Sterile Tuberculous Granuloma in a Patient With XDR-TB ......regimen, may have sterilized a...
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PRESENTED IN COLLABORATION WITH Sterile Tuberculous Granuloma in a Patient With XDR-TB Treated With Bedaquiline, Pretomanid and Linezolid Authors: Pauline JB Howell 1 , Caryn Upton 2 , Nokuphiwa Mvuna 1 , Christo van Niekerk 3 , Daniel Everitt 4 , Morounfolu Olugbosi 3 , Francesca Conradie 1 . Institutions: 1. University of Witwatersrand, Faculty of Health Sciences, Department of Medicine, South Africa; 2. TASK Applied Science, Cape Town, South Africa; 3. TB Alliance, Pretoria, South Africa; 4. TB Alliance, New York, USA. Introduction The Nix-TB study is an open-label trial to assess the safety and efficacy of a 6-month regimen of bedaquiline, pretomanid and linezolid in participants with pulmonary infection with either extensively drug-resistant tuberculosis (XDR-TB) or treatment intolerant/non- responsive multidrug-resistant TB. In a recent report of the first 75 patients to complete the regimen, 89% of the patients had a favourable outcome at primary end-point 1 . References 1. F Conradie, A Diacon, D Everitt, C Mendel, A Crook, P Howell, K Comins, M Spiegelman, Sustained high rate of successful treatment outcomes: interim results of 75 patients in the Nix-TB clinical study of pretomanid, bedaquiline and linezolid OA03-213-25, 49th World Conference on Lung Health of the International Union AgainstTuberculosis and Lung Disease (The Union). The Hague, Netherlands 2. Tho DQ, Estée Török M, Yen NTB, Bang ND, Lan NTN, Kiet VS, et al. Influence of antituberculosis drug resistance and Mycobacterium tuberculosis lineage on outcome in HIV-associated tuberculous meningitis. Antimicrob Agents Chemother. 2012;56(6):3074–9. 3. Thwaites GE, Lan NT, Dung NH, Quy HT, Oanh DT, Thoa NT, et al. Effect of antituberculosis drug resistance on response to treatment and outcome in adults with tuberculous meningitis. J Infect Dis. 2005;192(1):79–88. Heemskerk AD, Nguyen MTH, Dang HTM, Vinh Nguyen C Van, Nguyen LH, Do 4. TDA, et al. Clinical Outcomes of Patients with Drug-Resistant Tuberculous Meningitis Treated with an Intensified Antituberculosis Regimen. Clin Infect Dis. 2017;65(1):20–8. 5. Akkerman OW, Odish OFF, Bolhuis MS, De Lange WCM, Kremer HPH, Luijckx GJR, et al. Pharmacokinetics of Bedaquiline in Cerebrospinal Fluid and Serum in Multidrug-Resistant Tuberculous Meningitis. Clin Infect Dis. 2015;62(4):523–4. 6. Shobo A, Bratkowska D, Baijnath S, Naiker S, Somboro AM, Bester LA, et al. Tissue distribution of pretomanid in rat brain via mass spectrometry imaging. Xenobiotica. 2016;46(3):247–52. 7. Nau R, So F, Eiffert H. Penetration of Drugs through the Blood-Cerebrospinal Fluid/ Blood-Brain Barrier for Treatment of Central Nervous System Infections. ClinMicrobiol Rev. 2010;23(4):858–83. Discussion Drug-resistant tuberculous meningitis has an almost 100% mortality rate 2,3,4 . Many TB medications fail to penetrate the blood-brain- barrier (BBB) resulting in poor outcomes. While it cannot be conclusively stated, this case makes a strong argument that this shortened, all oral regimen, may have sterilized a tuberculoma. Assessing the BBB penetration of new drugs is a priority in this devastating disease. Literature suggests bedaquiline penetrates the BBB poorly 5 . Pretomanid penetrates well in animal studies (no human studies exist) 6 .Linezolid is known to have excellent penetration 7 . Case Description A 38 year-old, HIV-1 positive female (CD4: 101 cells/uL) was enrolled with pulmonary XDR-TB. She had no history of seizures and normal neurological findings on examination. She was started on NNRTI-based regimen two months prior to starting on trial. She changed to abacavir/ lamivudine/ lopinavir/ ritonavir for the trial and was virally suppressed. She sputum culture converted after four weeks of the Nix-TB regimen and completed 26 weeks of treatment with one treatment interruption for asymptomatic pancreatitis. She developed new-onset seizures one day after completing TB treatment and was hospitalized after a second seizure. Investigations Neurological examination and lumbar puncture were normal. An outpatient CT brain a month later showed a rim-enhancing lesion in the right temporal lobe suggestive of tuberculoma. Investigations for toxoplasmosis and neurocysticercosis were negative. Lymphoma was also considered. A neurologist assessment and MRI suggested tuberculoma (Image 1). An excisional biopsy was done the following month. Histological results confirmed a tuberculoma. Management She was started on phenytoin 300mg 3x/day orally after the first seizure. Anticonvulsants were tapered after a MRI six months post- surgery showed no new lesions. She experienced no further seizures. She made a full, uneventful recovery. Two years after completion of treatment , she remained sputum culture negative on her final trial sample. Biospy Results GeneXpert Positive Rifampicin resistant Culture Negative at 42 days Histology Granulomatous lesion with central necrosis Hain MTBDRplus Rifampicin resistant Isoniazid resistant Hain MTBDRsl Indeterminate Image 2: MRI 6 months post surgery Image 2: T2 weighed MRI 6 months post surgery with resolution of granuloma in right temporal lobe Image 1: T1 weighed MRI showing rim enhancing lesion in right temporal lobe measuring 11 x 15 x 11mm (AP x ML x CC) with mild perilesional vasogenic oedema
Transcript of Sterile Tuberculous Granuloma in a Patient With XDR-TB ......regimen, may have sterilized a...
PRESENTED IN COLLABORATION WITH
Sterile Tuberculous Granuloma in a Patient With XDR-TB Treated With Bedaquiline, Pretomanid and Linezolid
Authors: Pauline JB Howell1, Caryn Upton2, Nokuphiwa Mvuna1, Christo van Niekerk3, Daniel Everitt4, Morounfolu Olugbosi3, Francesca Conradie1. Institutions: 1. University of Witwatersrand, Faculty of Health Sciences, Department of Medicine, South Africa; 2. TASK Applied Science, Cape Town, South Africa; 3. TB Alliance, Pretoria, South Africa; 4. TB Alliance, New York, USA.
Introduction
The Nix-TB study is an open-label trial to assess the safety and efficacy of a 6-month regimen of bedaquiline, pretomanid and linezolid in participants with pulmonary infection with either extensively drug-resistant tuberculosis (XDR-TB) or treatment intolerant/non-responsive multidrug-resistant TB. In a recent report of the first 75 patients to complete the regimen, 89% of the patients had a favourable outcome at primary end-point1.
References1. F Conradie, A Diacon, D Everitt, C Mendel, A Crook, P Howell, K Comins, M Spiegelman, Sustained high rate of successful treatment outcomes: interim results of 75 patients in the Nix-TB clinical study of pretomanid, bedaquiline and linezolid OA03-213-25, 49th World Conference on Lung Health of the International Union AgainstTuberculosis and Lung Disease (The Union). The Hague, Netherlands2. Tho DQ, Estée Török M, Yen NTB, Bang ND, Lan NTN, Kiet VS, et al. Influence of antituberculosis drug resistance and Mycobacterium tuberculosis lineage on outcome in HIV-associated tuberculous meningitis. Antimicrob Agents Chemother. 2012;56(6):3074–9.3. Thwaites GE, Lan NT, Dung NH, Quy HT, Oanh DT, Thoa NT, et al. Effect of antituberculosis drug resistance on response to treatment and outcome in adults with tuberculous meningitis. J Infect Dis. 2005;192(1):79–88.Heemskerk AD, Nguyen MTH, Dang HTM, Vinh Nguyen C Van, Nguyen LH, Do 4. TDA, et al. Clinical Outcomes of Patients with Drug-Resistant Tuberculous Meningitis Treated with an Intensified Antituberculosis Regimen. Clin Infect Dis. 2017;65(1):20–8.5. Akkerman OW, Odish OFF, Bolhuis MS, De Lange WCM, Kremer HPH, Luijckx GJR, et al. Pharmacokinetics of Bedaquiline in Cerebrospinal Fluid and Serum in Multidrug-Resistant Tuberculous Meningitis. Clin Infect Dis. 2015;62(4):523–4.6. Shobo A, Bratkowska D, Baijnath S, Naiker S, Somboro AM, Bester LA, et al. Tissue distribution of pretomanid in rat brain via mass spectrometry imaging. Xenobiotica. 2016;46(3):247–52. 7. Nau R, So F, Eiffert H. Penetration of Drugs through the Blood-Cerebrospinal Fluid/ Blood-Brain Barrier for Treatment of Central Nervous System Infections. ClinMicrobiol Rev. 2010;23(4):858–83.
Discussion
Drug-resistant tuberculous meningitis has an almost 100% mortality rate2,3,4. Many TB medications fail to penetrate the blood-brain-barrier (BBB) resulting in poor outcomes. Whileit cannot be conclusively stated, this case makes a strong argument that this shortened, all oral regimen, may have sterilized a tuberculoma. Assessing the BBB penetration of new drugs is a priority in this devastating disease. Literature suggests bedaquiline penetrates the BBB poorly5. Pretomanid penetrates well in animal studies (no human studies exist)6.Linezolid is known to have excellent penetration7.
Case Description
A 38 year-old, HIV-1 positive female (CD4: 101 cells/uL) was enrolled with pulmonary XDR-TB. She had no history of seizures and normal neurological findings on examination.
She was started on NNRTI-based regimen two months prior to starting on trial. She changed to abacavir/ lamivudine/ lopinavir/ ritonavir for the trial and was virally suppressed. She sputum culture converted after four weeks of the Nix-TB regimen and completed 26 weeks of treatment with one treatment interruption for asymptomatic pancreatitis.
She developed new-onset seizures one day after completing TB treatment and was hospitalized after a second seizure.
Investigations
Neurological examination and lumbar puncture were normal. An outpatient CT brain a month later showed a rim-enhancing lesion in the right temporal lobe suggestive of tuberculoma.
Investigations for toxoplasmosis and neurocysticercosis were negative. Lymphoma was also considered. A neurologist assessment and MRI suggested tuberculoma (Image 1). An excisional biopsy was done the following month. Histological results confirmed a tuberculoma.
Management
She was started on phenytoin 300mg 3x/day orally after the first seizure. Anticonvulsants were tapered after a MRI six months post-surgery showed no new lesions. She experienced no further seizures. She made a full, uneventful recovery. Two years after completion of treatment , she remained sputum culture negative on her final trial sample.
Biospy Results
GeneXpertPositiveRifampicin resistant
Culture Negative at 42 days
HistologyGranulomatous lesion with central necrosis
Hain MTBDRplusRifampicin resistantIsoniazid resistant
Hain MTBDRsl Indeterminate
Image 2: MRI 6 months post
surgery
Image 2: T2 weighed MRI 6 months post surgery with resolution of granuloma in right temporal lobe
Image 1: T1 weighed MRI showing rim enhancing lesion in right temporal lobe measuring 11 x 15 x 11mm (AP x
ML x CC) with mild perilesional vasogenic oedema
