2. Name of the focal point in WHO submitting or supporting the application (where relevant)

Transcription

1 Essential Medicines List (EML) 2015 Application for the inclusion of terizidone in the WHO Model List of Essential Medicines, as reserve second line drugs for the treatment of multidrug resistant tuberculosis (complementary lists of anti tuberculosis drugs for use in adults and children) General items 1. Summary statement of the proposal for inclusion, change or deletion This application concerns the updating of section Antituberculosis medicines in the 2013 editions of both the WHO Model List of Essential Medicines (18th list) and the WHO Model List of Essential Medicines for Children (4th list)(1),(2). The proposal is to add terizidone to both the complementary list of anti tuberculosis medicines for adults and in children. Terizidone is not on the EML, but its sister medication, cycloserine, is on the complementary list in section Antituberculosis medicines The applicant considers that terizidone should be viewed as an essential medicine for patients with multidrug resistant (MDR TB) and extensively drug resistant (XDR TB) disease. In many low resource settings, patients with these forms of tuberculosis are inadequately treated and often die because not enough medications are available to compose a suitable regimen (3). Second line drugs for the treatment of M/XDR TB are frequently not available; and global stock outs occur regularly. Terizidone should become more widely available to specialized care centres of national TB programmes and other health care providers treating M/XDR TB patients. The inclusion of terizidone as an anti tuberculosis agent on the EML will encourage pharmaceutical manufacturers to invest more in its production and will facilitate its inclusion in the national EML and its registration in countries where MDR and XDR TB are a health threat. Additionally, this harmonization of treatment regimens is key to medication price reduction through an increase in the volume of medications purchased. A major initiative to help enhance the treatment of TB and MDR TB patients has recently attracted UNITAID funding up to USD 60 million and aims to create new regimens using combinations of both the new TB medicines and older medications such as terizidone (5). This request to the EML is thus very timely and in line with the position of WHO and its technical partners on the subject. If approved, it would synergise with their concerted efforts to improve outcomes and reduce avoidable mortality for the close to half a million patients estimated to develop MDR TB in the world every year. Globally, 30% (95%CI: 24% 35%) of patients with MDR TB have resistance to a fluoroquinolone, a second line injectable agent, or both i.e. XDR TB. These patients would be eligible to receive regimens containing new and repurposed TB drugs, when options to treat them with existing drugs have been exhausted [3] 2. Name of the focal point in WHO submitting or supporting the application (where relevant) The focal point is the Unit of Laboratories, Diagnostics and Drug resistance of the Global TB Programme of WHO Headquarters (WHO/HTM/GTB/LDR). The technical personnel directly concerned are Dennis FALZON, Linh Nhat NGUYEN and Ernesto JARAMILLO. This application was prepared in close collaboration with WHO/GTB by Elizabeth HARAUSZ and the GRADE Tables (Sections 10 and 11) by Dick MENZIES. The guidance of Nicola MAGRINI of WHO/EMP in this work is acknowledged.

2 3. Name of the organization(s) consulted and/or supporting the application Not applicable. 4. International Nonproprietary Name (INN, generic name) of the medicine The WHO INN (generic name) is terizidone (6, 22, 23). 5. Formulation proposed for inclusion; including adult and paediatric (if appropriate) (1,2,4) The proposed formulation is 250 mg capsule for both adults and children. A drug information sheet for terizidone is attached as Annex 1 [4]. 6. International availability sources, of possible manufacturers and trade names (4, 26) Generic Drug Trade Names Availability Logistics Terizidone Terivalidin, Terizidon, Terizidona Fatol in Germany is the only quality assured source (27). However, Sanofi pharmaceuticals manufactures terizidone in South Africa under the name Terivalidin and exports to Zambia, Angola, Mozambique, Botswana, Namibia and Kenya, with plans for future expansion (36). Tablets: no special storage or administrative needs. Store at room temperature in airtight container. 7. Whether listing is requested as an individual medicine or as an example of a therapeutic group Terizidone is applying as an individual medicine without a square box symbol. 8. Information supporting the public health relevance (epidemiological information on disease burden, assessment of current use, target population) Each year it is estimated that half a million new MDR TB cases emerge in the world and over 200,000 MDR TB patients die (3). Many MDR TB cases go undetected and are not placed on appropriate treatment, increasing the risk that they die and/or transmit drug resistant strains to others. In 2013, countries reported that about 100,000 patients started MDR TB treatment worldwide. The effectiveness of these efforts vary considerably and data on outcome reporting in recent years showed that only about half the MDR TB patients complete their treatment successfully (9). The rest die, fail treatment, interrupt treatment, or are otherwise lost to follow up. Given the low treatment success of MDR and XDR TB, every effort must be made to ensure that all possible medications used to treat MDR and XDR TB are widely available. This is particularly the case in about one third of MDR TB cases who have lost susceptibility to fluoroquinolones, second line injectable agents, or both (i.e. XDR TB) (3). XDR TB represents about 9 % of MDR TB cases and some 100 countries have now detected at least one such case (3). The transmissibility of XDR TB strains has been documented in outbreaks and regular reports of cases without a previous history of TB treatment (28 34); this poses a formidable, additional public health concern making the proper treatment of M/XDR TB patients all the more important. The likelihood of treatment success in MDR TB patients diminishes with the acquisition of additional resistance and is particularly low in XDR TB patients. The availability of all available possible medications to treat MDR/XDR TB is therefore essential to successfully treat these patients.

3 9. Treatment details (dosage regimen, duration; reference to existing WHO and other clinical guidelines; need for special diagnostics, treatment or monitoring facilities and skills) There are two main indications for terizidone in the treatment of MDR TB patients: 1) MDR TB treatment regimens : A typical MDR TB regimen is composed of pyrazinamide plus at least 4 second line anti TB drugs considered to be effective, including a later generation fluoroquinolones, a second line injectable, ethionamide (or prothionamide) and cycloserine or PAS(10). When one or more of these drugs are considered ineffective, as a result of in vitro resistance, severe intolerance, or prolonged use in the same patient, the regimen should be bolstered by Group 5 drugs. Terizidone, which is a Group 4 drug, can be used in the place of cycloserine. 2) XDR TB regimens : XDR TB is difficult to treat. WHO guidelines recommend using pyrazinamide and any other Group 1 medication that may be effective, an injectable agent and a higher generation fluoroquinolone (if the strain retains susceptibility)(4). However, often these medications are no longer effective. Therefore, use of all Group 4 agents that are likely to be effective, use of 2 or more Group 5 drugs and consideration of high dose isoniazid and investigational drugs are recommended (4). As stated above, terizidone can be used in the place of cycloserine. Terizidone Drug Treatment Regimen (4) Duration of treatment Adults: mg/kg/day, can divide into 2 doses Child: (>3kg and >28 days of age): mg/kg/day divided every 12 hours (25) Duration of TB treatment Special diagnostics, treatment or monitoring facilities and skills Baseline and monthly depression screening. 10. Summary of comparative effectiveness in a variety of clinical settings: [See Annex 2] 11. Summary of comparative evidence on safety: [See Annex 2] 12. Summary of available data on comparative cost and cost effectiveness within the pharmacological class or therapeutic group: Drug Source Price (US$) Terizidone Global Drug Facility 250 mg: /50 capsules MSH International Drug Price Indicator Guide Médecins sans Frontières (15) 250 mg: /tab 250 mg: /tab

4 Regulatory information 13. Summary of regulatory status of the medicine (in various countries) The table below summarizes the regulatory status of terizidone vis à vis the stringent regulatory authorities and WHO s Prequalification Programme. Drug Authority Regulatory status and indications Terizidone First marketed in Germany 1 January 1978 (15). Only quality assured supplier if Fatol, in Germany (15). However, terizidone is a scheduled medication in South Africa, regulated by the Medicines Control Council (35). Sanofi pharmaceuticals manufactures terizidone in South Africa under the name Terivalidin (36). United States Food and Drug Administration European Medicines Agency WHO List of Prequalified Medications Health Canada Australian Government Department of Health Pharmaceuticals and Medical Devices Agency (Japan) Not found Not found Not found Not found Not found Not found 14. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia, European Pharmacopeia) Drug Standard Reference (accessed ) Terizidone Not found in the British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia or European Pharmacopeia 15. Proposed (new/adapted) text that could be included in a revised WHO Model Formulary If this request is approved, it is proposed that identical modifications are made to the tabulations in the WHO Model List of Essential Medicines (18th list)(1), and the WHO Model List of Essential Medicines for Children (4th list)(2) to accommodate the new addition. It is recommended that the suggested change be made as shown hereunder : Complementary List Reserve second line drugs for the treatment of multidrug resistant tuberculosis (MDR TB) should be used in specialized centres adhering to WHO standards for TB control. Terizidone Capsule: 250 mg

5 References 1. WHO Model List of Essential Medicines [Internet]. 18th list. Geneva, World Health Organization; Available from: 2. WHO Model List of Essential Medicines for Children [Internet]. 4th list. Geneva, World Health Organization; Available from: 3. Global tuberculosis report 2014 (WHO/HTM/TB/ ) [Internet]. Geneva, World Health Organization Available from: 4. Companion handbook to the WHO guidelines for the programmatic management of drug resistant tuberculosis. (WHO/HTM/TB/2014.xx). Geneva, World Health Organization UNITAID Approves Grants of $160 million [Internet]. [cited 2014 Jul 26]. Available from: centre/releases/1352 unitaid approves grants of 160 million 6. WHO Drug Information. Recommended INN List 39. International Nonproprietary Names for Pharmaceutical Substances [Internet]. Geneva, World Health Organization Available from: 7. Udwadia ZF, Amale RA, Ajbani KK, Rodrigues C. Totally drug resistant tuberculosis in India. Clin Infect Dis Off Publ Infect Dis Soc Am Feb 15;54(4): WHO Totally Drug Resistant tuberculosis: a WHO consultation on the diagnostic definition and treatment options [Internet]. Available from: 9. Falzon D, Jaramillo E, Wares F, Zignol M, Floyd K, Raviglione MC. Universal access to care for multidrug resistant tuberculosis: an analysis of surveillance data. Lancet Infect Dis Aug;13(8): Guidelines for the programmatic management of drug resistant tuberculosis, 2011 Update. (WHO/HTM/TB/2011.6) [Internet]. Geneva, World Health Organization Available from: Ahuja SD, Ashkin D, Avendano M, Banerjee R, Bauer M, Bayona JN, et al. Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data metaanalysis of 9,153 patients. PLoS Med. 2012;9(8):e Jacobson KR, Tierney DB, Jeon CY, Mitnick CD, Murray MB. Treatment outcomes among patients with extensively drug resistant tuberculosis: systematic review and meta analysis. Clin Infect Dis Off Publ Infect Dis Soc Am Jul 1;51(1):6 14.

6 13. Falzon D, Gandhi N, Migliori GB, Sotgiu G, Cox H, Holtz TH, et al. Resistance to fluoroquinolones and second line injectable drugs: impact on MDR TB outcomes. Eur Respir J. 2013;42(1): UNICEF, WHO. Sources and prices of selected medicines for children. Including therapeutic food, dietary vitamin and mineral supplementation [Internet]. 2nd ed Available from: MSF, UNION. DR TB Drugs Under the Microscope [Internet]. Geneva, Switzerland and Paris, France; Available from: G_2011.pdf 16. Rüsch Gerdes S, Pfyffer G E, Casal M, Chadwick M, Siddiqi S. Multicenter laboratory validation of the BACTEC MGIT 960 technique for testing susceptibilities of Mycobacterium tuberculosis to classical second line drugs and newer antimicrobials. J Clin Microbiol 2006; 44: Andrews R H, Devadatta S, Fox W, Radhakrishna S, Ramakrishnan C V, Velu S. Prevalence of tuberculosis among close family contacts of tuberculosis patients in south India and influence of segregation of the patient on the early attack rate. Bull World Health Organ 1960; 23: Crofton J. The contribution of treatment to the prevention of tuberculosis. Bull Int Union Tuberc 1962; 32 (2): Brooks S M, Lassiter N L, Young E. A pilot study concerning the infection risk of sputum positive with tuberculosis patients on chemotherapy. Am Rev Respir Dis 1973; 108: Gunnels J, Bates J, Swindoll H. Infectivity of sputum positive tuberculosis patients on chemotherapy. Am Rev Respir Dis 1974; 109: Rouillon A, Perdrizet S, Parrot R. Transmission of tubercle bacilli: the effects of chemotherapy. Tubercle 1976; 57: Drugs@FDA. FDA Approved Drug Products. [internet] US Food and Drug Administration. October 21, 2014 [cited ]. Available at: _Name 23. Toxnet : Toxicology Data network. [internet]. US National Library of Medicine. NIH. [cited ]. Available at : Dooley KE, Obuku EA, Durakovic N, Belitsky V, Mitnick C, Nuermberger EL; Efficacy Subgroup, RESIST TB. World Health Organization group 5 drugs for the treatment of drug resistant tuberculosis: unclear efficacy or untapped potential? J Infect Dis May 1;207(9): Epub 2012 Jul MDR TB Weight Based Dosing Chart for children. Sentinel Project on Pediatric Drug Resistant Tuberculosis. [cited ] Available at: project.org/treatment guidance/

7 26. Lexicomp. [internet] Available at: Hwang TJ, Wares DF, Jafarov A, Jakubowiak W, Nunn P, Keshavjee S. Safety of cycloserine and terizidone for the treatment of drug resistant tuberculosis: a meta analysis. Int J Tuberc Lung Dis Oct;17(10): Dharmadhikari A S, Basaraba R J, Van Der Walt M L, et al. Natural infection of guinea pigs exposed to patients with highly drug resistant tuberculosis. Tuberculosis (Edinb) 2011; 91: Rüsch Gerdes S, Pfyffer G E, Casal M, Chadwick M, Siddiqi S. Multicenter laboratory validation of the BACTEC MGIT 960 technique for testing susceptibilities of Mycobacterium tuberculosis to classical second line drugs and newer antimicrobials. J Clin Microbiol 2006; 44: Andrews R H, Devadatta S, Fox W, Radhakrishna S, Ramakrishnan C V, Velu S. Prevalence of tuberculosis among close family contacts of tuberculosis patients in south India and influence of segregation of the patient on the early attack rate. Bull World Health Organ 1960; 23: Crofton J. The contribution of treatment to the prevention of tuberculosis. Bull Int Union Tuberc 1962; 32 (2): Brooks S M, Lassiter N L, Young E. A pilot study concerning the infection risk of sputum positive with tuberculosis patients on chemotherapy. Am Rev Respir Dis 1973; 108: Gunnels J, Bates J, Swindoll H. Infectivity of sputum positive tuberculosis patients on chemotherapy. Am Rev Respir Dis 1974; 109: Rouillon A, Perdrizet S, Parrot R. Transmission of tubercle bacilli: the effects of chemotherapy. Tubercle 1976; 57: Medicines Control Council. [internet] South Africa. [cited 3 Dec 2014]. Available at: Sanofi. [Internet]. Tuberculosis. [cited 3 Dec 2014]. Available at: D F ABC3 4D3C8AFF Migliori GB, Sotgiu G, Gandhi NR, Falzon D, DeRiemer K, Centis R, et al. Drug resistance beyond extensively drug resistant tuberculosis: individual patient data meta analysis. Eur Respir J Jul;42(1): Bastos ML, Hussain H, Weyer K, Garcia Garcia L, Leimane V, Leung CC, et al. Treatment Outcomes of Patients With Multidrug Resistant and Extensively Drug Resistant Tuberculosis According to Drug Susceptibility Testing to First and Second line Drugs: An Individual Patient Data Meta analysis. Clin Infect Dis Nov 15;59(10):

8 Annex 1. Drug information sheets (4) Drug information sheet for terizidone

9 Drug information sheet for terizidone (continued)

10 No of studies Design Annex 2. GRADE tables terizidone Risk of bias Quality assessment Inconsisten cy Grade Tables summary of evidence: Grade Table: Effect of Terizidone (TZD) on Outcomes in MDR-TB Indirectn ess Imprecision Treatment success (vs Failure/relapse/death from IPD Meta-analysis) Insufficient numbers to perform this analysis Other consideratio ns N. Events/N. patients Proportion, TZD & Others Summary of findings No TZD & Others Treatment success (vs Failure/relapse/death/default from Kvasnovsky (2011) et al observational study) Many other drugs 1 Observational Very serious None (only None Serious 2 60/90 used - limitations 1 study) 1 (67%) imprecision individualized Toxicity of TZD in treatment of DR-TB from Systematic review by Hwang et al (IJTLD 2012) 1 0 Observational Very serious Serious None Serious Many other drugs - individualized 35/116 (30%) Absolute Difference TZD - No TZD Quality 37% Very low Importance 3 Critical 33/450 (7.4%) 4 NR --- Very low Moderate Toxicity of all types from Cycloserine in treatment of DR-TB from Systematic review by Hwang et al (IJTLD 2012) 2 7 Observational Very serious Serious None Serious Many other drugs - individualized 33/2164 (9.1%) 5 ( %) NR --- Very low Moderate Major Psychiatric Toxicity from Cycloserine in treatment of DR-TB from Systematic review by Hwang et al (IJTLD 2012)

11 2 7 Observational Very serious Serious None Serious Many other drugs - individualized 33/2164 (5.7%) 5 ( %) NR --- Very low Moderate Notes: 1 No inconsistency because only one study 2 Imprecise because only one study, with very small number of participants. 3 Importance taken from Grade summary tables from WHO Expert meetings: on BDQ, Delamanid and MDR treatment guidelines. Toxicity considered only of moderate importance, due to poor alternatives and high mortality of MDR-TB. 4 From simple pooling. Authors (Hwang et al) concluded NOT significantly different from Cycloserine. 5 Pooled estimates from meta-analysis using der Simoniam & Laird methods

12 Table 1. Selected characteristics for studies of the efficacy of Meropenem, Terizidone Amoxicillin-clavulanate and macrolides in the treatment of multidrug and extensively drug resistant tuberculosis. Author (year) Study years ARV Total drugs Mean Age HIV + TB Study design/ Location of Sample treatment resistant Positive Cavitation on (range or (% of Resistance Population study size (n receiving / [mean (SD or smear x-ray SD) tested) Type Selection HIV +) range)] Meropenem De Lorenzo (2013) (1) Terizidone Ferrera (2004) (2) Dheda (2010) (3) Kvasnovsky (2011) (4) Seddon (2012) (5) O'Donnell (2013) (6) Diacon (2014) (7) Italy and Netherlands (24 38) 9.0 (6 / 8) Series1 : MDR: 77%; 24 %, Series 2 : MDR: 97%; 3% Italy ± MDR South Africa 174 Median 33 (IQR 26-45) 47 AZT, EFV, and 3TC (52/82) XDR South Africa ± XDR South Africa South Africa 114 Brazil, India, Latvia, Peru, Philippines, Russia, S. Africa, Thailand Median 50 months (19-108) Median 35 (30 42) (43/43) EFV-based regimens (50/82) MDR-XDR XDR MDR Two case series cohort study, among 4323 TB cases Cohort Age: >16yo cohort - All cases reported to NHLS Cohort Age: <15 yo Prospective cohort study RCT for bedaquiline 3.7 (2-9) 7 (IQR 6 8) Series1 87% Series2 30% 4.2 ± % Series1 24% Series2 16% 85% 100% Bilateral disease on X-ray: 93% Bilateral cavity 27% 7 (4 13) 62% 34% 59% 100% 83% Abbreviations: : Not available; MDR: Multidrug resistant; extensively drug resistant; 3TC: lamivudine; D4T: Stavudine; EFV: Efavirenz; NVP: Nevirapine; AZT: Zidovudine; LPV/RTV: Lopinovir ritonavir.

13 NHLS: National Health Laboratory Services. Series1 were individuals treated in Italy with an anti-tb regimen containing LZD and meropenem; Series2 were treated in the Netherlands with a regimen containing linezolid but NOT meropenem

14 Table 1. Selected characteristics for studies of the efficacy of Meropenem, Terizidone Amoxicillin-clavulanate and macrolides in the treatment of multidrug and extensively drug resistant tuberculosis (cont d) Mean Age ARV HIV + TB Study design/ Total drugs Location of years treatment Positive Cavitation Author (year) Study years Sample size (% of Resistance Population resistant [mean study (range or (n receiving / smear on x-ray tested) Type Selection (SD or range)] SD) HIV +) Terizidone (cont d) Pietersen (2014) (8) Seddon (2014) (5) Amoxicillin-clavulanate Kim (2007) (9) Cox (2007) (10) Mitnick (2008) (11) Jeon (2009) (12) South Africa South Africa South Korea (27-43) Uzbekistan Peru South Korea 48 MDR: 603 Median 36 months (18 66) Median 35 (16 69) Median 34 (17 72) 22 3TC, D4T, EFV, NVP, AZT and LPV/RTV (35 / 44) Regimen (32/32) XDR MDR-XDR 0.0 MDR-XDR MDR-XDR 32 ± MDR-XDR ± XDR Cohort* Cohort Age: <15 years cohort Prospective cohort Age: >16 years cohort cohort 16% 15% 76% 70% 8.4 ± 1.1 MDR: 5.3 ± % MDR: 55% 7.5 ± % Dheda (2010) (3) Leimane (2010) (13) Isaakidis (2012) (14) Jiang (2013) (15) South Africa Latvia India China 158 Median 33 (IQR 26-45) Median 43.1 Median ) MFX: 43.8±10.3 LFX: 45.1± AZT, EFV, and 3TC (52/82) XDR 3.0 MDR-XDR 100 (63/67) MDR-XDR 0.0 MDR-XDR Cohort Age: >16yo cohort Prospective Cohort cohort Median 7 (IQR 6 8) 100% 51% 46% MFX: 6.4 ± 1.1 LFX: 6.3 ± % 66%

15 Abbreviations: : Not available; MDR: Multidrug resistant; extensively drug resistant; 3TC: lamivudine; D4T: Stavudine; EFV: Efavirenz; NVP: Nevirapine; AZT: Zidovudine; LPV/RTV: Lopinovir ritonavir. * Patients admitted to Brooklyn Chest Hospital, Cape Town, Western Cape; Gordonia Hospital, Upington, Northern Cape; and Sizwe Tropical Diseases Hospital, Johannesburg, Gauteng province (results are for > 24 months)

16 Table 1. Continued Author (year) Study years Amoxicillin-clavulanate (Cont d) Tahaoglu (2001) (16) Torun (2005) (17) Shin (2007) (18) Palacios (2009) (19) Pietersen (2014) (8) Xu (2011) (20) Singla (2012) (21) Seung (2014) (22) Location of study Sample size Turkey Turkey Russia Peru 38 March Aug 2012 Jan March 2011 South Africa Mean Age (range) 36 ±12 42 ± (14 68) No AE: 31 (18 54) AE: 32.6 (17 65) years HIV + (% of tested) (27-43) 41 ARV treatment (n receiving / HIV +) TB Resistance Type 0.0 MDR 0.0 MDR MDR 8.0 MDR-XDR 3TC, D4T, EFV, NVP, AZT and LPV/RTV (35 / 44) XDR China (20-54) MDR Russia 244 August 1996 to April 2007 Peru Salvage only included : 213 No AE: 31 (18 54) AE: 32.6 (17 65) 28 (16) 0.0 MDR MDR Study design / Population Selection cohort cohort cohort case series of pregnant women Cohort* review of hospital records cohort cohort Total drugs resistant [mean (SD or range)] Positive smear Cavitation on x-ray 5 and 4 100% 96% 4.0 (3 9) Na 81% 8.4 ± 1.1 MDR: 5.3 ± (2 11) 100% 80% 100% 59% 50% Abbreviations: MDR: Multidrug resistant; extensively drug resistant; LAM: lamivudine; Stav: Stavudine; EFA: Efavirenz; NEV: Nevirapine; Zid: Zidovudine; LPN: Lopinovir ritonavir. Successful outcome: 36±12 unsuccessful outcome: 42±11. Successful outcome and unsuccessful outcome groups respectively. * Patients admitted to Brooklyn Chest Hospital, Cape Town, Western Cape; Gordonia Hospital, Upington, Northern Cape; and Sizwe Tropical Diseases Hospital, Johannesburg, Gauteng province. Salvage therapy refers to the change in regimen in response to persistent positive cultures (failure) during MDR therapy. Regimen added new (previously unused) drugs.

17 Interquartile range. Table 1. Continued Author (year) Azithromycin Pietersen (2014) (8) Clarithromycin Xu (2011) (20) Mitnick (2008) (11) Pietersen (2014) (8) Seung (2014) (22) Study years March Aug 2012 Jan March 2011 February 1999, to July 2002 March Aug 2012 August 1996 to April 2007 Location of study South Africa Sample size 107 China 39 Peru 651 South Africa Peru 107 Salvage only included : 213 Mean Age (range) 33 (27-43) 38 (20-54) 32±9.9 MDR: 31.5± (27-43) 28 (16) HIV + (% of tested) 41.1 ARV treatment (n receiving / HIV +) 3TC, D4T, EFV, NVP, AZT and LPV/RTV (35 / 44) TB Resistance Type XDR MDR 0.0 MDR: TC, D4T, EFV, NVP, AZT and LPV/RTV (35 / 44) 48 MDR: 603 XDR MDR Study Design/ Population Selection Cohort* review of hospital records cohort Cohort* cohort Total drugs resistant [mean (SD or range)] 8.4 ± 1.1 MDR: 5.3 ± 1.5 Positive smear Cavitation on x-ray 6 (2 11) 88% 88% 58% MDR: 55% 50%

18 Abbreviations: MDR: Multidrug resistant; extensively drug resistant; LAM: lamivudine; Stav: Stavudine; EFA: Efavirenz; NEV: Nevirapine; Zid: Zidovudine; LPN: Lopinovir ritonavir. * Patients admitted to Brooklyn Chest Hospital, Cape Town, Western Cape; Gordonia Hospital, Upington, Northern Cape; and Sizwe Tropical Diseases Hospital, Johannesburg, Gauteng province. Salvage therapy refers to the change in regimen in response to persistent positive cultures (failure) during MDR therapy. Regimen added new (previously unused) drugs. Interquartile range.

19 Table 2. Summary of the treatment characteristics and outcomes of the studies investigating the efficacy of Amoxicllin, Meropenem, Terizidone, and Macrolides for treatment of multidrug and extensively drug resistant tuberculosis. Patients Average Dose Standardized / Met Laserson Author (year) receiving drug Companion drugs number (duration in individualized Cured (n) Deaths (n) Failure (n) Defaults (n) Relapse (n) criteria / total drugs (n) months) treatment All patients received drug of interest Amoxicillin-clavulanate Mitnick (2008) (11) 48 / 48 CS, AMX/CLV, PAS, and CFZ (highly variable) 8.4 ± 1.1 MDR: 5.3 ± 1.5 Dose: Duration: 24.0 months ( ) Some patients received drug: Treatment outcomes stratified by receipt of drug of interest Meropenem De Lorenzo (2013) (1) Amoxicillin-clavulanate Seung (2014) (22) 37 / 98 ( Salvage only) 50 / 213 Linezolid (among others not mentioned) E or Z, KM or CM, Cipro or OFX, and ETO, PAS, and CS (highly variable) New: 2 (1-6) Total: 9 (5-13) 1 g, 3 times a day (51 [28-75] days) Individualized Fixed dose Individualized 29/48 5/48 11/48 3/48 Outcomes for those that received drug 31/37 Outcomes for those that did not receive drug 15/24 Outcomes for those that received drug 16 / 50 Outcomes for those that did not receive drug 49 / 163 Yes No: (3 month/ culture conversion) No (Culture conversion) Abbreviations: Cm: Capreomycin; Z: Pyrazinamide; E: Ethambutol, PAS: Para-amino-salicylic acid, ETO: Ethionamide, AMC/CLV: Amoxicillin-clavulanate; R: Rifampicin; H: Isoniazid; S: streptomycin; CS: Cycloserine; CFZ: Clofazamine; PTO: Prothionamide; PA: pasiniazide; MFX: Moxifloxacin; KM: Kanamycin; Cipro: Ciprofloxacin; and OFX: Ofloxacin. Number is estimated from a graph. Number of patients with terizidone where treatment was considered effective (treatment considered effective if (1) it is recognized as an agent for the treatment of TB7; (2) the patient had either never received it or received it for less than 3 months before XDR-TB treatment; and (3) patient isolates were not found to be resistant to the drug on DST). Number of those in salvage group not receiving AMX/CLV. Numbers are reported for those with sputum-culture conversions (comparing cases to controls group; p=0.03).

20 Table 2. Summary of the treatment characteristics and outcomes of the studies investigating the efficacy of Amoxicllin, Meropenem, Terizidone, and Macrolides for treatment of multidrug and extensively drug resistant tuberculosis (continued). Patients Average Dose Standardized / Cured Deaths Failur Defaults Relapse Met Laserson Author (year) receiving Companion drugs number (Mean individualized (n) (n) e (n) (n) (n) criteria drug / total drugs (n) duration mos) treatment Some patients received drug: Treatment outcomes stratified by receipt of drug of interest (cont d) Amoxicillin-clavulanate (cont d) Xu (2011) (20) Clarithromycin Xu (2011) (20) Seung (2014) (22) 5 / / 39 ( Salvage only) 44 / 213 CFZ and one or more of H, GFX, PTO, Z, CLR, MFX, PA, RFB, CM, PAS CFZ and one or more of H, GFX, PTO, Z, CLR, MFX, PA, RFB, CM, PAS E or Z, KM or CM, Cipro or OFX, and ETO, PAS, and CS (highly variable) 6 (4-7) Dose: (11.8 avg.) 6 (4-7) Dose: (Dur: 11.8) New: 2 (1-6) Total: 9 (5-13) Some patients received drug: Treatment outcomes reported overall - for entire cohort Individualized Individualized Individualized Terizidone Cured Deaths Ferrera (2004) (2) Dheda, 2010 (3) Kvasnovsky (2011) (4) Seddan (2012) (23) O'Donnell (2013) (6) 45 / 127 R, H, E, and S / / / / 114 KM, OFX, ETO E, and Z (Regimens highly variable) CM, Z, E, PAS, ETO, AMX/CLV, and R H, AMK, CM, OFX (Regimens highly variable) E, ETO, CM, PAS, Z, MFX, or OFX (Regimens highly variable) 7 (IQR 6-8) Dose: (Dur: 12 ± 11) Dose: (Dur: Median: 9.2) Outcomes for those that received drug 1/5 0/5 2/5 1/5 0/5 Outcomes for those that did not receive drug 14/34 0/34 7/34 3/34 0/34 Outcomes for those that received the drug 6/17 0/17 4/17 2/17 0 Outcomes for those that did not receive drug 8/22 0/22 7/22 3/22 0/22 Outcomes for those that received drug 14 / 44 Outcomes for those that did not receive drug 51 / 169 Failur e Defaults Relapse Yes Yes No (Culture conversion) Individualized 49 / / / / / 127 No Individualized 33/174 62/174 62/174 0/174 1/174 No 5.2 ± 0.7 N/A Individualized 16 / / 195 Median 6 (IQR 5-7) mg/kg (Dur: Median 18 (8 26)) Dose: (Dur: 12) No (Culture conversion) Individualized 91/111 11/111 10/111 8/111 9/111 Yes Individualized 25/114 48/114 70/114 19/114 Yes Abbreviations: Cm: Capreomycin; Z: Pyrazinamide; E: Ethambutol, PAS: Para-amino-salicylic acid, ETO: Ethionamide, AMC/CLV: Amoxicillin-clavulanate; R: Rifampicin; H: Isoniazid; S: streptomycin; CS: Cycloserine; CFZ: Clofazamine; PTO: Prothionamide; PA: Pasiniazide; MFX: Moxifloxacin; KM: Kanamycin; Cipro: Ciprofloxacin; and OFX: Ofloxacin

21 Number is estimated from a graph. Odds Ratio for amoxicillin in the salvage group: 1.1 (95% CI ). Number of cured for those not receiving the drug. Odds ratio for Terizidone: 1.24 (95% CI ).

22 Table 2. Summary of the treatment characteristics and outcomes of the studies investigating the efficacy of Amoxicllin, Meropenem, Terizidone, and Macrolides for treatment of multidrug and extensively drug resistant tuberculosis (continued). Patients Mean Standardized / receiving number Dose (duration Deaths Failure Defaults Relapse Met Laserson Author (year) Companion drugs individualized Cured (n) drug / drugs in months) (n) (n) (n) (n) criteria treatment total (%) (range) Some patients received drug: Treatment outcomes reported overall - for entire cohort Terizidone (Cont d) Diacon (2014) (7) Pietersen (2014) (8) Seddon (2014) (5) 51 / / /137 Bedaquiline, aminoglycoside, quinolone, ETO or PTO, Z, E, (highly variable) CM and PAS (Other treatments highly variable H, AMK, CM, and OFX (Regimens highly variable) 8 (IQR 6-10) Dose: (Dur: ) Individualized 62/132 12/132 35/132 38/132 Yes (WHO) Individualized 17 / / / / / 107 Yes Dose: (Dur: Median 17 IQR: ) Individualized 137/149 3/149 0/149 9/149 Yes Amoxicillin-clavulanate Cured Deaths Failure Defaults Relapse Tahaoglu, 2001 AMK, KM, S 2-4g daily 44/158 5 (16) (highly variable) (>18 ) Individualized 121/158 7/158 20/158 17/158 1/158 Yes OFX, PTH, PAS, CS Torun, g daily 50/263 RBT, CFZ, CM 5.3 (3-9) (17) (>18) (highly variable) Individualized 204/263 18/263 34/263 25/263 Yes Kim (Regimens highly 6 (3 Median 88/211 (2007) (9) variable) 12) 26 (1 136) Individualized 132/211 19/211 40/211 14/211 6/211 Yes Cox (2007) (10) Shin (2007) (18) Jeon (2009) (12) Leimane (2010) (13) 52/87 20/244 29/ /1027 Z, OFX, ETO, PAS, CS and either CM or KM (Regimens variable) PZA, SM, KM, CM, CS, LFX, and PAS. (Regimens highly variable) H, R, E, Z, S, KM, OFX, PAS, PTO, and CS (highly variable) ETO, Z, OFX, KM, CM, PTO, CS, PAS, THZ (highly variable Median 6 (IQR 5-7) (IQR 7-9) Dose: median 22 (range 18 30)) mg (Dur: 18.5, ]) Dose: (Dur: >18) Dose: (Dur 18 (IQR 12-30) Individualized 54/87 13/87 8/87 12/87 Yes Individualized 187/244 12/244 28/244 28/244 Yes Individualized 28/158 36/158 63/158 31/158 Yes Individualized MDR: 679/979 MDR: 56/979 MDR: 157/979 MDR: 143/979 Yes

23 18/48 4/48 27/48 3/48 Abbreviations: AMK: Amakacin; Cm: Capreomycin; Z: Pyrizinamide; E: Ethambutol, PAS: Para-amino-salicylic acid, ETO: Ethionamide, AMC/CLV: Amoxicillin-clavulanate; R: Rifampicin; H: Isoniazid; S: streptomycin; CS: Cycloserine; CFZ: Clofazamine; PTO: Protionamide; PA: Pasiniazide; THS: thioacetazone; MFX: Moxifloxacin; KM: Kanamycin; Cipro: Ciprofloxacin; and OFX: Ofloxacin. 51 patients on terizidone or cycloserine. Table 2. Summary of the treatment characteristics and outcomes of the studies investigating the efficacy of Amoxicillin, Meropenem, Terizidone, and Macrolides for treatment of multidrug and extensively drug resistant tuberculosis (continued). Patients Average Dose Standardized / Companion Cured Deaths Failure Defaults Met Laserson Author (year) receiving drug number (duration in individualized Relapse (n) drugs (n) (n) (n) (n) criteria / total drugs (n) months) treatment Some patients received drug: Treatment outcomes reported overall - for entire cohort (continued) Amoxicillin-clavulanate (cont d) Palacios (2009) (19) Dheda (2010) (3) Singla (2012) (21) Isaakidis (2012) (14) Jiang (2013) (15) Pietersen (2014) (8) Azithromycin Pietersen (2014) (8) Clarithromycin Mitnick (2008) (11) 17/38 66/174 23/29 24/ / / / / 48 KM, CM, AMK and S KM, OFX, ETO E, and Z ((Regimens highly variable) Median 6 (6-7) Z, CM, MFX, ETO, CS, and PAS MFX: 6.4±1.1 LFX: 6.3±1.2 CM and PAS (Regimens highly variable) CM and PAS (Regimens highly variable) CS, AMX/CLV, PAS, and CFZ 5 7 (IQR 6-8) MFX 5.6 ± 1.2 LFX 5.5 ± 1.9 Dose: (Dur: >18) Dose: Dur: Median 7.1 ( ) Dose: (Dur: > 12) Dose Dur: Median 10 (range ) MFX: 17.2±3.8 LFX: 16.9±5.1 Individualized 23/38 5/38 9/38 6/38 Yes Individualized 33/174 62/174 0/174 0/174 1/174 No Individualized 9/29 3/29 5/29 15/29 Yes Individualized 13/67 14/67 2/67 38/67 Yes Individualized MFX: 27/72 LFX: 29/86 MFX: 1/75 LFX: 1/86 MFX: 8/72 LFX: 17/86 MFX: 0/72 LFX: 2/86 MFX: 4/72 LFX: 5/86 8 (6-10) Individualized 22 / / / / / (6-10) Individualized 22/ / / / / ± 1.1 Dose: Dur: 14.5 Individualized 29/48 5/48 11/48 3/48 Yes Yes (cited Laserson et al.) Yes (cited Laserson et al.) Yes (cited Laserson et al.)

24 Pietersen (2014) (8) 80 / 107 (Regimens highly variable) CM and PAS (Regimens highly variable) MDR: 5.3 ± (6-10) ( ) Dose: Dur: Median 22.1 ( ) Individualized 22/ / / / / 107 Abbreviations: Cm: Capreomycin; Z: Pyrazinamide; E: Ethambutol, PAS: Para-amino-salicylic acid, ETO: Ethionamide, AMC/CLV: Amoxicillin-clavulanate; R: Rifampicin; H: Isoniazid; S: streptomycin; CS: Cycloserine; CFZ: Clofazamine; PTO: Prothionamide; PA: pasiniazide; MFX: Moxifloxacin; KM: Kanamycin; Cipro: Ciprofloxacin; and OFX: Ofloxacin Yes (cited Laserson et al.)

25 Table 3. Summary of the treatment characteristics and outcomes of the studies reporting the toxicity of Amoxicillin-clavulanate, Meropenem, Terizidone, and macrolides for treatment of any form of MDR or XDR-TB. Serious External Any adverse Drug was Protocol on Patients Avg Any adverse adverse effect Adverse standardized event/effect stopped toxicity Author (year) receiving Companion drugs number effect caused (Grade 3-4), outcome defined grading (from all because of assessment drug / total drugs (n) by drug caused by a priori (Yes/No) system drugs) adverse event (Yes/No) drug (Yes/No) All patients received drug of interest Meropenem Mitnick (2008) (11) 48 / 48 CS, AMX/CLV, PAS, and CFZ (Regimens highly variable) 8.4 ± 1.1 MDR: 5.3 ± (increased transaminase levels) No No No Some patients received drug: Adverse events reported for events attributed to drug of interest Terizidone E, ETO, CM, PAS, O'Donnell Z, MFX, or OFX Median 6 34 / 114 (2013) (6) (Regimens highly (IQR 5-7) 52/114 8/34 8/34 Yes Yes No variable) Clarithromycin Xu (2011) (20) Amoxicillin Xu (2011) (20) Cox (2007) (10) Shin (2007) (18) 17 / 39 5 / 39 52/87 20/244 CFZ, and one or more of H, GFX, PTO, Z, CLR, MFX, PA, RFB, CM, PAS CFZ and one or more of H, GFX, PTO, Z, CLR, MFX, PA, RFB, CM, PAS Z, OFX, ETO, PAS, CS and either CM or KM (Regimens highly variable) PZA, SM, KM, CM, CS, LFX, and PAS. (Regimens highly variable) 6 (4-7) 17/39 0/17 11/17 No No Yes 6 (4-7) 4/39 0/5 3 / 5 No No Yes Median 6 (5-7) More than 67/87 2/52 2/52 Yes No Yes 179/244 2/20 2 /20 No No No Abbreviations: extensively drug resistant; AMK: Amikacin; Cm: Capreomycin; Z: Pyrazinamide; E: Ethambutol, PAS: Para-amino-salicylic acid, ETO: Ethionamide, AMC/CLV: Amoxicillinclavulanate; R: Rifampicin; H: Isoniazid; S: streptomycin; CS: Cycloserine; CFZ: Clofazamine; PTO: Prothionamide; PA: pasiniazide; MFX: Moxifloxacin; KM: Kanamycin; Cipro: Ciprofloxacin; and OFX: Ofloxacin

26 Notes: One for nausea/vomiting and one for arthralgia

27 Table 3. Summary of the treatment characteristics and outcomes of the studies reporting the toxicity of Amoxicillin, Meropenem, Terizidone, and macrolides for treatment of MDR or XDR-TB (continued). Serious External Patients Drug was Protocol on Mean Any adverse adverse event Adverse events standardized receiving Any adverse stopped toxicity Author (year) Companion drugs number event caused (Grade 3-4), defined a priori grading drug / event because of assessment drugs (n) by drug caused by (Yes/No) system total adverse event (Yes/No) drug (Yes/No) Some patients received drug: Adverse events reported overall - for all drugs and in entire cohort Terizidone Montaner 8 / 511 S, E, H, and R No No Yes (1982) (24) Ferrera (2004) (2) Dheda, 2010 (3) Seddon (2014) (5) 45 / 127 R, H, E, and S /127 14/ / /149 Amoxicillin-clavulanate Torun, 2005 (17) Kim (2007) (9) Dheda, 2010 (3) Leimane (2010) (13) Isaakidis (2012) (14) 50/263 88/ / / /67 KM, OFX, ETO E, and Z (Regimens highly variable) H, AMK, CM, and OFX (Regimens highly variable) OFX, PTH, PAS, CS RBT, CFZ, CM (Regimens highly variable) (Regimens highly variable) KM, OFX, ETO E, and Z (Regimens highly variable) ETO, Z, OFX, KM, CM, PTO, CS, PAS, THZ ((Regimens highly variable) Z, CM, MFX, ETO, CS, and PAS Median 7 (IQR 6-8) Yes: WHO 1997 guidelines 67/115 26/115 No No No 137/149 Grade 4: 1* Grade 3: 2-3 Yes 1/149 Yes No 5.3 (3-9) 182/ /263 Yes No Yes 6 (3 12) 54/211 No No No Median 7 (IQR 6-8) Median 8 (IQR 7-9) 67/115 26/115 No No No MDR: 759/979 39/48 No No No 48/67 3 /67 27/67 No Yes Yes Abbreviations: : Not available; extensively drug resistant; AMK: Amikacin; Cm: Capreomycin; Z: Pyrazinamide; E: Ethambutol, PAS: Para-amino-salicylic acid, ETO: Ethionamide, AMC/CLV: Amoxicillin-clavulanate; R: Rifampicin; H: Isoniazid; S: streptomycin; CS: Cycloserine; CFZ: Clofazamine; PTO: Prothionamide; PA: pasiniazide; MFX: Moxifloxacin; KM: Kanamycin; Cipro: Ciprofloxacin; and OFX: Ofloxacin No

28 In Dheda et al, adverse events determined in only 115 patients reported for all drugs. Many adverse events reported at least 137/149 subjects with minor adverse events * DRESS syndrome, nausea/appetite, MSK pain. 146 patients had at least one drug withdrawn, but causative agent not identified One patient had severe hypokalemia, two had severe renal impairment; Notes on review of Terizidone: The search for amoxicillin-clavulanate, the macrolides, meropenem and terizidone was conducted together, although for efficacy and toxicity separately. As seen in Table 8 (below), a larger number of studies were found describing toxicity, but this was because studies were included that described toxicity of these 4 drugs during treatment of Non-Tuberculous mycobacteria (NTM), in addition to treatment of drug resistant Tuberculosis. Studies that described efficacy of these 4 drugs were limited to those describing patients with active drug resistant TB. Impact of drugs on treatment outcomes and toxicity in patients with MDR and XDR-TB: A limited number of studies were found that described use of these drugs in treatment of MDR-TB or XDR-TB. As seen in Table 1 (attached), only two studies were found that described results with use of Meropenem, 8 were found describing use of Terizidone (TZD), 16 of use of Amoxicillin-clavulanate (Amx-Clv), and only 5 describing use of macrolides. Many of these studies overlapped i.e. the authors described use of multiple different drugs together in treatment. All studies were observational and most used a retrospective cohort design. Most studies included some patients with XDR a few excluded these patients and one included only XDR patients. The majority of patients had smear positive disease, with cavitation on chest radiograph (CXR), although information on extent of disease was missing in many studies. The mean number of drugs to which isolates were resistant ranged from 4 to 8 not surprisingly these Group 5 drugs of uncertain efficacy tended to be used in patients with more advanced drug resistance and therefore fewer available treatment options. Very few of these studies provided adequate data to be able to compare treatment outcomes in those who received or did not receive one or another of the drugs of interest. As seen in Table 2, only one study (for Amx-Clv) used the drug in all patients. In the remainder the drugs of interest were used for some patients, but only 5 studies provided outcome data stratified by the drugs of interest only one study for meropenem, and two each for macrolides and Amx-Clv. For meropenem, macrolide, and Amx-Clv the treatment outcomes were similar in those who got these drugs, compared to the other patients in the same cohort who did not. When

29 comparing the outcomes in cohorts who differed by the proportion who received the drug of interest no relationship between the proportion receiving the drug and the proportion with treatment success was seen. The difficulty in these studies is that treatment was individualized hence patients received certain drugs, especially these drugs of uncertain efficacy, when other treatment options were not available. In addition patients received many other drugs and these other drugs may have contributed more importantly to bacteriological improvement, and the final treatment outcomes seen. As seen in Table 3, adverse events were reported in 15 studies. However, the assessment and reporting of adverse events in these studies was very heterogeneous, and the data of very low quality. Very few studies used a standardized and pre-established protocol to detect and investigate or manage adverse events, and very few utilized any standardized or external, validated system to grade these events. Adverse events were common, but in nine studies these were not attributed, in the report, to a specific drug. The SAE were attributed to the drugs of interest in only 5 studies one each for macrolides and TZD and 3 for Amx-Clv. Hence the estimates of toxicity due to specific drugs are extremely uncertain. For TZD however, Hwang and colleagues recently reviewed the occurrence of adverse events overall and by type - with particular attention to psychiatric and CNS toxicity (see ref 27 in page 7). They identified 27 studies in which 2164 patients received CS, and 10 studies in which 450 patients received TZD. They concluded that SAE were similar with the two drugs in frequency and type. Their published estimates were used for Cycloserine and TZD toxicity in the Grade tables. Effect of these drugs on treatment outcomes in an individual patient data meta-analysis: Because of the problems of confounding by indication in the use of these drugs in highly selected patients, we used a large data set of individual data for over 9,000 patients assembled from 31 centres in over 20 countries. This data set has been used to assess role of individual drugs, number of drugs and duration in treatment of MDR (ref 11 page 5), XDR (ref 13 page 5) and resistance additional to XDR (ref 37 page 7), as well as to validate drug susceptibility testing (DST) for second line drugs (ref 38 page 7), and assess the role of surgery. In this data set a sufficient number of patients had received Amx, macrolides, and/or clofazamine so as to be able to analyze the association of use of these drugs with treatment outcomes.

30 This data set could not be used for assessment of toxicity as the methods of data gathering, adverse event assessment and grading, and management, were not standardized at all in the different centres. This data set also could not be used for the assessment of Meropenem or Terizidone as Meropenem was used for only a total of 4 patients in 2 centres, Terizidone was given to 12 patients at a single centre. Grade Tables: The evidence summarized above and in the accompanying tables is summarized in the attached Grade table. The evidence for Terizidone efficacy is very limited; only one small observational study included in this review assessed the efficacy. We incorporated the results of a recent systematic review in the Grade table for TZD toxicity. This review identified a large number of studies (25) describing toxicity of Cycloserine, and ten studies describing toxicity of TZD. The authors concluded that SAE from TZD were not significantly different, in frequency or type, from those due to Cycloserine (Hwang, IJTLD 2012). It should be noted that this evidence is from observational and unblinded studies hence of very low quality due to potential for allocation and ascertainment biases.

31 Table 8a. Results of the title/abstract screening for TOXICITY. Search results Number of citations Medline 560 EmBase 2945 Combined 3505 After duplicates removed 3237 Title/Abstract review Reasons for Exclusion Reviews/updates/reports/guidelines/letters 1598 Case reports/case studies 1080 Less than 20 subjects 78 Not drugs of interest / not efficacy toxicity 190 Lab/pharmacokin/isolate strain study/animal 118 Reviews 13 Citations selected for further review 158 Studies excluded Studies selected for review Notes

32 Table 8b. Results of the title/abstract screening for EFFICACY Search results Medline EmBase Combined After duplicates removed Title/Abstract review Reasons for Exclusion Number of citations Reviews/updates/reports/guidelines/letters 461 Case reports/case studies 85 Less than 20 subjects 23 Not drugs of interest / not efficacy toxicity 55 Lab/pharmacokin/isolate strain study/animal 54 Reviews 18 Duplicates 3 Citations selected for further review 50 Studies excluded 32 Studies selected for review 18 Notes

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