Treatment of MDR/XDR-TB. Short course chemotherapy for MDR-TB: practical issues. CHIANG Chen-Yuan MD, MPH, DrPhilos

Treatment of MDR/XDR-TB Short course chemotherapy for MDR-TB: practical issues CHIANG Chen-Yuan MD, MPH, DrPhilos

Treatment strategies for MDR-TB Standardized treatment: drug resistance survey data from representative patient populations are used to base regimen design in the absence of individual drug susceptibility testing result. Individualized treatment: Each regimen is designed based on the patient s past history of TB treatment and individual DST results.

Treatment of drug-resistant tuberculosis...the selection of anti-tb agents is based upon the history of previous therapy and the results of reliable DST. ATS. A Statement by the Committee on Therapy. Treatment Drug- Resistant TB. Am Rev Respir Dis 1966;94:125-7

Standardized treatment for MDR-TB much feasible under program condition for MDR-TB patients who has not been treated with second line drugs before, especially in settings where second-line drugs have not yet been widely used But, an inadequately designed standardized regimen not well matched to the general susceptibility pattern may perform poorly. Chiang C-Y, et al. Int J Tuberc Lung Dis 2010;14:672 682

Essential components in individualized treatment for MDR-TB Ensure quality of drug susceptibility testing (DST). Short turn around time of DST (otherwise, the pattern of drug resistance may change). Detail history of previously anti-tuberculosis treatment, especially previous treatment with second line anti-tuberculosis drugs Well trained in interpreting DST results Well trained in designing a MDR-TB regimen Chiang C-Y, et al. Int J Tuberc Lung Dis 2010;14:672 682

MDR-TB patient previously treated with second line drugs Individualized treatment is usually applied for MDR- TB patients previously treated with second-line drugs, taking into account history of drug use and quality assured drug susceptibility testing results Standardized approach might be feasible if rapid DST of fluoroquinolone and second line injectables is available

Previous WHO recommendations, 2008 should consist of at least 4 drugs with either certain or almost certain effectiveness, do not depend on DST in individual regimen design for ethambutol, pyrazinamide, and Group 4 and 5 drugs an injectable agent is used for a minimunm of 6 months and 4 months after culture conversion, the minimum duration of treatment is 18 months after culture conversion WHO/HTM/TB/2008.402:1-247

MDR-TB: an Individual Patient Data (IPD) Meta-Analysis of 9153 patients three types of drug-exposure : 1. specific drugs administered 2. number of likely effective drugs used 3. duration of treatment regimen. PLoS Med 9(8): e1001300. doi:10.1371/journal.pmed.1001300

MDR-TB: an Individual Patient Data (IPD) Meta-Analysis of 9153 patients estimated odds of treatment success (defined as treatment cure or completion) compared to one of three alternate outcomes: [i] treatment failure and/or relapse; [ii] treatment failure, relapse and/or death; and [iii] treatment failure, relapse, death and/or default. PLoS Med 9(8): e1001300. doi:10.1371/journal.pmed.1001300

MDR-TB treatment regimens and patient outcomes: an Individual Patient Data (IPD) Meta-Analysis of 9153 patients Treatment success, compared to failure/relapse, was associted with use of: later generation quinolones ofloxacin ethionamide or prothionamide use of four or more likely effective drugs in the initial intensive phase three or more likely effective drugs in the continuation phase PLoS Med 9(8): e1001300. doi:10.1371/journal.pmed.1001300

MDR-TB treatment regimens and patient outcomes: an Individual Patient Data (IPD) Meta- Analysis of 9153 patients Among those who did not die, or default during treatment, the maximum odds of success was seen with duration of the initial intensive phase of 7.1-8.5 months, and total treatment duration of 18.6-21.5 months PLoS Med 9(8): e1001300. doi:10.1371/journal.pmed.1001300

3. Composition of second-line antituberculosis regimens 3.1 In the treatment of patients with MDR-TB, a fluoroquinolone should be used (strong recommendation, /very low quality evidence). 3.2 In the treatment of patients with MDR-TB, a latergeneration fluoroquinolone rather than an earlier-generation fluoroquinolone should be used (conditional recommendation, /very low quality evidence). 3.3 In the treatment of patients with MDR-TB, ethionamide (or prothionamide) should be used (strong recommendation, /very low quality evidence).

3. Composition of second-line antituberculosis regimens 3.4 In the treatment of patients with MDR-TB, four secondline anti-tuberculosis drugs likely to be effective (including a parenteral agent), as well as pyrazinamide, should be included in the intensive phase (conditional recommendation, /very low quality evidence). 3.5 In the treatment of patients with MDR-TB, regimens should include at least pyrazinamide, a fluoroquinolone, a parenteral agent, ethionamide (or prothionamide), and either cycloserine or PAS (p-aminosalicylic acid) if cycloserine cannot be used (conditional recommendation, /very low quality evidence).

4. Duration of second-line antituberculosis regimens 4.1 In the treatment of patients with MDR-TB, an intensive phase of at least 8 months duration is recommended (conditional recommendation, / very low quality evidence). 4.2 In the treatment of patients with MDR-TB, a total treatment duration of at least 20 months is recommended in patients without any previous MDR-TB treatment (conditional recommendation, /very low quality evidence).

Odds ratios of treatment success by duration of intensive phase and total treatment

the recommendation of at least Based on inadequate combination of : 1) the highest odds ratio in the duration analysis, 2) modification of duration according to response to treatment. Chiang C-Y, communication after 2 nd gglc meeting, Geneva, Feb 2012

Maximum duration of treatment? Duration of initial intensive phase (reference 1.0 2.5 mo) PLoS Med 9(8): e1001300. doi:10.1371/journal.pmed.1001300 17

WHO recommendations, 2011 (revised) 4.1 In the treatment of patients with MDR-TB, an intensive phase of 8 months is suggested for most patients, and the duration may be modified according to the patient s response to therapy (conditional recommendation, /very low quality evidence). 4.2 In the treatment of patients newly diagnosed with MDR-TB (i.e. not previously treated for MDR-TB), a total treatment duration of 20 months is suggested for most patients, and the duration may be modified according to the patient s response to therapy (conditional recommendation, /very low quality evidence). http://www.who.int/tb/challenges/mdr/programmatic_guidelines_for_mdrtb/en/index.html

WHO Treatment Guidelines for drugresistant tuberculosis - 2016 update

Medicines recommended for the treatment of rifampicin-resistant and multidrug-resistant TB A. Fluoroquinolones Levofloxacin Moxifloxacin Gatifloxacin B. Second-line injectable agents Amikacin Capreomycin Kanamycin (Streptomycin) C. Other core second-line agents Ethionamide / Prothionamide Cycloserine / Terizidone Linezolid Clofazimine * Medicines in Groups A and C are shown by decreasing order of usual preference for use

Medicines recommended for the treatment of rifampicin-resistant and multidrug-resistant TB D. Add-on agents (not part of the core MDR-TB regimen) 1 Pyrazinamide Ethambutol High-dose isoniazid 2 3 Bedaquiline Delamanid p-aminosalicylic acid Imipenem-Cilastatin Meropenem Amoxicillin-Clavulanate* (Thioacetazone)* *Carbapenems and clavulanate are meant to be used together; clavulanate is only available in formulations combined with amoxicillin; HIV-status must be tested and confirmed to be negative before thioacetazone is started

Emerging Infectious Diseases 2017

isoniazid (INH) 300 mg, levofloxacin 1000 mg, gatifloxacin 400 mg, or moxifloxacin 400 mg daily for 7 days Moxifloxacin, gatifloxacin, and high-dose levofloxacin have excellent EBA, only slightly less than for INH, and greater extended EBA.

The early bactericidal activity of antituberculosis drugs: a literature review In nearly all studies, whether over 0 2, 0 5 or 0 7 days, the fluoroquinolones have shown bactericidal activity close to, or equal to, that of INH. Despite being in vitro amongst the most bactericidal agents available, all the aminoglycosides have a relatively low EBA. Donald PR, et al. Tuberculosis 2008

Success Rates Levofloxacin Group Ofloxacin Group Overall 90% 79.7% Ofloxacin Susceptible 96,2% 87.5% Ofloxacin Resistant 78.6% 45.5% Levofloxacin was found to be more efficacious than ofloxacin when incorporated into multidrug regimens used for treatment of MDR-TB. Yew WW. Chest 2003; 124: 1476-1481

Comparison of Levofloxacin versus Moxifloxacin for Multidrug-Resistant Tuberculosis Comparison of time to culture (a) and smear (b) conversion between levofloxacin and moxifloxacin group adjusting for body mass index and pyrazinamide use Koh W-J, et al. Am J Respir Crit Care Med 2013

Fluoroquinolone-Containing Third-Line Regimen against M. tuberculosis In Vivo From 9 months onward, all of the organs of mice treated with the MXF-containing third-line regimen were culture negative. The majority of organs from mice treated with the OFX-containing regimen continued to be culture positive, and the mean CFU counts remained unchanged for as long as 12 months. The results for mice treated with the LVX-containing regimen fell between those for the groups receiving the MXF- and OFX containing regimens. Veziris N, et al. Antimicrob Agents Chemother 2003;47:3117 3122

Phenotypic drug susceptibility testing for four fluoroquinolones in M. tuberculosis Coeck N, et al. J Antimicrob Chemother 2016; 71: 1233 1240

Correlation Between Type of gyra Mutation and Ofloxacin and Moxifloxacin MIC gyra mutations Ala90Val+Pro102Hi s No. of strains OFX 4 MOX 0.5 OFX 4 MOX 1 2 1 1 OFX 8 MOX 1 Asp94Ala 5 1 3 1 OFX 8 MOX 2 OFX 16 MOX 2 Ala90Val 8 2 4 1 1 Ser91Pro 1 1 Ala126Arg 2 1 1 Asp94His 1 1 Asp94Gly 12 8 3 1 Asp94Tyr 2 1 1 No specific mutation 2 1 1 OFX 16 MOX 4 Total 35 4 11 2 12 4 2 Kam KM, et al. Microb Drug Resistance 2006;12:7-11

Concordance of Mycobacterium tuberculosis fluoroquinolone resistance testing Farhat MR, et al. Int J Tuberc Lung Dis 2015;9:339 341

Zignol M, et al Lancet Infect Dis 2016

Zignol M, et al Lancet Infect Dis 2016

Zignol M, et al Lancet Infect Dis 2016

Changes in treatment outcomes of MDR-TB, Korea The treatment success rate improved from 53.5% in 1996 2000 to 68.8% in 2001 2005 and 83.7% in 2006 2010 (P<0.001). Improved outcomes were accompanied with more frequent use of later-generation fluoroquinolones and linezolid Kwak N, et al. Int J Tuberc Lung Dis 2015;19:525 530

Aminoglycosides and Polypeptides Streptidine Streptomycin Deoxystreptamine Amikacin Kanamycin Polypeptides Capreomycin Viomycin

Cross-resistance between the aminoglycosides and/or the polypeptides Isolates that acquire resistance to streptomycin are usually susceptible to kanamycin, amikacin and capreomycin. rare strains with apparently single-step mutations that confer resistance to both streptomycin and kanamycin have been observed, although the molecular mechanism is not known World Health Organization. Policy guidance on drug-susceptibility testing (DST) of second-line antituberculosis drugs. 2008

Molecular Analysis of Cross-Resistance to Capreomycin, Kanamycin, Amikacin, and Viomycin in M. tuberculosis Maus CE, et al. Antimicrob Agents Chemother 2005

High Level of Cross-Resistance between Kanamycin, Amikacin, and Capreomycin among Mycobacterium tuberculosis Isolates from Georgia and a Close Relation with Mutations in the rrs Gene Of 78 kanamycin-resistant strains, 9 (11.5%) were susceptible to amikacin 16 (20.5%) were susceptible to capreomycin. Four strains were resistant to capreomycin but were susceptible to the other drugs, all amikacin-resistant isolates were resistant to kanamycin. Sequencing revealed six types of mutations in the rrs gene but no mutations in the tlya gene. Jugheli L, et al. Antimicrob Agents Chemother 2009;53:5064 5068

Resistance and Cross-Resistance to Aminoglycosides and Capreomycin in M. tuberculosis Isolates, South Korea Most (33 of 36) of the resistant isolates showed polymorphisms in the 16S ribosome components. Three resistant strains (3 of 36) were identified that had no known polymorphisms in ribosomal constituents Via LE, et al. Antimicrob Agents Chemother 2010

Performance Assessment of the GenoType MTBDRsl Test and DNA Sequencing for Detection of Second-Line and Ethambutol Drug Resistance among MDR-TB Patients the sensitivities of resistance detection using the GenoType MTBDRsl test were kanamycin 43.2%, amikacin 84.2%, capreomycin 71.4% with the inclusion of an extra gene, eis, in sequencing, the sensitivity reached 70.3% for detection of KM resistance. Huang W-L. et al. 2011

Streptomycin for the treatment of second line injectable-resistant MDR-TB In cases where the strain is resistant to all the second-line injectable drugs (amikacin, kanamycin, and capreomycin), except streptomycin, streptomycin should be considered, as there is little cross-resistance between streptomycin and the other injectable agents. WHO Companion Handbook 2014

Hearing and balance functions of the inner ear The cochlea is the hearing part of the inner ear, The semicircular canals are part of our balance system Challenge TB. Audiometry in the Management of Drug-Resistant Tuberculosis 2017

Progressive damage to the organ of Corti. Scanning electron micrographs showing the progression of damage in the basal coil of the guinea pig organ of Corti after gentamicin treatment Loss of outer hair cells Initial loss of inner hair cells Complete loss of inner hair cells Organ of Corti replaced by squamous epithelium Forge A. Audiol Neurootol 2000;5:3 22

Challenge TB. Audiometry in the Management of Drug-Resistant Tuberculosis 2017

First synthesized in 1954.

Comparative Intracellular Activities Against the Virulent H37Rv Strain in Human Macrophages Rastogi N, et al. Current Microbiology 1996;33:167-175 48

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Clofazimine Study designed and supervised by: Jacques Grosset, MD And conducted by: Sandeep Tyagi, BS, Si-yang Li, BS, Deepak Almeida, PhD, Paul Converse, PhD 50

Long-term outcomes of patients with extensively drug-resistant tuberculosis in South Africa: a cohort study Pietersen E, et al. Lancet 2014; 383: 1230 39

Long-term outcomes of patients with extensively drug-resistant tuberculosis in South Africa: a cohort study predictors of net culture conversion no history of multidrug-resistant tuberculosis (p=0 0007) use of clofazimine (p=0 0069). predictors of survival net culture conversion (p<0 0001) treatment with clofazimine (p=0 021). Antiretroviral therapy in patients with HIV (p=0 003). Pietersen E, et al. Lancet 2014; 383: 1230 39

Early and Extended Early Bactericidal Activity of Linezolid in Pulmonary Tuberculosis Am J Respir Crit Care Med 2008;178:1180 1185 54

Linezolid for Treatment of Chronic XDR-TB N Engl J Med 2012;367:1508-18 55

Linezolid for Treatment of Chronic XDR-TB N Engl J Med 2012;367:1508-18 56

Linezolid :systematic review and metaanalysis Sotgiu G, et al. Eur Respir J 2012; 40: 1430 1442 57

Linezolid :systematic review and metaanalysis Sotgiu G, et al. Eur Respir J 2012; 40: 1430 1442 58

Isoniazid (INH):a prodrug that requires the activation of bacterial catalaseperoxidase enzyme (katg). katg mutation Reduce ability to activate the prodrug cause INH resistance (low or high level) Could be restored by transformation with a functional katg gene Zhang Y,et al. 1992, 1993, 2000

Isoniazid (INH) inha encodes the NADH-dependent enoyl ACP reductase ( an enzyme involved in synthesis of cell wall mycolic acid) Cause low level INH resistance Also confer resistance to the structurally related ethionamide Zhang Y, et al. ASM 2000

After adjustment for potential confounders, subjects who received high-dose INH became sputum negative 2.38 times (95%CI 1.45 3.91, P 0.001) more rapidly than those who did not receive it had a 2.37 times (95%CI 1.46 3.84, P 0.001) higher likelihood of being sputum-negative at 6 months.

Mycobacterium tuberculosis drug susceptibility testing Böttger EC. Clin Microbiol Infect 2011;17:1128-34

Meropenem-Clavulanate and XDR-TB (A) Aerobic growth (B) Nonreplicating anaerobic M. tuberculosis Science 2009;323:1215 1218 64

Clinical use of the meropenem-clavulanate combination for XDR-TB Int J Tuberc Lung Dis 2012;16:558 560 65

Clinical use of the meropenemclavulanate combination for XDR-TB Int J Tuberc Lung Dis 2012;16:558 560 66

Efficacy and safety of meropenem clavulanate added to linezolid-containing regimens in the treatment of MDR-/XDR-TB De Lorenzo S, et al. Eur Respir J 2013;41:1386-92.

Conventional treatment regimens for rifampicin-resistant TB In patients with rifampicin-resistant or multidrugresistant TB, a regimen with at least five effective TB medicines during the intensive phase is recommended, including pyrazinamide and four core second-line TB medicines - one chosen from group A, one from group B, and at least two from group C (conditional recommendation, very low certainty in the evidence). If the minimum of effective TB medicines cannot be composed as above, an agent from group D2 and other agents from D3 may be added to bring the total to five WHO Treatment Guidelines for drug-resistant tuberculosis - 2016 update

In patients with rifampicin-resistant or multidrug-resistant TB, it is recommended that the regimen be further strengthened with high-dose isoniazid and/or ethambutol (conditional recommendation, very low certainty in the evidence). WHO Treatment Guidelines for drug-resistant tuberculosis - 2016 update

Treatment outcomes for patients diagnosed with MDR- TB by WHO region, 2007 2012 cohorts WHO. Global Tuberculosis Report 2015 70

Predicting the future of XDR tuberculosis Blower S. Lancet Infect Dis 2007;7:443 71

Short Standardized Treatment of Multidrugresistant Tuberculosis Intensive phase: GEZC KHP 4 months, extended till sputum conversion Continuation phase: GEZC 5 months Kanamycin (K) Prothionamide (P) Isoniazid (H)* Gatifloxacin (G)* Clofazimine, C Ethambutol, E Pyrazinamide, P Gatifloxacin (G)* Clofazimine, C Ethambutol, E Pyrazinamide, P *high dose Van Deun A, et al. Am J Respir Crit Care Med 2010;182:684 692 72

Regimens sequentially used in the treatment of multidrugresistant tuberculosis, Bangladesh Damien Foundation Projects K Kanamycin, C Clofazimine, O Ofloxacin, G Gatifloxacin, E Ethambutol, H Isoniazid Z Pyrazinamide, P Prothionamide Van Deun A, et al. Am J Respir Crit Care Med 2010;182:684 692

Daily Drug Dosages Used For Standardized Multidrug-resistant Antituberculosis Treatment, Bangladesh Damien Foundation Projects *KM reduced by 25% for patients aged 45, later precisely as 15 mg/kg, 3 times weekly 4th month onward Gatifloxacin was used at a lower dosage for the first 50 patients enrolled The high dose of isoniazid was used with the gatifloxacin-based regimen, whereas the normal dose was given in all ofloxacin-based regimens Van Deun A, et al. Am J Respir Crit Care Med 2010;182:684 692

Regimens sequentially used in the treatment of multidrugresistant tuberculosis, Bangladesh Damien Foundation Projects Van Deun A, et al. Am J Respir Crit Care Med 2010;182:684 692

Van Deun A, et al. Am J Respir Crit Care Med 2010;182:684 692

Outcome of treatment of multidrug-resistant tuberculosis, by grouped regimen category, Bangladesh Damien Foundation Projects. R1+2, 3KCOEHZP/12 OEHZP, few failures (5.8%), but 14.6% defaulted R3, 3(4) KCOEZP/12 OEZP, without H had a very low effectiveness (57.1% cure). R4, 3(+) KCOEHZP/12 OHEZ, problematic continuation phase, resulted in 13.3% failures R5, 3(+) KCOEHZP/12 OHEZC, no relapse with any of the five regimens during 2 years of follow-up, one reinfection Van Deun A, et al. Am J Respir Crit Care Med 2010;182:684 692

Outcome of Treatment with the Gatifloxacin-based Regimen Of the 206 patients, 35 (17.0%) with a positive smear at 4 months required extension of the intensive phase. one treatment failure and 12 defaults(5.8%) Of the 182 patients who completed treatment, one had a relapse at 6 months. Van Deun A, et al. Am J Respir Crit Care Med 2010;182:684 692

Treatment Antecedents and Initial Drug Resistance the gatifloxacin-based regimen, in contrast to the ofloxacin based regimens, did not lead to additional acquired resistance Van Deun A, et al. Am J Respir Crit Care Med 2010;182:684 692

Dysglycemia 2/221 patients on ofloxacin 8/206 patients on gatifloxacin regimens No patient required permanent stopping of treatment due to adverse drug reactions, but 3 patients had gatifloxacin replaced by ofloxacin (and treatment prolonged accordingly) Van Deun A, et al. Am J Respir Crit Care Med 2010;182:684 692

MDR-TB, Niger 12-month standardised regimen: 4 Km Gfx Pto H Cfz E Z / 8 Gfx Cfz E Z (Gfx, high dose) 65 MDR-TB patients Cure: 58 patients (89.2%, 95%CI 81.7 96.7), died 6 Defaulted 1. No relapse at the 24-month follow-up after cure (49 patients) Piubello A, et al. Int J Tuberc Lung Dis 2014;18:1188 1194 81

High effectiveness of a 12-month regimen for MDR-TB patients in Cameroon Kuaban C, et at. Int J Tuberc Lung Dis 2015; 19:517 524.

Kuaban C, et at. Int J Tuberc Lung Dis 2015; 19:517 524

High effectiveness of a 12-month regimen for MDR-TB patients in Cameroon 150 MDR-TB patients (20% HIV-positive) 4 Km Gfx Pto H Cfz E Z / 8 Gfx Cfz Pto E Z (Gfx 400 mg) Kuaban C, et at. Int J Tuberc Lung Dis 2015; 19:517 524 84

Bangladesh MDR-TB, 2005-2011 4 Km Gfx Pto H Cfz E Z / 5 Gfx Cfz E Z relapse-free treatment success 84% (N = 515) cured 423 (82%) completed 12 (2%) defaulted 40 (8%) died 29 (6%) failed 7 (1%) relapsed 4 (0.8%) Aung KJM et al. Int J Tuberc Lung Dis 2014;18:1180 1187 85

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Successful 9-month Bangladesh regimen for MDR-TB patients Of the 515 patients 435 (84.4%) had a bacteriologically favorable outcome Eleven patients failed (n=7) or relapsed (n=4) Amplification of drug resistance occurred only once, in a patient strain that was initially only susceptible to kanamycin and clofazimine

Acquired Resistance to Fluoroquinolones Among 832 Adults With Pulmonary Multidrug-Resistant Tuberculosis Starting Treatment With Second-line Drugs, 2005 2010, in 9 Countries Of those without baseline resistance to specific secondline drugs, 68 (8.9%) acquired extensively drug-resistant (XDR) tuberculosis, 79 (11.2%) acquired fluoroquinolone (FQ) resistance, and 56 (7.8%) acquired resistance to second-line injectable drugs Cegielski JP, et al. Clin Infect Dis 2014;59:1049 63

Acquired Resistance to Fluoroquinolones Among 832 Adults With Pulmonary Multidrug-Resistant Tuberculosis Starting Treatment With Second-line Drugs, 2005 2010, in 9 Countries Baseline DST Ethambutol Resistance susceptible kanamycin Resistance susceptible Ethionamide Resistance susceptible Acquired FQ resistance 17.4% 7.9% 36.8% 6.0% 11.5% 12.1% RR (95% CI) 1.86 (1.14 3.05) 1 6.14 (4.08 9.24) 1 0.95 (.55 1.63) 1 Cegielski JP, et al. Clin Infect Dis 2014;59:1049 63

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Characteristics of patients with a programmatically favorable outcome vs. those with an unfavorable treatment outcome Aung KJM et al. Int J Tuberc Lung Dis 2014;18:1180 1187

Standardised regimens lasting up to 12 months for the treatment of patients with multidrug-resistant TB Recommendation: In patients with rifampicin-resistant or multidrugresistant TB who have not been previously treated with second-line drugs and in whom resistance to fluoroquinolones and second-line injectable agents has been excluded or is considered highly unlikely, a shorter MDR-TB regimen of 9-12 months may be used instead of a conventional regimen (conditional recommendation, very low certainty in the evidence) WHO Treatment Guidelines for drug-resistant tuberculosis - 2016 update

Treatment success in patients treated with a shorter MDR-TB regimen versus conventional MDR-TB regimens Resistance pattern Shorter regimen Conventional regimen All cases (n=1116 vs 5850) 90.3% (87.8%- 92.4%) Pyrazinamide R; fluoroquinolone R (n=28 vs 137) Pyrazinamide R; fluoroquinolone S (n=100 vs 1075) Pyrazinamide S; fluoroquinolone R (n=15 vs 120) Pyrazinamide S; fluoroquinolone S (n=125 vs 1119) 67.9% (47.6%-84.1%) 88.8% (47.3%-98.6%) 80.0% (50.0%-94.1%) 96.8% (77.3%-99.6%) 78.3% (71.2%- 84%) 59.1% (50.6%-67.1%) 81.4% (71.6%-88.4%) 64.4% (49.6%-76.9%) 83.5% (75.7%-89.2%) treatment success (cured or treatment completed(14),(9)) versus failure/relapse/death in patients not previously treated with secondline TB medications

Subgroup considerations - RR-TB without MDR-TB All patients children or adult - with rifampicin-resistant TB in whom isoniazid resistance is not confirmed may be treated with the shorter MDR-TB treatment regimen WHO Treatment Guidelines for drug-resistant tuberculosis - 2016 update

Subgroup considerations - Resistance additional to MDR-TB In patients infected with strains known or strongly suspected of being resistant to one or more drugs in the shorter MDR-TB treatment regimen (e.g. pyrazinamide) it is recommended not to use the shorter regimen until more evidence becomes available about its performance in such a situation.

The recommendations from the WHO on the use of shortened MDR-TB regimens controversially indicated that shortened MDR-TB regimens should not be used in patients who have documented or likely resistance to medicines in the regimen, leading to the concept that MDR-TB patients with additional resistance to not only fluoroquinolones (FQs) or second-line injectables (SLIs), but also ethambutol (EMB), prothionamide (Pto) and pyrazinamide (PZA) would not be eligible for the regimens. This is a highly conservative approach that will greatly limit the applicability of shortened MDR-TB regimens and deprive many MDR-TB patients in high-burden countries of short and highly effective regimens. Van Deun A, Chiang C-Y. Shortened multidrug-resistant tuberculosis regimens overcome low-level fluoroquinolone resistance. Eur Respir J 2017; 49: 1700223 [https://doi.org/10.1183/ 13993003.00223-2017].

Subgroup considerations - People living with HIV People living with HIV need to be given the same consideration for treatment with the shorter MDR-TB treatment regimen as people who are HIV seronegative.

Subgroup considerations - Children Children were generally excluded from studies of the shorter MDR-TB treatment regimens. However, there is no plausible biological reason to believe that these regimens are less effective in children than in adults. As a result, it is recommended that children with confirmed RR-/MDR-TB be given the same consideration for treatment with a shorter MDR-TB treatment regimen as adults

Subgroup considerations - Pregnant women Pregnancy was an exclusion criterion for the shorter MDR-TB treatment regimen studies. Two of the core components of the shorter MDR-TB regimens the injectable agent and ethionamide (or prothionamide) are usually contraindicated in pregnancy it is thus recommended that an individualised, conventional regimen is used which can allow the inclusion of four or more effective medicines with no known teratogenic properties

Subgroup considerations - Extrapulmonary disease The findings from studies of shorter MDR-TB regimen were limited to patients with pulmonary disease, and they cannot be extrapolated directly to extrapulmonary TB. No recommendation is thus possible at this stage to use the shorter regimen in patients with extrapulmonary MDR-TB.

Implementation considerations Patients are tested for susceptibility or resistance to fluoroquinolones and to the second-line injectable agent used in the regimen before being started on a shorter MDR-TB regimen: patients with strains resistant to any of the two groups of medicines are to be transferred to treatment with a conventional MDR-TB regimen. the Genotype MTBDRsl line probe assay may be used as an initial direct test, over phenotypic culture-based DST, to detect resistance to fluoroquinolones and to the second-line injectable drugs

Implementation considerations In settings in which laboratory capacity for DST to fluoroquinolones and injectable agents is not yet available, treatment decisions would need to be decided on the basis of the likelihood of resistance to these medicines, informed by the patient s clinical history and recent representative surveillance data.