Application for the inclusion of GATIFLOXACIN in the 20th WHO Model List of Essential Medicines (“EML”), as a reserve second-line drug 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 2015 editions of both the WHO Model List of Essential Medicines (19th list) and the WHO Model List of Essential Medicines for Children (5th list)(1),(2)). The proposal is to add gatifloxacin to both complementary lists in section 6.2.4 Antituberculosis medicines, as an alternative fluoroquinolone to and . The applicant considers that this medication should be viewed as an essential medicine for patients with multidrug-resistant (combined resistance to and ; MDR-TB) and extensively drug- resistant (MDR-TB with additional resistance to a fluoroquinolone and a second-line injectable; 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. The revised WHO policy for the treatment of MDR-TB recommends the use of a shorter MDR-TB regimen(4); such regimens have shown promise to drastically reduce the length of treatment for MDR- TB patients to 9 months(5),(6),(7),(8) and are currently being used in various treatment programmes. The effectiveness and safety of these shorter regimens are also being studied in four countries under randomized controlled (RCT) conditions(9). Gatifloxacin may be included as part of both shorter MDR-TB regimens and longer regimens for M/XDR- TB. The 2016 update of the WHO treatment guidelines for drug-resistant tuberculosis now includes a regrouping of TB medicines which differs from the one in former guidelines(4),(10). The position of gatifloxacin however does not differ and it continues to feature alongside the other fluoroquinolones - levofloxacin and moxifloxacin – of Group A. Gatifloxacin used to be a mainstay fluoroquinolone of the shorter MDR-TB regimen until a global shortage of quality-assured formulations of the medicine occurred as a result of safety concerns(11). This constrained clinicians to replace this medicine with other later-generation fluoroquinolones in both shorter and longer regimens. Given that gatifloxacin is cheaper to manufacture than other later-generation fluoroquinolones, should production recommence it could substantially lower the costs of regimens. The inclusion of the drug as an antituberculosis agent on the EML will encourage pharmaceutical manufacturers to invest more in the production of this drug. 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 these older medications(12). 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 patient access to treatment, ensure more favourable outcomes and reduce avoidable mortality for the 580,000 patients estimated to develop rifampicin-resistant or MDR-TB in the world every year and who would need second-line TB treatment regimens to increase their likelihood of a successful outcome.

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2. Name of the WHO technical department and focal point 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, Tiziana MASINI and Ernesto JARAMILLO.

3. Name of the organization(s) consulted and/or supporting the application Dr Kaspars Lunte of Global Drug Facility (GDF)

4. International Nonproprietary Name (INN, generic name) and Anatomical Therapeutic Chemical (ATC) code of the medicine The WHO INN (generic name) of the medicine is Gatifloxacin(13),(14). The Anatomical Therapeutic Chemical (ATC) code is J01MA16(16).

5. Formulation(s) and strength(s) proposed for inclusion; including adult and paediatric (if appropriate) The formulations proposed, for both adults and children, are tablets in dosages of 200 mg or 400 mg. A drug information sheet for gatifloxacin is available in Annex 1(10).

Details of the current market availability Gatifloxacin was marketed by Bristol-Myers Squibb (400 mg or 200 mg tablets) under the brand name Tequin®(17), having licensed the medication from Kyorin Pharmaceutical Company (Japan). However, following safety concerns reported in older patients, its production was stopped and the manufacturer announced its plan to stop producing and selling Tequin® in May 2006(18),(19). The company Allergan still manufactures a gatifloxacin-containing eye-drop formulation under the names Zymar® and Zymaxid®(20). In India and Bangladesh, generic manufacturers are known to produce gatifloxacin tablets for export. However, these manufacturers are not yet quality-assured. A number of manufacturers are listed as having GMP certificate for gatifloxacin in the “Database of approved Active Pharmaceutical Ingredients (APIs) and API manufacturers in China” of the China Food and Drug Administration(21). In October 2016 WHO added gatifloxacin to the list of TB medicines for which manufacturers will be invited to submit an Expression of Interest for API or Finished Pharmaceutical Products to the WHO Prequalification Team(22). It is expected that a number of manufacturers will respond to this invitation.

6. Whether listing is requested as an individual medicine or as representative of a pharmacological class This application is being made for gatifloxacin to be included with a square box symbol, alongside other fluoroquinolones which are already included as reserve second‐line drugs in the EML for both adults and children - levofloxacin and moxifloxacin(1),(2). There are other medications in the fluoroquinolone class (e.g. and ) which are not included among the agents forming part of MDR and XDR-TB regimens. A separate application is being made to have ofloxacin eventually removed from the EML given that it has now been superseded by the other three fluoroquinolones.

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Treatment details, public health relevance and evidence appraisal and synthesis 7. Treatment details (requirements for diagnosis, treatment and monitoring) Gatifloxacin could be an important component of both the intensive and the continuation phase of the shorter MDR-TB regimen recommended by WHO(4),(5). The regimen is usually composed of , , isoniazid, gatifloxacin (or moxifloxacin), kanamycin (or amikacin), (or ) and for four months (prolonged to six months in case of failure of sputum conversion), followed by a continuation phase of pyrazinamide, ethambutol, gatifloxacin (or moxifloxacin), and clofazimine for five months. Since May 2016, WHO recommends the shorter MDR-TB regimen in selected patients; gatifloxacin could thus have a central role in a regimen which is offered to patients as a standard of care unless they have specific exclusion criteria. Moreover, gatifloxacin could be the fluoroquinolone of choice for the longer regimens for both MDR-TB and XDR- TB, which is usually composed of pyrazinamide plus at least 4 second-line anti-TB drugs considered to be effective, including a later-generation fluoroquinolone, a second-line injectable, and two or more of : ethionamide (or prothionamide), , linezolid or clofazimine(4). In the shorter MDR-TB regimen gatifloxacin is used for 9-11 months. A high dose based on body weight has been used (400-800 mg per day)(5),(6). The dose for the treatment of children with MDR-TB has not been well defined although when used to treat enteric infections gatifloxacin has been used at a dosage of 10 mg/kg/day, albeit for a few days(23),(24). Blood glucose monitoring every 1-2 weeks in patients taking gatifloxacin should be carried out(25). Electrocardiography should also be monitored regularly owing to concerns about potential cardiotoxicity(26),(27). These monitoring measures have proven to be feasible under programmatic conditions in low-resource settings. In August 2012, WHO advised countries to introduce shorter MDR-TB regimen only under operational research conditions, subject to the approval of a national ethics review, and with an appropriate assessment of the effectiveness and safety of treatment. Following a review of evidence which accrued from such studies, in May 2016 WHO conditionally recommended the use of a shorter MDR-TB regimen under normal programmatic conditions in patients who fulfil the eligibility criteria for this treatment(4),(28).

8. Information supporting the public health relevance Each year it is estimated that 580,000 new rifampicin-resistant and multidrug-resistant TB (MDR/RR-TB) cases emerge in the world and 250,000 MDR/RR-TB patients die(3). Many MDR-TB cases go undetected and are not placed on an appropriate treatment, increasing their risk of dying and of continued transmission of drug-resistant strains to others. About one half of MDR-TB cases globally have also lost susceptibility to key drugs in the MDR-TB regimen: fluoroquinolones, second-line injectable agents, or both (i.e. XDR-TB). XDR-TB represents about 10 % of MDR-TB cases and 122 countries and other settings have now detected at least one such case. In 2015, countries reported that about 125,000 MDR/RR-TB patients and over 7,000 XDR-TB patients started treatment worldwide. The effectiveness of these efforts vary considerably and the likelihood of treatment success in MDR-TB patients diminishes with the acquisition of additional resistance and is particularly low in XDR-TB patients(29). Treatment outcome reporting to WHO in recent years showed that only about one half of MDR/RR-TB patients and just over one fourth of XDR-TB patients complete their treatment successfully(30). The rest die, sustain a treatment failure, interrupt treatment or are otherwise lost to follow up. Given the low treatment coverage and success of M/XDR-TB, every effort must be made to ensure that all possible medications used to treat this condition are more widely available.

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The transmissibility of M/XDR-TB strains has been documented in outbreaks and sporadic episodes in both hospital and household settings(31),(32),(33),(34). This poses an additional public health concern making the proper treatment of M/XDR-TB patients all the more important. Medications such as gatifloxacin are thus essential to help curb such challenges into the future, to ensure that MDR/RR-TB patients are treated appropriately and to avert the emergence of further resistance among them.

9. Review of benefits: summary of comparative effectiveness in a variety of clinical settings In general treatment success among MDR/RR-TB patients is much lower than drug-susceptible TB patients, despite the use of combination regimens with second-line drugs. However, gatifloxacin- containing shorter MDR-TB regimens lasting up to 12 months, when used in carefully-selected patients, have been associated with much higher success rates comparable to those in patients with drug- susceptible disease (see GRADE Table in Annex 2)(5),(6). Deaths among patients on gatifloxacin (2.7%) were lower than those in patients who received another fluoroquinolone or none (8.6%), suggesting improved outcome rather than any risk of excess mortality in patients exposed to this medicine. 10. Review of harms and toxicity: summary of evidence on safety Reports of blood glucose disorders in patients treated with gatifloxacin for conditions other than drug- resistant TB led the parent company to stop manufacture of the drug in 2006(11). A global shortage in quality-assured formulations of this drug ensued. This impacted negatively upon efforts to expand access to MDR-TB regimens in which gatifloxacin was an important and affordable option. A trial of a four-month standardised regimen for drug-susceptible TB which included gatifloxacin (400 mg once daily) published in 2014 reported no significant risk of hyperglycaemia associated with exposure to gatifloxacin(35). A review of available evidence for effectiveness and harms was undertaken as part of the 2016 revision of treatment guidance for drug-resistant TB (see GRADE Table in Annex 2). Although adverse events were incompletely recorded in studies reviewed, there was a lower risk of serious adverse events (defined as grade 3-4 adverse events or drugs stopped due to adverse event) in patients taking gatifloxacin (3.6%) than in those who did not, including those receiving no fluoroquinolones (8%; adjusted confidence limits show statistically significant difference).

11. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group Gatifloxacin is an affordable drug and had been commonly used by TB treatment programmes until the concerns about its effects on glucose metabolism led to a global shortage in this medicine. A restart of the manufacture of quality-assured formulations of the medicine could substantially lower the costs of regimens by substituting more expensive options in fluoroquinolones.

Regulatory information

12. Summary of regulatory status of the medicine Gatifloxacin was approved by the US Food and Drug Administration (FDA) on 19 Dec 1999 for the treatment of various infections, including upper and lower respiratory tract infections and urinary tract infections. It was marketed by Bristol-Myers Squibb (200 mg or 400 mg tablets) under the brand name Tequin®, having licensed the medication from Kyorin Pharmaceutical Company (Japan)(36). However, following reports of blood glucose disturbances among elderly patients(11), its production was stopped and the manufacturer announced its plan to stop producing and selling Tequin® in May 2006(Error! Bookmark not defined.,Error! Bookmark not defined.).

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Gatifloxacin, in its tablet formulation, was not found among the drugs registered by FDA, the European Medicines Agency, Health Canada, the Australian Therapeutic Goods Administration or Pharmaceuticals, and the Medical Devices Agency (Japan). A number of manufacturers of gatifloxacin are listed in the “Database of approved Active Pharmaceutical Ingredients (APIs) and API manufacturers in China” of the China Food and Drug Administration(21)

13. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia, European Pharmacopeia) A reference standard for gatifloxacin can be found in the United States Pharmacopeia(37)

14. Reference list 1. WHO Model List of Essential Medicines [Internet]. 19th list. Geneva, World Health Organization; 2015. Available from: http://www.who.int/selection_medicines/committees/expert/20/EML_2015_FINAL_amended_AUG2015.pd f

2. WHO Model List of Essential Medicines for Children [Internet]. 5th list. Geneva, World Health Organization; 2015. Available from: http://www.who.int/medicines/publications/essentialmedicines/EMLc_2015_FINAL_amended_AUG2015.pd f

3. Global tuberculosis report 2016 (WHO/HTM/TB/2016.13) [Internet]. Geneva, World Health Organization; 2016. Available from: http://www.who.int/tb/publications/global_report/en/

4. WHO treatment guidelines for drug-resistant tuberculosis, 2016 update (WHO/HTM/TB/2016.04) [Internet]. Geneva, World Health Organization. 2016. Available from: http://www.who.int/tb/areas-of-work/drug- resistant-tb/treatment/resources/en/

5. Van Deun A, Maug AKJ, Salim MAH, Das PK, Sarker MR, Daru P, et al. Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med. 2010 Sep 1;182(5):684–92.

6. Piubello A, Harouna SH, Souleymane MB, Boukary I, Morou S, Daouda M, et al. High cure rate with standardised short-course multidrug-resistant tuberculosis treatment in Niger: no relapses. Int J Tuberc Lung Dis. 2014 Oct;18(10):1188–94.

7. Kuaban C, Noeske J, Rieder HL, Aït-Khaled N, Abena Foe JL, Trébucq A. High effectiveness of a 12-month regimen for MDR-TB patients in Cameroon. Int J Tuberc Lung Dis. 2015 May;19(5):517–24.

8. Aung K, van Deun A, Declercq E, Sarker M, Das P, Hossain M, et al. Successful ‘9-month Bangladesh regimen’ for multidrug resistant tuberculosis among over 500 consecutive patients. Int J Tuberc Lung Dis. 2014;18(10):1180–7.

9. Nunn AJ, Rusen ID, Van Deun A, Torrea G, Phillips PPJ, Chiang C-Y, et al. Evaluation of a standardized treatment regimen of anti-tuberculosis drugs for patients with multi-drug-resistant tuberculosis (STREAM): study protocol for a randomized controlled trial. Trials. 2014;15:353.

10. Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis. (WHO/HTM/TB/2014.11) [Internet]. Geneva, World Health Organization. 2015. Available from: http://apps.who.int/iris/bitstream/10665/130918/1/9789241548809_eng.pdf

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11. Park-Wyllie LY, Juurlink DN, Kopp A, Shah BR, Stukel TA, Stumpo C, et al. Outpatient Gatifloxacin Therapy and Dysglycemia in Older Adults. N Engl J Med. 2006;354(13):1352–61.

12. UNITAID Approves Grants of $160 million [Internet]. [cited 2014 Jul 26]. Available from: http://www.unitaid.org/en/press-releases/1352-unitaid-approves-grants-of-160-million

13. Chambers M. ChemIDplus - 112811-59-3 - XUBOMFCQGDBHNK-UHFFFAOYSA-N - Gatifloxacin [USAN:INN] - Similar structures search, synonyms, formulas, resource links, and other chemical information. [Internet]. [cited 2016 Jun 30]. Available from: http://chem.sis.nlm.nih.gov/chemidplus/rn/112811-59-3

14. Drugs@FDA: FDA Approved Drug Products [Internet]. [cited 2016 Jun 30]. Available from: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Overview&DrugNam e=GATIFLOXACIN

15. WHO Drug Information. Recommended INN List 39. International Nonproprietary Names for Pharmaceutical Substances [Internet]. Geneva, World Health Organization. Vol. 12. 1998. Available from: http://apps.who.int/medicinedocs/index/assoc/s14167e/s14167e.pdf

16. WHOCC - ATC/DDD Index [Internet]. [cited 2016 Jun 30]. Available from: http://www.whocc.no/atc_ddd_index/?code=J01MA16&showdescription=yes

17. Bristol-Myers Squibb Company. TEQUIN (gatifloxacin) Tablets TEQUIN (gatifloxacin) Injection TEQUIN (gatifloxacin in 5% dextrose) Injection [Internet]. [cited 2016 Jun 30]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/21061s023,024,21062s026,037lbl.pdf

18. Department of Health and Human Services and Food and Drug Administration. [Docket Nos. FDA-2006-P- 0081 (formerly Docket No. 2006P-0178) and FDA-2005-P-0369 (formerly Docket No. 2005P-0023)] Determination That TEQUIN (Gatifloxacin) Was Withdrawn From Sale for Reasons of Safety or Effectiveness [Internet]. [cited 2016 Jun 30]. Available from: http://www.fda.gov/OHRMS/DOCKETS/98fr/cd07129-n.pdf

19. FDA (Federal Food and Drug Administration). Information for Healthcare Professionals: Gatifloxacin (marketed as Tequin) [Internet]. Available from: http://www.fda.gov/downloads/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandprovider s/ucm126166.pdf

20. PRESCRIBING INFORMATION (ZYMAXID (R); gatifloxacin ophthalmic solution 0.5% ) [Internet]. [cited 2016 Jul 1]. Available from: http://www.allergan.com/assets/pdf/zymaxid_pi.pdf

21. China Food and Drug Administration. Database of approved Active Pharmaceutical Ingredients (APIs) and API manufacturers in China [Internet]. [cited 2016 Jul 1]. Available from: http://app1.sfda.gov.cn/datasearcheng/face3/base.jsp?tableId=85&tableName=TABLE85&title=Database%2 0of%20approved%20Active%20Pharmaceutical%20Ingredients%20(APIs)%20and%20API%20manufacturers %20in%20China&bcId=136489131226659132460942000667

22. 14th Invitation to manufacturers of antituberculosis medicines to submit an Expression of Interest (EOI) for product evaluation to the WHO Prequalification Team - Medicines [Internet]. Geneva, World Health Organization; 2016. Available from: http://apps.who.int/prequal/info_applicants/eoi/2016/EOI- TuberculosisV14.pdf

23. Vinh H, Anh VTC, Anh ND, Campbell JI, Hoang NVM, Nga TVT, et al. A multi-center randomized trial to assess the efficacy of gatifloxacin versus ciprofloxacin for the treatment of shigellosis in Vietnamese children. PLoS Negl Trop Dis. 2011 Aug;5(8):e1264.

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24. Koirala S, Basnyat B, Arjyal A, Shilpakar O, Shrestha K, Shrestha R, et al. Gatifloxacin versus ofloxacin for the treatment of uncomplicated enteric fever in Nepal: an open-label, randomized, controlled trial. PLoS Negl Trop Dis. 2013;7(10):e2523.

25. Yamada C, Nagashima K, Takahashi A, Ueno H, Kawasaki Y, Yamada Y, et al. Gatifloxacin acutely stimulates insulin secretion and chronically suppresses insulin biosynthesis. Eur J Pharmacol. 2006 Dec 28;553(1–3):67– 72.

26. Frothingham R. Rates of torsades de pointes associated with ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, and moxifloxacin. Pharmacotherapy. 2001 Dec;21(12):1468–72.

27. Bertino JS, Owens RC, Carnes TD, Iannini PB. Gatifloxacin-Associated Corrected QT Interval Prolongation, Torsades de Pointes, and Ventricular Fibrillation in Patients with Known Risk Factors. Clin Infect Dis. 2002 Mar 15;34(6):861–3.

28. WHO | Treatment of drug-resistant TB: Resources [Internet]. [cited 2016 Jun 30]. Available from: http://www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/resources/en/

29. 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.

30. 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. The Lancet Infectious Diseases. 2013 Aug;13(8):690– 7.

31. Shenoi SV, Escombe AR, Friedland G. Transmission of Drug-Susceptible and Drug-Resistant Tuberculosis and the Critical Importance of Airborne Infection Control in the Era of HIV Infection and Highly Active Antiretroviral Therapy Rollouts. Clin Infect Dis. 2010 May 15;50(Supplement 3):S231–7.

32. Schaaf HS, Van Rie A, Gie RP, Beyers N, Victor TC, Van Helden PD, et al. Transmission of multidrug-resistant tuberculosis. Pediatr Infect Dis J. 2000 Aug;19(8):695–9.

33. Gandhi NR, Moll A, Sturm AW, Pawinski R, Govender T, Lalloo U, et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet. 2006 Nov 4;368(9547):1575–80.

34. HIV-Associated XDR TB Is Transmitted in Households and Hospitals in South Africa | CROI Conference [Internet]. [cited 2016 Jun 30]. Available from: http://www.croiconference.org/sessions/hiv-associated-xdr- tb-transmitted-households-and-hospitals-south-africa

35. Merle CS, Fielding K, Sow OB, Gninafon M, Lo MB, Mthiyane T, et al. A Four-Month Gatifloxacin-Containing Regimen for Treating Tuberculosis. New England Journal of Medicine. 2014 Oct 23;371(17):1588–98.

36. Search Result | KYORIN Pharmaceutical Co., Ltd. [Internet]. [cited 2016 Jul 1]. Available from: http://www.kyorin- pharm.co.jp/en/search/?cx=005156942806306160388%3Auec1ow7sny4&cof=FORID%3A11&ie=UTF- 8&q=gatifloxacin&sa=Search

37. U.S. Pharmacopeial Convention. Gatifloxacin (300 mg) [Internet]. [cited 2016 Jul 1]. Available from: http://store.usp.org/OA_HTML/ibeCCtpItmDspRte.jsp?sitex=10020:22372:US&item=18045%20

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Annex 1 (source: (10))

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Annex 2: GRADE Table summarizing the evidence for effectiveness and harms of gatifloxacin in MDR-TB treatment(4) Author(s): Menzies R, Bastos M, Lan Z, Cerigo H, Ronald L (11 November 2015) Question: Gatifloxacin compared to no gatifloxacin for the treatment of adults with rifampicin-resistant or multidrug-resistant tuberculosis Setting: Treatment of adults with RR-/MDR-/XDR-TB using conventional regimens lasting about 24 months and shorter MDR-TB regimens, in low and high resource settings, within hospital or ambulatory models of care Bibliography: (1) Van Deun A, Maug AKJ, Salim MAH, Das PK, Sarker MR, Daru P, et al. Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med. 2010 Sep 1;182(5):684–92 (2) Butov DA, Efremenko YV, Prihoda ND, Yurchenko LI, Sokolenko NI, Arjanova OV, Stepanenko AL, Butova TS, Zaitzeva SS, Jirathitikal V, Bourinbaiar AS, Kutsyna GA. Adjunct immune therapy of first-diagnosed TB, relapsed TB, treatment-failed TB, multidrug-resistant TB and TB/HIV. Immunotherapy 2012: 4(7): 687-695 (3) Xu HB, Jiang RH, Xiao HP. Clofazimine in the treatment of multidrug-resistant tuberculosis. Clinical microbiology and infection 2012: 18(11): 1104-1110 (4) Xu HB, Jiang RH, Li L, Xiao HP. Linezolid in the treatment of MDR-TB: a retrospective clinical study. IJTLD 2012: 16(3): 358-363 (5) Carroll MWL, M.; Cai, Y.; Hallahan, C. W.; Shaw, P. A.; Min, J. H.; Goldfeder, L. C. et al. Frequency of adverse reactions to first- and second-line anti-tuberculosis chemotherapy in a Korean cohort. IJTLD 2012: 16(7): 961-966. (6) Jawahar MS, Banurekha VV, Paramasivan CN, Rahman F, Ramachandran R, Venkatesan P et al. Randomized clinical trial of thrice-weekly 4-month moxifloxacin or gatifloxacin containing regimens in the treatment of new sputum positive pulmonary tuberculosis patients. PLoS One 2013: 8(7): e67030. (7) Jo KW, Lee SD, Kim WS, Kim DS, Shim TS. Treatment outcomes and moxifloxacin susceptibility in ofloxacin-resistant multidrug-resistant tuberculosis. IJTLD 2014: 18(1): 39-43. (8) Rustomjee R, Lienhardt C, Kanyok T, Davies GR, Levin J, Mthiyane T et al. A Phase II study of the sterilising activities of ofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. IJTLD 2008: 12(2): 128-138.

Quality assessment № of patients Effect

Quality Importance № of Relative Absolute Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations gatifloxacin no gatifloxacin studies (95% CI) (95% CI)

Treatment success versus failure/relapse/death (assessed with: van Deun 2010; Butov 2011; Xu 2012a, 2012b)1

2 4 observational very serious serious not serious serious strong association 189/225 (84.0%) 174/268 (64.9%) not 191 more per 1,000 ⨁◯◯◯ CRITICAL studies estimable (116 more to 265 more) VERY LOW

Death versus all other outcomes (assessed with: van Deun 2010, Butov 2011, Xu 2012a, 2012b)1

2 4 observational very serious serious not serious serious none 6/225 (2.7%) 23/268 (8.6%) not 59 fewer per 1,000 ⨁◯◯◯ CRITICAL studies estimable (20 fewer to 99 fewer) VERY LOW

Serious adverse events (Grade 3 or 4, or drugs stopped due to adverse events) in patients on gatifloxacin vs. no gatifloxacin (assessed with: comparative observational studies: Caroll 2012, Jawahar 2013, Jo 2014, Rustomjee 2008, and van Deun 2010)1

3 4 5 observational very serious serious not serious serious none 15/422 (3.6%) 137/1711 (8.0%) not ⨁◯◯◯ CRITICAL 5 3 studies estimable VERY LOW

CI: Confidence interval

1. In the no gatifloxacin group the other fluoroquinolone used was either ofloxacin, levofloxacin or moxifloxacin 2. Small observational studies using individualized regimens with substantial potential for bias; in the van Deun et al study gatifloxacin was used as part of shorter MDR-TB regimens reserved for patients selected upon specific criteria 3. Serious adverse events (SAEs) reported in patients were attributed to a medicine by the authors who were unblinded and used non-standardized methods to define, ascertain and report SAEs. No valid comparisons possible with patients not on the target medicine, because SAEs in these patients could be due to other drugs received. 4. Pooled proportion: FE 95%CI= 2.0%-5.8% 5. Pooled proportion: FE 95%CI= 6.8%-9.4%

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