MDR-TBPhase 3STREAMNCT02409290
The Evaluation of a Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients With MDR-TB
A Phase 3 study testing Regimen A locally-used WHO-approved MDR-TB regimen (2011 guideline), Moxifloxacin and Clofazimine in people with MDR-TB, run by IUATLD, Inc at 13 sites in 7 countries.
Trial summary
Tuberculosis (TB) is a common, infectious, bacterial disease that is spread when an infected person transmits their saliva through the air by coughing or sneezing. Despite the availability and effectiveness of affordable six-month treatments for tuberculosis (TB), the worldwide control of this disease is currently… Read more about this study
- Who is it for?
- Ages 15 years and older
- Conditions the study is for
- MDR-TB
- What is being tested?
- Regimen A locally-used WHO-approved MDR-TB regimen (2011 guideline), Moxifloxacin and Clofazimine
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 588 participants
- Where
- 13 sitesin 7 countries
- Study dates
- Mar 2016to 2 May 2023
- Phase
- Phase 3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 15 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Consent: Is willing and able to give informed consent to participate in the trial treatment and follow-up (signed or witnessed consent if the patient is illiterate). If the patient is below the age of consent (according to local regulations), the parent/caregiver should be able and willing to give consent, and the patient be informed about the study and asked to give positive assent, if feasible
- Age: Is aged 18 years or older (Stage 1) or 15 years or older (Stage 2)
- AFB or GeneXpert results: Has a positive AFB sputum smear result at screening (at least scanty), or a positive GeneXpert result (with a cycle threshold (Ct) value of 25 or lower) from a test performed at screening or from a test performed within the four weeks prior to screening
- Has evidence of resistance to rifampicin either by line probe assay (Hain Genotype), GeneXpert or culture-based drug susceptibility testing (DST), from a test performed at screening or from a test performed within the four weeks prior to screening
- Is willing to have an HIV test and, if positive, is willing to be treated with ART in accordance with the national policies but excluding ART contraindicated for use with bedaquiline
- Is willing to use effective contraception: pre-menopausal women or women whose last menstrual period was within the preceding year, who have not been sterilised must agree to use a barrier method or an intrauterine device unless their partner has had a vasectomy; men who have not had a vasectomy must agree to use condoms. In Stage 2 pre-menopausal women or women whose last menstrual period was within the preceding year, who have not been sterilised must agree to use two methods of contraception, for example a hormonal method and a barrier method
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- Resides in the area and expected to remain for the duration of the study.
- Has had a chest X-ray that is compatible with a diagnosis of pulmonary TB (if such a chest X-ray taken within 4 weeks of randomisation is available, a repeat X-ray is not required)
- Has normal K+, Mg2+ and corrected Ca2+ at screening.
Who cannot join
- Is infected with a strain of M. tuberculosis resistant to second-line injectables by line probe assay (Hain Genotype) from a test performed at screening or from a test performed within the four weeks prior to screening
- Is infected with a strain of M. tuberculosis resistant to fluoroquinolones by line probe assay (Hain Genotype) from a test performed at screening or from a test performed within the four weeks prior to screening
- Has tuberculous meningitis or bone and joint tuberculosis
- Is critically ill, and in the judgment of the investigator, unlikely to survive more than 4 months
- Is known to be pregnant or breast-feeding
- Is unable or unwilling to comply with the treatment, assessment, or follow-up schedule
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- Is unable to take oral medication
- Has AST or ALT more than 5 times the upper limit of normal for Stage 1, and AST or ALT more than 3 times the upper limit of normal for Stage 2
- Has any condition (social or medical) which in the opinion of the investigator would make study participation unsafe
- In the investigator's opinion the patient is likely to be eligible for treatment with bedaquiline according to local guidelines due to a pre-existing medical condition such as hearing loss or renal impairment
- Is taking any medications contraindicated with the medicines in any trial regimen
- Has a known allergy to any fluoroquinolone antibiotic
- Is currently taking part in another trial of a medicinal product
- Has a QT or QTcF interval at screening or immediately prior to randomisation of more than or equal to 500 ms for Stage 1, and more than or equal to 450 ms for Stage 2
- In addition to the criteria above, for Stage 2 only, a patient will not be eligible for randomisation to the study if he/she:
- Has experienced one or more of the following risk factors for QT prolongation:
- A confirmed prolongation of the QT or QTcF more than or equal to 450 ms in the screening ECG (retesting to reassess eligibility will be allowed once using an unscheduled visit during the screening phase)
- Pathological Q-waves (defined as Q-wave more than 40 ms or depth more than 0.4-0.5 mV)
- Evidence of ventricular pre-excitation (e.g., Wolff Parkinson White syndrome)
- Electrocardiographic evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block
- Evidence of second or third degree heart block
- Intraventricular conduction delay with QRS duration more than 120 ms
- Bradycardia as defined by sinus rate less than 50 bpm
- Personal or family history of Long QT Syndrome
- Personal history of cardiac disease, symptomatic or asymptomatic arrhythmias, with the exception of sinus arrhythmia
- Syncope (i.e. cardiac syncope not including syncope due to vasovagal or epileptic causes)
- Risk factors for Torsades de Pointes (e.g., heart failure, hypokalaemia, or hypomagnesemia)
- Has received treatment for MDR-TB in the 12 weeks prior to screening, other than the maximum permitted treatment specified in Section 5.2.1
- Has a history of cirrhosis and classified as Child's B or C at screening or a bilirubin more than 1.5 times upper limit of normal.
- Has an estimated creatinine clearance (CrCl) less than 30 mL/min based on the Cockcroft-Gault equation
- Is HIV positive and has a CD4 count less than 50 cells/mm3
- Has pancreatic amylase elevation more than two times above the upper limit of normal
- Has a history of alcohol and/or drug abuse
- Has had previous treatment with bedaquiline
- Has taken rifampicin in the seven days prior to randomisation
- There has been a delay of more than four weeks between the screening consent and randomisation
- Is an employee or family member of the investigator or study site staff with direct involvement in the proposed study.
Trial locations and contacts
13 sites in 7 countries.
13 sites in 7 countries
South Africa4 sites
King Dinizulu Hospital
Durban
Helen Joseph Hospital
Johannesburg
Doris Goodwin Hospital
Pietermaritzburg
Empilweni TB Hospital
Port Elizabeth
India3 sites
BJ Medical College Civil Hospital
Ahmedabad
The National Institute for Research in Tuberculosis
Chennai
Rajan Babu Institute for Pulmonary Medicine and Tuberculosis
New Delhi
Ethiopia2 sites
Armauer Hanssen Research Institute
Addis Ababa
St. Peter's Tuberculosis Specializes Hospital
Addis Ababa
About this study
Official title: STREAM: The Evaluation of a Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients With MDR-TB
Tuberculosis (TB) is a common, infectious, bacterial disease that is spread when an infected person transmits their saliva through the air by coughing or sneezing. Despite the availability and effectiveness of affordable six-month treatments for tuberculosis (TB), the worldwide control of this disease is currently being impacted by the emergence of multidrug resistant TB (MDR-TB). MDR-TB refers to TB that is resistant to at least isoniazid and rifampicin. These are the two most powerful first-line drugs used to treat pulmonary TB. MDR-TB usually develops while a person is taking TB treatment due to either inappropriate treatment or failure of patients to comply with their treatment. This strain of drug-resistant bacteria can also be spread to other people through the air. With the incident rate of MDR-TB on the rise, there is a need to investigate optimal treatment regimens using effective drugs.
Read the detailed description
The STREAM study is an international, multi-centre, parallel-group, open-label, randomised, controlled trial in patients with multi-drug resistant tuberculosis (MDR-TB) including patients with rifampicin-resistant and isoniazid-sensitive TB.
Background and Rationale:
In 2011, World Health Organisation (WHO) guidelines for the treatment for MDR-TB recommended an intensive phase of treatment based on at least four drugs known to be effective and given for a minimum of 20 months; this is referred to as the WHO 2011 long regimen. Outcomes with this approach are generally poor. In the most recent WHO TB surveillance report only 50% of MDR-TB patients were successfully treated and a recent meta-analysis reported on average 62% successful outcome and a mortality of 11%.
In 2010, Van Deun et al (2010) reported excellent long-term outcomes in a cohort of over 200 patients in Bangladesh with MDR-TB who were treated with a regimen given for only nine to 11 months. Such a regimen, if successful, would represent a considerable advance over current practice. Evaluation of this regimen is the objective of Stage 1 of STREAM.
In 2016, following review of the available data, the WHO MDR TB treatment guidelines were modified to recommend a 9-12 month shortened regimen under specific conditions similar to Regimen B used in STREAM Stage 1 (referred to as the WHO 2016 short regimen).
Bedaquiline is a novel diarylquinoline antibiotic with bactericidal activity. In a phase II trial of patients with MDR-TB time to culture conversion was significantly less in patients receiving bedaquiline compared to those receiving an optimised background regimen only (Diacon et al (2012). In December 2012 the US Food and Drug Administration (FDA) approved bedaquiline as part of the treatment regimen for MDR-TB when other agents are unavailable. Stage 2 of STREAM was designed to investigate ways in which Regimen B could be improved either by removing the second-line injectable, which is associated with severe drug toxicity, or by shortening the regimen to 6 months.
Treatments that are evaluated within the STREAM trial include:
Regimen A The locally-used MDR-TB regimen in accordance with 2011 WHO MDR-TB treatment guidelines.
Regimen B is based on the regimen described by Van Deun 2010. At the start of STREAM this consisted of clofazimine, ethambutol, moxifloxacin, and pyrazinamide given for 40 weeks, supplemented by isoniazid, kanamycin, and prothionamide in the first 16 weeks (intensive phase). ); this combination is referred to as Regimen Bmox. With Version 8.0 of the protocol Regimen B is modified by replacement of moxifloxacin with levofloxacin (referred to as Regimen Blev). Regimen B without specification of which fluoroquinolone is in the regimen refers to either (Bmox or Blev).
Regimen C is a 40-week all-oral regimen consisting of bedaquiline, clofazimine, ethambutol, levofloxacin, and pyrazinamide given for 40 weeks supplemented by isoniazid and prothionamide for the first 16 weeks (intensive phase).
Regimen D is a 28-week regimen consisting of bedaquiline, clofazimine, levofloxacin, and pyrazinamide given for 28 weeks supplemented by isoniazid and kanamycin for the first 8 weeks (intensive phase).
The primary objectives of the STREAM2 trial are:
To assess whether the proportion of participants with a favourable efficacy outcome at week 76 on Regimen C is non-inferior to that on Regimen B
Study Population: Stage 2 will aim to randomise at least 200 patients to each of Regimens B and C.
All patients will be followed up to Week 132. The primary analysis will be based on the data accrued to Week 76 and is based on the proportion of patients with a favourable outcome at that time point ; the data accrued to Week 132 will be used in secondary analyses.
Although the STREAM study is an open-label study, wherever possible it will be conducted masked to treatment allocation.
- Conditions
- MDR-TB
- Being tested
- Regimen A locally-used WHO-approved MDR-TB regimen (2011 guideline), Moxifloxacin, Clofazimine, Ethambutol, Pyrazinamide
- Medical subject headings
- Tuberculosis, Multidrug-Resistant
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Regimen A locally-used WHO-approved MDR-TB regimen (2011 guideline)Drug
Drug: Locally-used WHO-approved MDR-TB regimen
MoxifloxacinDrug
Also called Avelox
Moxifloxacin is an 8-methoxy quinolone, and an anti-bacterial fluoroquinolone
ClofazimineDrug
Also called Lamprene
Clofazimine, is an antileprosy and anti-bacterial agent. Its chemical name is 3-(p-chloroanilino)-10-(p-chlorophenyl)-2, 10-dihydro-2-isopropyliminophenazine.
EthambutolDrug
Also called Myambutol
Ethambutol is a bacteriostatic that acts against virtually all strains of Mycobacterium tuberculosis and M. bovis and is also active against other mycobacteria such as M. Kansasii.
PyrazinamideDrug
Also called Zinamide
Pyrazinamide is bactericidal against intracellular mycobacterium tuberculosis. It is a prodrug that is converted into its active form, pyrazinoic acid, by a mycobacterial enzyme, pyrazinamidase, as well as through hepatic metabolism.
IsoniazidDrug
Also called Nydrazid, Isotamine
Isoniazid is a bactericidal in vitro and in vivo against actively dividing tubercle bacilli. Its primary action is to inhibit the synthesis of long-chain mycolic acids, which are unique constituents of mycobacterial cell wall.
ProthionamideDrug
Also called Peteha
Prothionamide has a bacteriostatic action.
KanamycinDrug
Also called Kantrex
Kanamycin is a bactericidal antibiotic from the group of aminoglycosides.
LevofloxacinDrug
Also called Levaquin
Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone class that acts on the DNA-DNA-gyrase complex and topoisomerase IV. It is the S (-) enantiomer of the racemic active substance ofloxacin.
BedaquilineDrug
Also called SIRTURO
Bedaquiline is a novel diarylquinoline antibiotic with bactericidal activity
| Study group | Role | What they receive |
|---|---|---|
| Regimen A | Active comparator | Regimen A locally-used WHO-approved MDR-TB regimen in accordance with 2011 WHO MDR-TB treatment guidelines. Receives: Drug: Regimen A locally-used WHO-approved MDR-TB regimen (2011 guideline) |
| Regimen B | Active comparator | Regimen B is based on the regimen described by Van Deun 2010. With Version 8.0 of the protocol Regimen B (Regimen Bmox) is modified by replacement of moxifloxacin with levofloxacin (Regimen Blev). Regimen B without specification of which fluoroquinolone is in the regimen refers to either (Bmox or Blev).
Product and dose for [<33 kg, 33-50kg, >50 kg] respectively:
Moxifloxacin [400mg, 600mg, 800mg] OR Levofloxacin [750mg, 750mg,1000mg]; Clofazimine [50mg,100mg,100mg]; Ethambutol [800mg,800mg,1200mg]; Pyrazinamide [1000mg,1500mg, 2000mg]; Isoniazid 300mg, 400mg, 600mg]; Prothionamide [250mg,500mg,750mg]; Kanamycin [15mg per kilogram body weight (maximum 1g)]. Receives: Drug: Moxifloxacin; Drug: Clofazimine; Drug: Ethambutol; Drug: Pyrazinamide; Drug: Isoniazid; Drug: Prothionamide; Drug: Kanamycin; Drug: Levofloxacin |
| Regimen C | Experimental | Regimen C is a 40-week all-oral regimen consisting of bedaquiline, clofazimine, ethambutol, levofloxacin, and pyrazinamide given for 40 weeks supplemented by isoniazid and prothionamide for the first 16 weeks (intensive phase).
Product and dose for [<33kg, 33-50kg, >50 kg] respectively:
Bedaquiline 400mg once daily for first 14 days/200 mg thrice weekly thereafter; Levofloxacin [750mg, 750mg,1000mg]; Clofazimine [50mg, 100mg, 100mg]; Ethambutol [800mg, 800mg, 1200mg]; Pyrazinamide [1000mg,1500mg, 2000mg]; Isoniazid [300mg, 400mg, 600mg]; Prothionamide [250mg, 500mg,750mg]. Receives: Drug: Clofazimine; Drug: Ethambutol; Drug: Pyrazinamide; Drug: Isoniazid; Drug: Prothionamide; Drug: Levofloxacin; Drug: Bedaquiline |
| Regimen D | Experimental | Regimen D is a 28-week regimen consisting of bedaquiline, clofazimine, levofloxacin, and pyrazinamide given for 28 weeks supplemented by isoniazid and kanamycin for the first 8 weeks (intensive phase).
Product and dose for [<33kg, 33 to<40kg, 40-50kg, >50-60 kg, >60 kg] respectively:
Bedaquiline 400mg once daily for first 14 days/200mg thrice weekly thereafter; Levofloxacin [750mg, 750mg, 750mg, 1000mg, 1000mg]; Clofazimine [50mg, 100mg, 100mg, 100mg, 100mg]; Pyrazinamide [1000mg,1500mg, 1500mg, 2000mg, 2000mg]; Isoniazid [400mg, 500mg, 600mg, 800mg, 900mg]; Kanamycin [15 mg per kilogram body weight (maximum 1g)]. Receives: Drug: Clofazimine; Drug: Pyrazinamide; Drug: Isoniazid; Drug: Kanamycin; Drug: Levofloxacin; Drug: Bedaquiline |
What is being measured
The primary outcome is the main question the study is designed to answer.
STREAM Stage 2 Primary Outcome Measure (the Proportion of Patients With a Favourable Outcome at Week 76)
The primary efficacy outcome of the STREAM Stage 2 comparison is status at Week 76 i.e. the proportion of patients with a favourable outcome at Week 76
Measured: 76 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Apr 2015 (estimated)
- Study startMar 2016
- Primary completion13 May 2022
- Study completion2 May 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (38)Papers the sponsor has linked to this study.
- Other trials for MDR-TBStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 588 participants (actual)
Sponsor and investigators
- Lead sponsor
- IUATLD, Inc
- Sponsor type
- University, hospital or other
- Collaborators
- Medical Research Council, Institute of Tropical Medicine, Belgium, Liverpool School of Tropical Medicine, Rede TB
- Responsible party
- Sponsor
- Investigators
- Sarah Meredith, MD, Principal investigator, Medical Research CouncilAndrew Nunn, PhD, Principal investigator, Medical Research Council
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02409290
- Sponsor's protocol ID
- 78372190/18148631 (Stage 1/2)
- Acronym
- STREAM
- Status last verified
- Sep 2023
- First submitted
- 31 Mar 2015
- Last updated
- 28 Sep 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- Yes: Data collected for the study, including individual participant data and a data dictionary defining each field in the set, will be made available no later than 12 months after the end of the trial through the TBPACT data repository.
Publications
Van Deun A, Maug AK, Salim MA, Das PK, Sarker MR, Daru P, Rieder HL. Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med. 2010 Sep 1;182(5):684-92. doi: 10.1164/rccm.201001-0077OC. Epub 2010 May 4.
PubMed 20442432Laserson KF, Wells CD. Reaching the targets for tuberculosis control: the impact of HIV. Bull World Health Organ. 2007 May;85(5):377-81; discussion 382-6. doi: 10.2471/blt.06.035329.
PubMed 17639223Zignol M, Hosseini MS, Wright A, Weezenbeek CL, Nunn P, Watt CJ, Williams BG, Dye C. Global incidence of multidrug-resistant tuberculosis. J Infect Dis. 2006 Aug 15;194(4):479-85. doi: 10.1086/505877. Epub 2006 Jul 12.
PubMed 16845631Wells CD, Cegielski JP, Nelson LJ, Laserson KF, Holtz TH, Finlay A, Castro KG, Weyer K. HIV infection and multidrug-resistant tuberculosis: the perfect storm. J Infect Dis. 2007 Aug 15;196 Suppl 1:S86-107. doi: 10.1086/518665.
PubMed 17624830Guidelines for the Programmatic Management of Drug-Resistant Tuberculosis: 2011 Update. Geneva: World Health Organization; 2011. Available from http://www.ncbi.nlm.nih.gov/books/NBK148644/
PubMed 23844450Seung KJ, Omatayo DB, Keshavjee S, Furin JJ, Farmer PE, Satti H. Early outcomes of MDR-TB treatment in a high HIV-prevalence setting in Southern Africa. PLoS One. 2009 Sep 25;4(9):e7186. doi: 10.1371/journal.pone.0007186.
PubMed 19779624Chiang CY, Enarson DA, Yu MC, Bai KJ, Huang RM, Hsu CJ, Suo J, Lin TP. Outcome of pulmonary multidrug-resistant tuberculosis: a 6-yr follow-up study. Eur Respir J. 2006 Nov;28(5):980-5. doi: 10.1183/09031936.06.00125705. Epub 2006 Jul 12.
PubMed 16837502Mitnick C, Bayona J, Palacios E, Shin S, Furin J, Alcantara F, Sanchez E, Sarria M, Becerra M, Fawzi MC, Kapiga S, Neuberg D, Maguire JH, Kim JY, Farmer P. Community-based therapy for multidrug-resistant tuberculosis in Lima, Peru. N Engl J Med. 2003 Jan 9;348(2):119-28. doi: 10.1056/NEJMoa022928.
PubMed 12519922Leimane V, Riekstina V, Holtz TH, Zarovska E, Skripconoka V, Thorpe LE, Laserson KF, Wells CD. Clinical outcome of individualised treatment of multidrug-resistant tuberculosis in Latvia: a retrospective cohort study. Lancet. 2005 Jan 22-28;365(9456):318-26. doi: 10.1016/S0140-6736(05)17786-1.
PubMed 15664227Orenstein EW, Basu S, Shah NS, Andrews JR, Friedland GH, Moll AP, Gandhi NR, Galvani AP. Treatment outcomes among patients with multidrug-resistant tuberculosis: systematic review and meta-analysis. Lancet Infect Dis. 2009 Mar;9(3):153-61. doi: 10.1016/S1473-3099(09)70041-6.
PubMed 19246019Diacon AH, Donald PR, Pym A, Grobusch M, Patientia RF, Mahanyele R, Bantubani N, Narasimooloo R, De Marez T, van Heeswijk R, Lounis N, Meyvisch P, Andries K, McNeeley DF. Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant tuberculosis: long-term outcome, tolerability, and effect on emergence of drug resistance. Antimicrob Agents Chemother. 2012 Jun;56(6):3271-6. doi: 10.1128/AAC.06126-11. Epub 2012 Mar 5.
PubMed 22391540Mann G, Squire SB, Bissell K, Eliseev P, Du Toit E, Hesseling A, Nicol M, Detjen A, Kritski A. Beyond accuracy: creating a comprehensive evidence base for TB diagnostic tools. Int J Tuberc Lung Dis. 2010 Dec;14(12):1518-24.
PubMed 21144235Johnson JL, Hadad DJ, Boom WH, Daley CL, Peloquin CA, Eisenach KD, Jankus DD, Debanne SM, Charlebois ED, Maciel E, Palaci M, Dietze R. Early and extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. Int J Tuberc Lung Dis. 2006 Jun;10(6):605-12.
PubMed 16776446Lancioni GE, Coninx F, Smeets PM. A classical conditioning procedure for the hearing assessment of multiply handicapped persons. J Speech Hear Disord. 1989 Feb;54(1):88-93. doi: 10.1044/jshd.5401.88.
PubMed 2521683Cegielski JP, Dalton T, Yagui M, Wattanaamornkiet W, Volchenkov GV, Via LE, Van Der Walt M, Tupasi T, Smith SE, Odendaal R, Leimane V, Kvasnovsky C, Kuznetsova T, Kurbatova E, Kummik T, Kuksa L, Kliiman K, Kiryanova EV, Kim H, Kim CK, Kazennyy BY, Jou R, Huang WL, Ershova J, Erokhin VV, Diem L, Contreras C, Cho SN, Chernousova LN, Chen MP, Caoili JC, Bayona J, Akksilp S; Global Preserving Effective TB Treatment Study (PETTS) Investigators. Extensive drug resistance acquired during treatment of multidrug-resistant tuberculosis. Clin Infect Dis. 2014 Oct 15;59(8):1049-63. doi: 10.1093/cid/ciu572. Epub 2014 Jul 23.
PubMed 25057101