological Response of Rifampin Administered at 600, 900, and 1,200 Milligrams Daily in Patients with Pulmonary Tuberculosis. Antimicrob Agents Chemother. 2017;61(11).
    1. Boeree MJ, Heinrich N, Aarnoutse R, Diacon AH, Dawson R, Rehal S, et al. High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial. Lancet Infect Dis. 2017;17(1):39–49. 10.1016/S1473-3099(16)30274-2
    1. Svensson RJ, Svensson EM, Aarnoutse RE, Diacon AH, Dawson R, Gillespie SH, et al. Greater Early Bactericidal Activity at Higher Rifampicin Doses Revealed by Modeling and Clinical Trial Simulations. J Infect Dis. 2018;218(6):991–9. 10.1093/infdis/jiy242
    1. Heemskerk AD, Bang ND, Mai NT, Chau TT, Phu NH, Loc PP, et al. Intensified Antituberculosis Therapy in Adults with Tuberculous Meningitis. N Engl J Med. 2016;374(2):124–34. 10.1056/NEJMoa1507062
    1. Ruslami R, Ganiem AR, Dian S, Apriani L, Achmad TH, van der Ven AJ, et al. Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial. Lancet Infect Dis. 2013;13(1):27–35. 10.1016/S1473-3099(12)70264-5
    1. Dian S, Yunivita V, Ganiem AR, Pramaesya T, Chaidir L, Wahyudi K, et al. A double-blinded randomised placebo-controlled phase II trial to evaluate high dose rifampicin for tuberculous meningitis: a dose finding study. Antimicrob Agents Chemother. 2018.
    1. Alsultan A, Peloquin CA. Therapeutic drug monitoring in the treatment of tuberculosis: an update. Drugs. 2014;74(8):839–54. 10.1007/s40265-014-0222-8
    1. Magis-Escurra C, Later-Nijland HM, Alffenaar JW, Broeders J, Burger DM, van Crevel R, et al. Population pharmacokinetics and limited sampling strategy for first-line tuberculosis drugs and moxifloxacin. Int J Antimicrob Agents. 2014;44(3):229–34. 10.1016/j.ijantimicag.2014.04.019
    1. Magis-Escurra C, van den Boogaard J, Ijdema D, Boeree M, Aarnoutse R. Therapeutic drug monitoring in the treatment of tuberculosis patients. Pulm Pharmacol Ther. 2012;25(1):83–6. 10.1016/j.pupt.2011.12.001
    1. Ruslami R, Nijland HM, Alisjahbana B, Parwati I, van Crevel R, Aarnoutse RE. Pharmacokinetics and tolerability of a higher rifampin dose versus the standard dose in pulmonary tuberculosis patients. Antimicrob Agents Chemother. 2007;51(7):2546–51. 10.1128/AAC.01550-06
    1. U.S. department of health and human services nioh, national cancer institute. Common terminology criteria for adverse events (CTCAE), version 4.0. 2009.
    1. Velasquez GE, Brooks MB, Coit JM, Pertinez H, Vargas Vasquez D, Sanchez Garavito E, et al. Efficacy and Safety of High-Dose Rifampin in Pulmonary Tuberculosis. A Randomized Controlled Trial. Am J Respir Crit Care Med. 2018;198(5):657–66. 10.1164/rccm.201712-2524OC
    1. Menzies D, Benedetti A, Paydar A, Royce S, Madhukar P, Burman W, et al. Standardized treatment of active tuberculosis in patients with previous treatment and/or with mono-resistance to isoniazid: a systematic review and meta-analysis. PLoS Med. 2009;6(9):e1000150 10.1371/journal.pmed.1000150
    1. de Steenwinkel JE, Aarnoutse RE, de Knegt GJ, ten Kate MT, Teulen M, Verbrugh HA, et al. Optimization of the rifampin dosage to improve the therapeutic efficacy in tuberculosis treatment using a murine model. Am J Respir Crit Care Med. 2013;187(10):1127–34. 10.1164/rccm.201207-1210OC
    1. de Steenwinkel JE, ten Kate MT, de Knegt GJ, Verbrugh HA, Aarnoutse RE, Boeree MJ, et al. Consequences of noncompliance for therapy efficacy and emergence of resistance in murine tuberculosis caused by the Beijing genotype of Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2012;56(9):4937–44. 10.1128/AAC.00124-12
    1. Magis-Escurra C, Anthony RM, van der Zanden AGM, van Soolingen D, Alffenaar JC. Pound foolish and penny wise-when will dosing of rifampicin be optimised? Lancet Respir Med. 2018;6(4):e11–e2. 10.1016/S2213-2600(18)30044-4
    1. Daskapan A, de Lange WC, Akkerman OW, Kosterink JG, van der Werf TS, Stienstra Y, et al. The role of therapeutic drug monitoring in individualised drug dosage and exposure measurement in tuberculosis and HIV co-infection. Eur Respir J. 2015;45(2):569–71. 10.1183/09031936.00142614
    1. van der Burgt EP, Sturkenboom MG, Bolhuis MS, Akkerman OW, Kosterink JG, de Lange WC, et al. End TB with precision treatment! Eur Respir J. 2016;47(2):680–2. 10.1183/13993003.01285-2015
    1. Srivastava S, Pasipanodya JG, Meek C, Leff R, Gumbo T. Multidrug-resistant tuberculosis not due to noncompliance but to between-patient pharmacokinetic variability. J Infect Dis. 2011;204(12):1951–9. 10.1093/infdis/jir658
    1. Baker MA, Harries AD, Jeon CY, Hart JE, Kapur A, Lonnroth K, et al. The impact of diabetes on tuberculosis treatment outcomes: a systematic review. BMC Med. 2011;9:81 10.1186/1741-7015-9-81
    1. Thwaites GE, van Toorn R, Schoeman J. Tuberculous meningitis: more questions, still too few answers. Lancet Neurol. 2013;12(10):999–1010. 10.1016/S1474-4422(13)70168-6
    1. Alkabab Y, Keller S, Dodge D, Houpt E, Staley D, Heysell S. Early interventions for diabetes related tuberculosis associate with hastened sputum microbiological clearance in Virginia, USA. BMC Infect Dis. 2017;17(1):125 10.1186/s12879-017-2226-y

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner