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 6.2.4 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 6.2.4 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. 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, Fatol in Germany is the only quality assured Tablets: no special storage or Terizidona source (27). However, Sanofi pharmaceuticals administrative needs. Store at manufactures terizidone in South Africa under room temperature in airtight the name “Terivalidin” and exports to Zambia, container. Angola, Mozambique, Botswana, Namibia and Kenya, with plans for future expansion (36).
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. 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.
Drug Treatment Regimen (4) Duration of Special diagnostics, treatment treatment or monitoring facilities and skills Terizidone Adults: 10‐15 mg/kg/day, can divide into 2 doses Duration of TB Baseline and monthly treatment Child: (>3kg and >28 days of age): 10‐20 mg/kg/day divided depression screening. every 12 hours (25)
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: 79.40‐83.30/50 capsules
MSH International Drug Price Indicator Guide 250 mg: 0.9152/tab
Médecins sans Frontières (15) 250 mg: 1.513‐1.666/tab
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 Not found Drug Administration European Medicines Not found Agency WHO List of Not found Prequalified Medications Health Canada Not found Australian Government Not found Department of Health Pharmaceuticals and Not found Medical Devices Agency (Japan)
14. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia, European Pharmacopeia)
Drug Standard Reference (accessed 22.10.2014) 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
References 1. WHO Model List of Essential Medicines [Internet]. 18th list. Geneva, World Health Organization; 2013. Available from: http://apps.who.int/iris/bitstream/10665/93142/1/EML_18_eng.pdf
2. WHO Model List of Essential Medicines for Children [Internet]. 4th list. Geneva, World Health Organization; 2013. Available from: http://apps.who.int/iris/bitstream/10665/93143/1/EMLc_4_eng.pdf
3. Global tuberculosis report 2014 (WHO/HTM/TB/2014.08) [Internet]. Geneva, World Health Organization. 2014. Available from: http://www.who.int/tb/publications/global_report/en/
4. Companion handbook to the WHO guidelines for the programmatic management of drug‐resistant tuberculosis. (WHO/HTM/TB/2014.xx). Geneva, World Health Organization. 2014.
5. UNITAID Approves Grants of $160 million [Internet]. [cited 2014 Jul 26]. Available from: http://www.unitaid.org/en/resources/press‐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. 1998. Available from: http://apps.who.int/medicinedocs/index/assoc/s14167e/s14167e.pdf
7. Udwadia ZF, Amale RA, Ajbani KK, Rodrigues C. Totally drug‐resistant tuberculosis in India. Clin Infect Dis Off Publ Infect Dis Soc Am. 2012 Feb 15;54(4):579–81.
8. WHO | “Totally Drug‐Resistant” tuberculosis: a WHO consultation on the diagnostic definition and treatment options [Internet]. Available from: http://www.who.int/entity/tb/challenges/xdr/Report_Meeting_totallydrugresistantTB_032012.pdf
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. 2013 Aug;13(8):690–7.
10. Guidelines for the programmatic management of drug‐resistant tuberculosis, 2011 Update. (WHO/HTM/TB/2011.6) [Internet]. Geneva, World Health Organization. 2011. Available from: http://whqlibdoc.who.int/publications/2011/9789241501583_eng.pdf
11. 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 meta‐ analysis of 9,153 patients. PLoS Med. 2012;9(8):e1001300.
12. 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. 2010 Jul 1;51(1):6–14. 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):156–68.
14. UNICEF, WHO. Sources and prices of selected medicines for children. Including therapeutic food, dietary vitamin and mineral supplementation [Internet]. 2nd ed. 2010. Available from: http://apps.who.int/medicinedocs/en/d/Js17031e/
15. MSF, UNION. DR‐TB Drugs Under the Microscope [Internet]. Geneva, Switzerland and Paris, France; 2011. Available from: http://www.msfaccess.org/sites/default/files/MSF_assets/TB/Docs/TB_report_UndertheMicro_EN 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: 688–692.
17. 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: 463–510.
18. Crofton J. The contribution of treatment to the prevention of tuberculosis. Bull Int Union Tuberc 1962; 32 (2): 643–653.
19. 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: 799–804.
20. Gunnels J, Bates J, Swindoll H. Infectivity of sputum positive tuberculosis patients on chemotherapy. Am Rev Respir Dis 1974; 109: 323.
21. Rouillon A, Perdrizet S, Parrot R. Transmission of tubercle bacilli: the effects of chemotherapy. Tubercle 1976; 57: 275–299.
22. Drugs@FDA. FDA Approved Drug Products. [internet] US Food and Drug Administration. October 21, 2014 [cited 21.10.14]. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Search_Drug _Name
23. Toxnet : Toxicology Data network. [internet]. US National Library of Medicine. NIH. [cited 21.10.2104]. Available at : http://chem.sis.nlm.nih.gov/chemidplus/rn/25683‐71‐0
24. 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. 2013 May 1;207(9):1352‐8. Epub 2012 Jul 17.
25. MDR‐TB Weight‐Based Dosing Chart for children. Sentinel Project on Pediatric Drug‐Resistant Tuberculosis. [cited 18.10.2014] Available at: http://sentinel‐project.org/treatment‐guidance/
26. Lexicomp. [internet] Available at: http://online.lexi.com/lco/action/api/find/globalid/5632?utd=1
27. 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. 2013 Oct;17(10):1257‐66.
28. 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: 329–338.
29. 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: 688–692.
30. 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: 463–510.
31. Crofton J. The contribution of treatment to the prevention of tuberculosis. Bull Int Union Tuberc 1962; 32 (2): 643–653.
32. 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: 799–804.
33. Gunnels J, Bates J, Swindoll H. Infectivity of sputum positive tuberculosis patients on chemotherapy. Am Rev Respir Dis 1974; 109: 323.
34. Rouillon A, Perdrizet S, Parrot R. Transmission of tubercle bacilli: the effects of chemotherapy. Tubercle 1976; 57: 275–299.
35. Medicines Control Council. [internet] South Africa. [cited 3 Dec 2014]. Available at: http://www.mccza.com/search/default.asp?doc=search.asp
36. Sanofi. [Internet]. Tuberculosis. [cited 3 Dec 2014]. Available at: http://www.sanofi.co.za/l/za/en/layout.jsp?scat=7DF3B927‐D434‐456F‐ABC3‐4D3C8AFF6586
37. 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. 2013 Jul;42(1):169–79.
38. 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. 2014 Nov 15;59(10):1364–74.
Annex 1. Drug information sheets (4)
Drug information sheet for terizidone
Drug information sheet for terizidone (continued)
Annex 2. GRADE tables – terizidone
Grade Tables – summary of evidence: Grade Table: Effect of Terizidone (TZD) on Outcomes in MDR-TB Summary of findings Quality assessment N. Events/N. patients Absolute Proportion, Difference Importance 3 Other Quality No of Risk of Inconsisten Indirectn TZD No TZD Design Imprecision consideratio TZD - No TZD studies bias cy ess & Others & Others ns Treatment success (vs Failure/relapse/death – from IPD Meta-analysis) Insufficient numbers to perform this analysis Treatment success (vs Failure/relapse/death/default – from Kvasnovsky (2011) et al – observational study) Many other drugs 60/90 35/116 1 Observational Very serious None (only None Serious2 used - 37% Very low (67%) (30%) Critical limitations 1 study)1 imprecision individualized Toxicity of TZD in treatment of DR-TB – from Systematic review by Hwang et al (IJTLD 2012) 1 Observational Very serious Serious None Serious Many other drugs 33/450 NR --- Very lowModerate 0 - individualized (7.4%)4 Toxicity of all types from Cycloserine in treatment of DR-TB – from Systematic review by Hwang et al (IJTLD 2012) 2 Observational Very serious Serious None Serious Many other drugs 33/2164 7 - individualized (9.1%)5 NR --- Very lowModerate (6.4-11.7%) Major Psychiatric Toxicity from Cycloserine in treatment of DR-TB – from Systematic review by Hwang et al (IJTLD 2012) 2 Observational Very serious Serious None Serious Many other drugs 33/2164 7 - individualized (5.7%)5 NR --- Very lowModerate (3.7-7.6%) 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
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. ARV Total drugs Mean Age HIV + TB Study design/ Location of Sample treatment resistant Positive Cavitation on Author (year) Study years (range or (% of Resistance Population study size (n receiving / [mean (SD or smear x-ray SD) tested) Type Selection HIV +) range)] Meropenem Series1¶: MDR: 77%; Series1 Series1 De Lorenzo Italy and NA XDR: 24 %, 87% 24% NA 98 30 (24–38) 9.0 Two case series NA (2013) (1) Netherlands (6 / 8) Series 2¶: Series2 Series2 MDR: 97%; 30% 16% XDR: 3% Terizidone Retrospective Ferrera cohort study, 3.7 1995 - 1999 Italy 127 44 ± 17 15 NA MDR 85% NA (2004) (2) among 4323 TB (2 - 9) cases Median 33 AZT, EFV, Retrospective Dheda 7 2002 - 2008 South Africa 174 (IQR 26- 47 and 3TC XDR Cohort 100% NA (2010) (3) (IQR 6–8) 45) (52/82) Age: >16yo Bilateral Retrospective disease on Kvasnovsky cohort - All 2008 - 2009 South Africa 206 36 ± 12 55 NA XDR 4.2 ± 0.5 48% X-ray: 93% (2011) (4) cases reported Bilateral to NHLS† cavity 27% Median Retrospective Seddon NA 2003-2008 South Africa 111 50 months 43 MDR-XDR Cohort 7 (4–13) 62% 34% (2012) (5) (43/43) (19-108) Age: <15 yo EFV-based O'Donnell Median 35 Prospective 2009 South Africa 114 72 regimens XDR NA 59% NA (2013) (6) (30–42) cohort study (50/82) Brazil, India, Latvia, Peru, Diacon Philippines, RCT for NA 132 18-65 0.0 NA MDR NA 100% 83% (2014) (7) Russia, S. bedaquiline Africa, Thailand Abbreviations: NA: Not available; MDR: Multidrug resistant; XDR: extensively drug resistant; 3TC: lamivudine; D4T: Stavudine; EFV: Efavirenz; NVP: Nevirapine; AZT: Zidovudine; LPV/RTV: Lopinovir–ritonavir. † 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 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) 3TC, D4T, EFV, NVP, Pietersen South Retrospective 2008 - 2012 107 33 (27-43) 41 AZT and XDR NA NA NA (2014) (8) Africa Cohort* LPV/RTV (35 / 44) Median Retrospective Seddon South Regimen NA 2009-2010 149 36 months 22 MDR-XDR Cohort NA 16% 15% (2014) (5) Africa (32/32) (18–66) Age: <15 years Amoxicillin-clavulanate Kim South Median Retrospective 1996-2005 211 0.0 NA MDR-XDR NA NA 76% (2007) (9) Korea 35 (16–69) cohort Cox Median 34 Prospective cohort 2003-2005 Uzbekistan 87 NA NA MDR-XDR NA NA 70% (2007) (10) (17–72) Age: >16 years XDR: Mitnick XDR: 48 Retrospective 8.4 ± 1.1 XDR: 58% 1999 - 2002 Peru 32 ± 11 1.0 NA MDR-XDR NA (2008) (11) MDR: 603 cohort MDR: MDR: 55% 5.3 ± 1.5 Jeon South Retrospective 2001-2005 176 42.1 ± 14.1 0.0 NA XDR 7.5 ± 1.5 NA 75% (2009) (12) Korea cohort
Median 33 Retrospective Dheda South AZT, EFV, Median 7 2002 - 2008 174 (IQR 26- 47 XDR Cohort 100% NA (2010) (3) Africa and 3TC (IQR 6–8) 45) Age: >16yo (52/82) Leimane Median Retrospective 2000-2004 Latvia 1027 3.0 NA MDR-XDR NA 51% 46% (2010) (13) 43.1 cohort Median Isaakidis Prospective 2007-2011 India 67 35.5 100 (63/67) MDR-XDR NA NA NA (2012) (14) Cohort 30.5–42) MFX: MFX: Jiang 43.8±10.3 Retrospective 6.4 ± 1.1 2005-2010 China 158 0.0 NA MDR-XDR 90% 66% (2013) (15) LFX: cohort LFX: 45.1±14.6 6.3 ± 1.2 Abbreviations: NA: Not available; MDR: Multidrug resistant; XDR: 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)
Table 1. Continued ARV Total drugs HIV + Study design / Location Mean Age treatment TB Resistance resistant Positive Cavitation on Author (year) Study years Sample size (% of Population of study (range) (n receiving / Type [mean (SD smear x-ray tested) Selection HIV +) or range)] Amoxicillin-clavulanate (Cont’d) Tahaoglu 36 ±12§ Retrospective 1992-1999 Turkey 158 0.0 NA MDR 5¶ and 4¶ 100% 96% (2001) (16) 42 ±11§ cohort Torun 37.8 Retrospective 1992-2004 Turkey 263 0.0 NA MDR NA NA NA (2005) (17) (14–68) cohort No AE: 31 Shin (18–54) Retrospective 2000-2002 Russia 244 NA NA MDR 4.0 (3–9) NA NA (2007) (18) AE: 32.6 cohort (17–65) Retrospective case Palacios 15–45 1996-2005 Peru 38 8.0 NA MDR-XDR series of pregnant NA Na 81% (2009) (19) years women 3TC, D4T, XDR: EFV, NVP, Pietersen March 2008 - South Retrospective 8.4 ± 1.1 107 33 (27-43) 41 AZT and XDR NA NA (2014) (8) Aug 2012 Africa Cohort* MDR: LPV/RTV 5.3 ± 1.5 (35 / 44) Retrospective Xu Jan 2008 - China 39 38 (20-54) NA NA MDR review of hospital 6 (2 – 11) 100% 80% (2011) (20) March 2011 records No AE: 31 Singla (18–54) Retrospective 2000-2002 Russia 244 0.0 NA MDR NA 100% 59% (2012) (21) AE: 32.6 cohort (17–65) “Salvage” only 28 (16)‡ Seung August 1996 Retrospective 50% Peru included†: NA NA MDR NA NA (2014) (22) to April 2007 cohort 213
Abbreviations: MDR: Multidrug resistant; XDR: 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. ‡ Interquartile range.
Table 1. Continued ARV Total drugs Mean HIV + Study Design/ Location of Sample treatment TB Resistance resistant Positive Cavitation on Author (year) Study years Age (% of Population study size (n receiving / Type [mean (SD smear x-ray (range) tested) Selection HIV +) or range)] Azithromycin 3TC, D4T, XDR: EFV, NVP, Pietersen March 2008 - South 33 Retrospective 8.4 ± 1.1 107 41.1 AZT and XDR NA NA (2014) (8) Aug 2012 Africa (27-43) Cohort* MDR: LPV/RTV 5.3 ± 1.5 (35 / 44) Clarithromycin Retrospective Xu Jan 2008 - 38 China 39 NA NA MDR review of hospital 6 (2 – 11) 88% 88% (2011) (20) March 2011 (20-54) records XDR: February 32±9.9 Mitnick XDR: 0.0 XDR: 48 Retrospective XDR: 58% 1999, to July Peru 651 MDR: NA NA NA (2008) (11) MDR: 1.0 MDR: 603 cohort MDR: 55% 2002 31.5±12. 4 3TC, D4T, EFV, NVP, Pietersen March 2008 - South 33 Retrospective 107 41.1 AZT and XDR NA NA NA (2014) (8) Aug 2012 Africa (27-43) Cohort* LPV/RTV (35 / 44) “Salvage” only 28 (16)‡ Seung August 1996 Retrospective 50% Peru included†: NA NA MDR NA NA (2014) (22) to April 2007 cohort 213
Abbreviations: MDR: Multidrug resistant; XDR: 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.
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 Dose: NA XDR: CS, AMX/CLV, Duration: Mitnick XDR: 8.4 ± 1.1 XDR: XDR: XDR: PAS, and CFZ 24.0 Individualized XDR: 5/48 NA Yes (2008) (11) 48 / 48 MDR: 29/48 11/48 3/48 (highly variable) months 5.3 ± 1.5 (11.7–28.1) Some patients received drug: Treatment outcomes stratified by receipt of drug of interest Meropenem 1 g, 3 times Outcomes for those that received drug Linezolid (among No: (3 month/ De Lorenzo a day 31/37† NA NA NA NA 37 / 98 others not NA Fixed dose culture (2013) (1) (51 [28-75] Outcomes for those that did not receive drug mentioned) conversion) days) 15/24† NA NA NA NA Amoxicillin-clavulanate E or Z, KM or Outcomes for those that received drug New: (“Salvage” CM, Cipro or 16 / 50 NA NA NA NA Seung 2 (1-6) No (Culture only) OFX, and ETO, NA Individualized Outcomes for those that did not receive drug (2014) (22) Total: conversion) 50 / 213 PAS, and CS 9 (5-13) 49 / 163¥ NA NA NA NA (highly variable) 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).
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) CFZ and one or more Outcomes for those that received drug Xu of H, GFX, PTO, Z, Dose: NA 1/5 0/5 2/5 1/5 0/5 5 / 39 6 (4-7) Individualized Yes (2011) (20) CLR, MFX, PA, RFB, (11.8 avg.) Outcomes for those that did not receive drug CM, PAS 14/34 0/34 7/34 3/34 0/34 Clarithromycin CFZ and one or more Outcomes for those that received the drug Xu of H, GFX, PTO, Z, 6 (4-7) Dose: NA – 6/17 0/17 4/17 2/17 0 17 / 39 Individualized Yes (2011) (20) CLR, MFX, PA, RFB, (Dur: 11.8) Outcomes for those that did not receive drug CM, PAS 8/22 0/22 7/22 3/22 0/22 E or Z, KM or CM, New: Outcomes for those that received drug (“Salvage” Seung Cipro or OFX, and 2 (1-6) 14 / 44 NA NA NA NA No (Culture only) NA Individualized (2014) (22) ETO, PAS, and CS Total: Outcomes for those that did not receive drug conversion) 44 / 213 (highly variable) 9 (5-13) 51 / 169¶ NA NA NA NA Some patients received drug: Treatment outcomes reported overall - for entire cohort Failur Terizidone Cured Deaths Defaults Relapse e Ferrera Dose: NA 45 / 127 R, H, E, and S 3.5 Individualized 49 / 127† 11 / 127 8 / 127 21 / 127 41 / 127 No (2004) (2) (Dur: 12 ± 11) KM, OFX, ETO 7 Dose: NA Dheda, 147 / 174 E, and Z (Regimens (IQR 6- (Dur: Median: Individualized 33/174 62/174 62/174 0/174 1/174 No 2010 (3) highly variable) 8) 9.2) Kvasnovsky CM, Z, E, PAS, ETO, No (Culture 90‡ / 195 5.2 ± 0.7 N/A Individualized 16 / 195 86 / 195 NA NA NA (2011) (4) AMX/CLV, and R conversion) H, AMK, CM, OFX 10-20 mg/kg Seddan 57/111 (Regimens highly NA (Dur: Median Individualized 91/111 11/111 10/111 8/111 9/111 Yes (2012) (23) variable) 18 (8–26)) E, ETO, CM, PAS, Z, Median 6 O'Donnell MFX, or OFX Dose: NA 34 / 114 (IQR 5- Individualized 25/114 48/114 70/114 19/114 NA Yes (2013) (6) (Regimens highly (Dur: 12) 7) variable) 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. § Odds Ratio for amoxicillin in the salvage group: 1.1 (95% CI 0.6 - 2.2). ¶ Number of cured for those not receiving the drug. † Odds ratio for Terizidone: 1.24 (95% CI 0.59–2.61).
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) Bedaquiline, Diacon aminoglycoside, Dose: NA 51‡/132 NA Individualized 62/132 12/132 35/132 38/132 NA Yes (WHO) (2014) (7) quinolone, ETO or PTO, (Dur: 0.5- 21) Z, E, (highly variable) CM and PAS Pietersen 8 (IQR 6 100 / 107 (Other treatments highly NA Individualized 17 / 107 49 / 107 25 / 107 7 / 107 17 / 107 Yes (2014) (8) - 10) variable Dose: NA H, AMK, CM, and OFX Seddon (Dur: Median 80/137 (Regimens highly NA Individualized 137/149 3/149 0/149 9/149 NA Yes (2014) (5) 17 IQR: 12– variable) 18.5) Amoxicillin-clavulanate Cured Deaths Failure Defaults Relapse Tahaoglu, 2001 AMK, KM, S 2-4g daily 44/158 5 Individualized 121/158 7/158 20/158 17/158 1/158 Yes (16) (highly variable) (>18 ) OFX, PTH, PAS, CS Torun, 2005 1.5 -2.0 g daily 50/263 RBT, CFZ, CM 5.3 (3-9) Individualized 204/263 18/263 34/263 25/263 NA Yes (17) (>18) (highly variable) Kim (Regimens highly 6 (3 – Median 88/211 Individualized 132/211 19/211 40/211 14/211 6/211 Yes (2007) (9) variable) 12) 26 (1–136) Z, OFX, ETO, PAS, CS Median Dose: NA Cox 52/87 and either CM or KM 6 (IQR median 22 Individualized 54/87 13/87 8/87 12/87 NA Yes (2007) (10) (Regimens variable) 5-7) (range 18–30)) PZA, SM, KM, CM, CS, 1500–2000 mg Shin LFX, and PAS. 20/244 NA (Dur: 18.5, Individualized 187/244 12/244 28/244 28/244 NA Yes (2007) (18) (Regimens highly 1.0–42.4]) variable) H, R, E, Z, S, KM, OFX, Jeon Dose: NA 29/142 PAS, PTO, and CS 5.2 Individualized 28/158 36/158 63/158 31/158 NA Yes (2009) (12) (Dur: >18) (highly variable) ETO, Z, OFX, KM, CM, Dose: NA MDR: MDR: MDR: MDR: Leimane 8 (IQR Yes 133/1027 PTO, CS, PAS, THZ (Dur 18 (IQR Individualized 679/979 56/979 157/979 143/979 NA (2010) (13) 7-9) (highly variable 12-30) XDR: XDR: XDR: XDR: 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 KM, CM, AMK Dose: NA 17/38 5 Individualized 23/38 5/38 9/38 6/38 NA Yes (2009) (19) and S (Dur: >18) KM, OFX, ETO Dose: NA Dheda E, and Z 7 66/174 Dur: Median Individualized 33/174 62/174 0/174 0/174 1/174 No (2010) (3) ((Regimens highly (IQR 6-8) 7.1 (3.1-12.2) variable) Singla Median 6 Dose: NA 23/29 NA Individualized 9/29 3/29 5/29 15/29 NA Yes (2012) (21) (6 - 7) (Dur: > 12) Dose NA Z, CM, MFX, Isaakidis Dur: Median 24/67 ETO, CS, and NA Individualized 13/67 14/67 2/67 38/67 NA Yes (2012) (14) 10 (range PAS 0.5–30) MFX MFX: MFX: MFX: MFX: MFX: 6.4±1.1 Jiang 5.6 ± 1.2 17.2±3.8 27/72 1/75 8/72 MFX: 0/72 MFX: 4/72 18-19/158 LFX: Individualized Yes (2013) (15) LFX LFX: LFX: LFX: LFX: LFX: 2/86 LFX: 5/86 6.3±1.2 5.5 ± 1.9 16.9±5.1 29/86 1/86 17/86 CM and PAS Pietersen Yes (cited 103 / 107 (Regimens highly 8 (6 - 10) NA Individualized 22 / 107 25 / 107 49 / 107 7 / 107 17 / 107 (2014) (8) Laserson et al.) variable) Azithromycin CM and PAS Pietersen Yes (cited 9 / 107 (Regimens highly 8 (6 - 10) NA Individualized 22/107 25 /207 49 / 207 7 / 207 17 / 207 (2014) (8) Laserson et al.) variable) Clarithromycin Mitnick XDR: CS, AMX/CLV, XDR: Dose: NA XDR: XDR: XDR: XDR: Yes (cited Individualized NA (2008) (11) 21 / 48 PAS, and CFZ 8.4 ± 1.1 Dur: 14.5 29/48 5/48 11/48 3/48 Laserson et al.) (Regimens highly MDR: (11.6-18.9) variable) 5.3 ± 1.5 Dose: NA CM and PAS Pietersen Dur: Median Yes (cited 80 / 107 (Regimens highly 8 (6 - 10) Individualized 22/107 25 / 107 49 / 107 7 / 107 17 / 107 (2014) (8) 22.1 Laserson et al.) variable) (8.8-34.3) 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
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 CS, AMX/CLV, XDR: 1 (increased Mitnick XDR: PAS, and CFZ 8.4 ± 1.1 5 5 0 transaminase No No No (2008) (11) 48 / 48 (Regimens highly MDR: 5.3 levels) variable) ± 1.5 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 52/114 NA 8/34 8/34 Yes Yes No (2013) (6) (Regimens highly (IQR 5-7) variable) Clarithromycin CFZ, and one or 6 Xu more of H, GFX, 17 / 39 (4-7) 17/39 NA 0/17 11/17 No No Yes (2011) (20) PTO, Z, CLR, MFX,
PA, RFB, CM, PAS Amoxicillin CFZ and one or Xu more of H, GFX, 5 / 39 6 (4-7) 4/39 NA 0/5 3 / 5 No No Yes (2011) (20) PTO, Z, CLR, MFX, PA, RFB, CM, PAS Z, OFX, ETO, PAS, Cox CS and either CM or Median More than 52/87 2/52 NA 2/52 Yes No Yes (2007) (10) KM (Regimens 6 (5-7) 67/87 highly variable) PZA, SM, KM, CM, Shin CS, LFX, and PAS. 20/244 NA 179/244 2/20 NA 2¥/20 No No No (2007) (18) (Regimens highly variable) Abbreviations: XDR: 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 Notes: ¥ One for nausea/vomiting and one for arthralgia 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 3 44 3 NA NA No No Yes (1982) (24) Ferrera Yes: WHO 1997 45 / 127 R, H, E, and S 3.5 22 NA 14/127 14/127 Yes No (2004) (2) guidelines KM, OFX, ETO Dheda, Median 7 147 / 174 E, and Z (Regimens 67/115¶ NA NA 26/115¶ No No No 2010 (3) (IQR 6-8) highly variable) H, AMK, CM, and OFX Seddon Grade 4: 1* 80/149 (Regimens highly NA 137/149§ NA 1/149 NA Yes No (2014) (5) Grade 3: 2-3 variable) Amoxicillin-clavulanate OFX, PTH, PAS, CS Torun, 2005 RBT, CFZ, CM 50/263 5.3 (3-9) 182/263 NA NA 146/263¢ Yes No Yes (17) (Regimens highly variable) Kim (Regimens highly 88/211 6 (3 – 12) 54/211 NA NA NA No No No (2007) (9) variable) KM, OFX, ETO Dheda, Median 7 66 / 174 E, and Z (Regimens 67/115¶ NA NA 26/115¶ No No No 2010 (3) (IQR 6-8) highly variable) ETO, Z, OFX, KM, CM, MDR: Leimane PTO, CS, PAS, THZ Median 8 759/979 133/1027 NA NA NA No No No (2010) (13) ((Regimens highly (IQR 7-9) XDR: variable) 39/48 Isaakidis Z, CM, MFX, ETO, CS, 24/67 NA 48/67 NA 3‡/67 27/67 No Yes Yes (2012) (14) and PAS
Abbreviations: NA: Not available; XDR: 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 ¶ 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 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.
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.
Table 8a. Results of the title/abstract screening for TOXICITY. Number of Notes citations Search results 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
Table 8b. Results of the title/abstract screening for EFFICACY Number of Notes citations Search results Medline EmBase Combined After duplicates removed Title/Abstract review ‐ Reasons for Exclusion 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
References:
1. S. De Lorenzo et al., Efficacy and safety of meropenem‐clavulanate added to linezolid‐containing regimens in the treatment of MDR‐/XDR‐TB. European Respiratory Journal 41, 1386 (Jun, 2013). 2. G. Ferrara et al., Management of multidrug‐resistant tuberculosis in Italy. International Journal of Tuberculosis and Lung Disease 9, 507 (May, 2005). 3. K. Dheda et al., Early treatment outcomes and HIV status of patients with extensively drug‐resistant tuberculosis in South Africa: a retrospective cohort study. The Lancet 375, 1798 (2010). 4. C. L. Kvasnovsky et al., Extensively drug‐resistant TB in Eastern Cape, South Africa: High mortality in HIV‐negative and HIV‐ positive patients. Journal of Acquired Immune Deficiency Syndromes 57, 146 (01 Jun, 2011). 5. J. A. Seddon, A. C. Hesseling, P. Godfrey‐Faussett, H. S. Schaaf, High treatment success in children treated for multidrug‐resistant tuberculosis: An observational cohort study. Thorax 69, 471 (May, 2014). 6. M. R. O'Donnell et al., Treatment outcomes for extensively drug‐resistant tuberculosis and HIV Co‐infection. Emerging Infectious Diseases 19, 416 (March, 2013). 7. A. H. Diacon et al., Multidrug‐resistant tuberculosis and culture conversion with bedaquiline. New England Journal of Medicine 371, 723 (2014). 8. E. Pietersen et al., Long‐term outcomes of patients with extensively drug‐resistant tuberculosis in South Africa: A cohort study. The Lancet 383, 1230 (2014). 9. H. R. Kim et al., Impact of extensive drug resistance on treatment outcomes in non‐HIV‐infected patients with multidrug‐resistant tuberculosis. Clinical Infectious Diseases 45, 1290 (15 Nov, 2007). 10. H. S. Cox et al., Multidrug‐resistant tuberculosis treatment outcomes in Karakalpakstan, Uzbekistan: Treatment complexity and XDR‐TB amont treatment failures. PloS one 2, (07 Nov, 2007). 11. C. D. Mitnick et al., Comprehensive treatment of extensively drug‐resistant tuberculosis. New England Journal of Medicine 359, 563 (07 Aug, 2008). 12. D. S. Jeon et al., Survival and predictors of outcomes in non‐HIV‐infected patients with extensively drug‐resistant tuberculosis. International Journal of Tuberculosis and Lung Disease 13, 594 (2009). 13. V. Leimane et al., Treatment outcome of multidrug/extensively drug‐resistant tuberculosis in Latvia, 2000‐2004. European Respiratory Journal 36, 584 (September, 2010). 14. P. Isaakidis et al., Adverse events among HIV/MDR‐TB co‐infected patients receiving antiretroviral and second line anti‐TB treatment in Mumbai, India. PloS one 7, (11 Jul, 2012). 15. R. H. Jiang, H. B. Xu, L. Li, Comparative roles of moxifloxacin and levofloxacin in the treatment of pulmonary multidrug‐resistant tuberculosis: A retrospective study. International journal of antimicrobial agents 42, 36 (July, 2013). 16. K. Tahaoglu et al., The treatment of multidrug‐resistant tuberculosis in Turkey. New England Journal of Medicine 345, 170 (19 Jul, 2001). 17. T. Torun et al., Side effects associated with the treatment of multidrug‐resistant tuberculosis. International Journal of Tuberculosis and Lung Disease 9, 1373 (December, 2005). 18. S. S. Shin et al., Adverse reactions among patients being treated for MDR‐TB in Tomsk, Russia. International Journal of Tuberculosis and Lung Disease 11, 1314 (December, 2007). 19. E. Palacios et al., Drug‐resistant tuberculosis and pregnancy: treatment outcomes of 38 cases in lima, peru. Clinical Infectious Diseases 48, 1413 (15 May, 2009). 20. H. B. Xu, R. H. Jiang, H. P. Xiao, Clofazimine in the treatment of multidrug‐resistant tuberculosis. Clinical Microbiology and Infection 18, 1104 (November, 2012). 21. R. Singla et al., Linezolid: An effective, safe and cheap drug for patients failing multidrug‐resistant tuberculosis treatment in India. European Respiratory Journal 39, 956 (01 Apr, 2012). 22. K. J. Seung et al., Salvage therapy for multidrug‐resistant tuberculosis. Clinical Microbiology and Infection 20, 441 (May, 2014). 23. J. A. Seddon, A. C. Hesseling, M. Willemse, P. R. Donald, H. S. Schaaf, Culture‐confirmed multidrug‐resistant tuberculosis in children: Clinical features, treatment, and outcome. Clinical Infectious Diseases 54, 157 (15 Jan, 2012). 24. L. J. G. Montaner, A. Dambrosi, M. Manassero, V. M. L. Dambrosi, Adverse effects of antituberculosis drugs causing changes in treatment. Tubercle 63, 291 (1982). 25. E. C. Oldfield, 3rd et al., Once weekly azithromycin therapy for prevention of Mycobacterium avium complex infection in patients with AIDS: a randomized, double‐blind, placebo‐controlled multicenter trial. Clinical Infectious Diseases 26, 611 (Mar, 1998). 26. W. M. El‐Sadr et al., Discontinuation of prophylaxis against Mycobacterium avium complex disease in HIV‐infected patients who have a response to antiretroviral therapy. New England Journal of Medicine 342, 1085 (13 Apr, 2000). 27. D. V. Havlir et al., Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin, or both. California Collaborative Treatment Group. New England Journal of Medicine 335, 392 (Aug 8, 1996). 28. S. L. Koletar et al., Azithromycin as treatment for disseminated Mycobacterium avium complex in AIDS patients. Antimicrobial Agents and Chemotherapy 43, 2869 (1999). 29. J. S. Currier et al., Discontinuation of Mycobacterium avium complex prophylaxis in patients with antiretroviral therapy ‐ Induced increases in CD4+ cell count: A randomized, double‐blind, placebo‐controlled trial. Annals of internal medicine 133, 493 (03 Oct, 2000). 30. W. T. Hughes et al., Comparison of atovaquone and azithromycin with trimethoprim‐ sulfamethoxazole for the prevention of serious bacterial infections in children with HIV infection. Clinical Infectious Diseases 40, 136 (01 Jan, 2005). 31. B. Dautzenberg et al., Clarithromycin and other antimicrobial agents in the treatment of disseminated Mycobacterium avium infections in patients with acquired immunodeficiency syndrome. Archives of Internal Medicine 153, 368 (1993). 32. R. E. Chaisson et al., Clarithromycin therapy for bacteremic Mycobacterium avium complex disease. A randomized, double‐blind, dose‐ranging study in patients with AIDS. AIDS Clinical Trials Group Protocol 157 Study Team. Annals of internal medicine 121, 905 (Dec 15, 1994). 33. M. Pierce et al., A randomized trial of clarithromycin as prophylaxis against disseminated Mycobacterium avium complex infection in patients with advanced acquired immunodeficiency syndrome. New England Journal of Medicine 335, 384 (Aug 8, 1996). 34. S. D. Shafran et al., A comparison of two regimens for the treatment of Mycobacterium avium complex bacteremia in AIDS: Rifabutin, ethambutol, and clarithromycin versus rifampin, ethambutol, clofazimine, and ciprofloxacin. New England Journal of Medicine 335, 377 (08 Aug, 1996). 35. M. P. Dube et al., A randomized evaluation of ethambutol for prevention of relapse and drug resistance during treatment of Mycobacterium avium complex bacteremia with clarithromycin‐based combination therapy. Journal of Infectious Diseases 176, 1225 (1997). 36. W. J. Burman, R. R. Reves, C. A. Rietmeijer, D. L. Cohn, A retrospective comparison of clarithromycin versus rifampin in combination treatment for disseminated Mycobacterium avium complex disease in AIDS: clarithromycin decreases transfusion requirements. The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease 1, 163 (Apr, 1997). 37. T. May et al., Comparison of combination therapy regimens for treatment of human immunodeficiency virus‐infected patients with disseminated bacteremia due to Mycobacterium avium. Clinical Infectious Diseases 25, 621 (1997). 38. T. T. Ward et al., Randomized, open‐label trial of azithromycin plus ethambutol vs. clarithromycin plus ethambutol as therapy for Mycobacterium avium complex bacteremia in patients with human immunodeficiency virus infection. Clinical Infectious Diseases 27, 1278 (November, 1998). 39. S. Fournier et al., Effect of adding clofazimine to combined clarithromycin‐ethambutol therapy for Mycobacterium avium complex septicemia in AIDS patients. European Journal of Clinical Microbiology and Infectious Diseases 18, 16 (1999). 40. F. M. Gordin et al., A randomized, placebo‐controlled study of rifabutin added to a regimen of clarithromycin and ethambutol for treatment of disseminated infection with Mycobacterium avium complex. Clinical Infectious Diseases 28, 1080 (May, 1999). 41. D. E. Griffith, B. A. Brown, W. M. Girard, D. T. Murphy, R. J. Wallace, Jr., Azithromycin activity against Mycobacterium avium complex lung disease in patients who were not infected with human immunodeficiency virus. Clinical Infectious Diseases 23, 983 (Nov, 1996). 42. D. E. Griffith et al., Azithromycin‐containing regimens for treatment of Mycobacterium avium complex lung disease. Clinical Infectious Diseases 32, 1547 (Jun 1, 2001). 43. R. J. Wallace Jr, B. A. Brown, D. E. Griffith, W. M. Girard, D. T. Murphy, Clarithromycin regimens for pulmonary Mycobacterium avium complex: The first 50 patients. American journal of respiratory and critical care medicine 153, 1766 (1996). 44. G. Roussel, J. Igual, Clarithromycin with minocycline and clofazimine for Mycobacterium avium intracellulare complex lung disease in patients without the acquired immune deficiency syndrome. International Journal of Tuberculosis and Lung Disease 2, 462 (1998). 45. E. Tanaka et al., Effect of clarithromycin regimen for Mycobacterium avium complex pulmonary disease. American Journal of Respiratory and Critical Care Medicine 160, 866 (1999). 46. D. E. Griffith, B. A. Brown, P. Cegielski, D. T. Murphy, R. J. Wallace Jr, Early results (at 6 months) with intermittent clarithromycin‐ including regimens for lung disease due to Mycobacterium avium complex. Clinical Infectious Diseases 30, 288 (2000). 47. I. Shafran, L. Kugler, F. A. El‐Zaatari, S. A. Naser, J. Sandoval, Open clinical trial of rifabutin and clarithromycin therapy in Crohn's disease. Digestive & Liver Disease 34, 22 (Jan, 2002). 48. Y. Kobashi, T. Matsushima, The effect of combined therapy according to the guidelines for the treatment of Mycobacterium avium complex pulmonary disease. Internal Medicine 42, 670 (01 Aug, 2003). 49. J. A. Lindeboom, E. J. Kuijper, E. S. Bruijnesteijn van Coppenraet, R. Lindeboom, J. M. Prins, Surgical excision versus antibiotic treatment for nontuberculous mycobacterial cervicofacial lymphadenitis in children: a multicenter, randomized, controlled trial. Clinical Infectious Diseases 44, 1057 (Apr 15, 2007). 50. Y. Kobashi, T. Matsushima, M. Oka, A double‐blind randomized study of aminoglycoside infusion with combined therapy for pulmonary Mycobacterium avium complex disease. Respiratory medicine 101, 130 (Jan, 2007). 51. P. A. Jenkins et al., Clarithromycin vs ciprofloxacin as adjuncts to rifampicin and ethambutol in treating opportunist mycobacterial lung diseases and an assessment of Mycobacterium vaccae immunotherapy. Thorax 63, 627 (July, 2008). 52. M. P. Murray, I. F. Laurenson, A. T. Hill, Outcomes of a standardized triple‐drug regimen for the treatment of nontuberculous mycobacterial pulmonary infection. Clinical Infectious Diseases 47, 222 (Jul 15, 2008). 53. N. Hasegawa et al., Therapeutic effects of various initial combinations of chemotherapy including clarithromycin against Mycobacterium avium complex pulmonary disease. Chest 136, 1569 (Dec, 2009). 54. K. Jeon et al., Antibiotic treatment of Mycobacterium abscessus lung disease: a retrospective analysis of 65 patients. American Journal of Respiratory & Critical Care Medicine 180, 896 (Nov 1, 2009). 55. J. Lyu et al., Outcomes in patients with Mycobacterium abscessus pulmonary disease treated with long‐term injectable drugs. Respiratory Medicine 105, 781 (May, 2011). 56. E. Y. Kim et al., Treatment outcome of combination therapy including clarithromycin for Mycobacterium avium complex pulmonary disease. Korean Journal of Internal Medicine 26, 54 (Mar, 2011). 57. M. Fujita et al., The clinical efficacy and safety of a fluoroquinolone‐containing regimen for pulmonary MAC disease. Journal of Infection and Chemotherapy 18, 146 (April, 2012). 58. Y. Kobashi et al., Relationship between clinical efficacy for pulmonary MAC and drug‐sensitivity test for isolated MAC in a recent 6‐ yearperiod. Journal of Infection and Chemotherapy 18, 436 (August, 2012). 59. D. P. O'Brien et al., Successful outcomes with oral fluoroquinolones combined with rifampicin in the treatment of Mycobacterium ulcerans: An observational cohort study. PLoS Neglected Tropical Diseases 6, (January, 2012). 60. N. D. Friedman et al., Mycobacterium ulcerans Disease: Experience with Primary Oral Medical Therapy in an Australian Cohort. PLoS Neglected Tropical Diseases 7, (July, 2013). 61. S. Miwa et al., Efficacy of clarithromycin and ethambutol for mycobacterium avium complex pulmonary disease: A preliminary study. Annals of the American Thoracic Society 11, 23 (2014). 62. D. E. Griffith, B. A. Brown, W. M. Girard, R. J. Wallace Jr, Adverse events associated with high‐dose rifabutin in macrolide‐containing regimens for the treatment of Mycobacterium avium complex lung disease. Clinical Infectious Diseases 21, 594 (September, 1995). 63. S. K. Field, R. L. Cowie, Treatment of Mycobacterium avium‐intracellulare complex lung disease with a macrolide, ethambutol, and clofazimine. Chest 124, 1482 (Oct, 2003). 64. W. J. Burman, R. R. Reves, C. A. Rietmeijer, D. L. Cohn, A retrospective comparison of clarithromycin versus rifampin in combination treatment for disseminated Mycobacterium avium complex disease in AIDS: clarithromycin decreases transfusion requirements. International Journal of Tuberculosis & Lung Disease 1, 163 (Apr, 1997). 65. C. A. Benson et al., Clarithromycin or rifabutin alone or in combination for primary prophylaxis of Mycobacterium avium complex disease in patients with AIDS: A randomized, double‐blind, placebo‐controlled trial. The AIDS Clinical Trials Group 196/Terry Beirn Community Programs for Clinical Research on AIDS 009 Protocol Team. Journal of Infectious Diseases 181, 1289 (Apr, 2000). 66. M. Dunne et al., A randomized, double‐blind trial comparing azithromycin and clarithromycin in the treatment of disseminated Mycobacterium avium infection in patients with human immunodeficiency virus. Clinical Infectious Diseases 31, 1245 (2000). 67. B. Dautzenberg et al., Clarithromycin and other antimicrobial agents in the treatment of disseminated Mycobacterium avium infections in patients with acquired immunodeficiency syndrome. Archives of internal medicine 153, 368 (Feb 8, 1993). 68. B. Dautzenberg et al., A randomized comparison of two clarithromycin doses for treatment of Mycobacterium avium complex infections. Infection 25, 16 (Jan‐Feb, 1997). 69. R. E. Chaisson et al., Clarithromycin and ethambutol with or without clofazimine for the treatment of bacteremic Mycobacterium avium complex disease in patients with HIV infection. AIDS (London, England) 11, 311 (Mar, 1997). 70. M. P. Dube et al., A randomized evaluation of ethambutol for prevention of relapse and drug resistance during treatment of Mycobacterium avium complex bacteremia with clarithromycin‐based combination therapy. California Collaborative Treatment Group. Journal of Infectious Diseases 176, 1225 (Nov, 1997). 71. D. L. Cohn et al., A prospective randomized trial of four three‐drug regimens in the treatment of disseminated Mycobacterium avium complex disease in AIDS patients: excess mortality associated with high‐dose clarithromycin. Terry Beirn Community Programs for Clinical Research on AIDS. Clinical Infectious Diseases 29, 125 (Jul, 1999). 72. C. A. Benson et al., A Prospective, Randomized Trial Examining the Efficacy and Safety of Clarithromycin in Combination with Ethambutol, Rifabutin, or Both for the Treatment of Disseminated Mycobacterium avium Complex Disease in Persons with Acquired Immunodeficiency Syndrome. Clinical Infectious Diseases 37, 1234 (01 Nov, 2003). 73. B. Dautzenberg, D. Piperno, P. Diot, C. Truffot‐Pernot, J. P. Chauvin, Clarithromycin in the treatment of Mycobacterium avium lung infections in patients without AIDS. Chest 107, 1035 (1995). 74. B. A. Brown, D. E. Griffith, W. Girard, J. Levin, R. J. Wallace, Jr., Relationship of adverse events to serum drug levels in patients receiving high‐dose azithromycin for mycobacterial lung disease. Clinical Infectious Diseases 24, 958 (May, 1997). 75. B. S. Davies, C. H. Roberts, S. Kaul, J. L. Klein, H. J. Milburn, Non‐tuberculous slow‐growing mycobacterial pulmonary infections in non‐HIV‐infected patients in south London. Scandinavian journal of infectious diseases 44, 815 (Nov, 2012).