Figures
- Figure 1–
Treatment success among different multidrug-resistant tuberculosis (MDR-TB) patient groups. Data are presented as point estimates and 95% CI. MDR−TB+INJr: MDRTB plus resistance to amikacin/kanamycin and/or capreomycin, but susceptible to fluoroquinolones; MDR-TB+FQr: MDR-TB plus resistance to any fluoroquinolone, but susceptible to amikacin/kanamycin and/or capreomycin (at least one second-line injectable drug tested); XDR-TB: extensively drug-resistant tuberculosis (MDR-TB plus resistance to any fluoroquinolone and any second-line injectable drug (amikacin/kanamycin and/or capreomycin)).
Tables
- Table 1– Characteristics of multidrug-resistant tuberculosis (MDR-TB) patients with different resistance patterns of Mycobacterium tuberculosis
MDR-TB only MDR-TB+INJr MDR-TB+FQr XDR-TB Total MDR-TB cases Studies n 26 22 18 17 26 Cases n 4763 1130 426 405 6724 Demographic characteristics Age years 39.2±13.5 39.9±13.3 41.6±14.3 40.6±13.8 39.5±13.5 Male 68 74 68 67 69 HIV-infected 14 5.1 1.7 3.7 11 Clinical characteristics Pulmonary TB only 97 97 96 97 97 Sputum-smear positive 73 73 79 79 74 Cavities on chest radiography 65 66 60 77 66 Extensive disease# 72 71 78 78 73 Previous TB treatment¶ None 20 24 19 16 30 First-line drugs only 73 60 64 57 60 Second-line drugs for MDR-TB 7 16 17 27 10 Had a serious adverse event during therapy 29 47 33 43 32 Data are presented as mean±sd or %, unless otherwise stated. Values shown were computed using simple pooling across all studies. Percentages were calculated on the number of patients in each group with information available. MDR-TB: multidrug-resistant TB (resistance to at least isoniazid and rifampicin); MDR-TB only: MDR-TB, but susceptible to fluoroquinolones, amikacin/kanamycin and capreomycin (at least one second-line injectable drug tested); MDR-TB+INJr: MDR-TB plus resistance to amikacin/kanamycin and/or capreomycin, but susceptible to fluoroquinolones; MDR-TB+FQr: MDR-TB plus resistance to any fluoroquinolone, but susceptible to amikacin/kanamycin and/or capreomycin (at least one second-line injectable drug tested); XDR-TB: extensively drug-resistant tuberculosis (MDR-TB plus resistance to any fluoroquinolone and any second-line injectable drug (amikacin/kanamycin and/or capreomycin)). #: Extensive disease was defined as sputum-smear positive, or cavities on chest radiography if information about sputum-smear was missing. ¶: Previous tuberculosis (TB) treatment was defined as treatment with any TB drug for ≥=1 month. Previous treatment could be with first-line drugs or with ≥2 second-line drugs for MDR. In some patients, information was only available that they had been treated previously for TB, but not whether this was with first- or second-line drugs.
- Table 2– Resistance to anti-tuberculosis drugs by multidrug-resistant tuberculosis (MDR-TB) patient group
MDR-TB only MDR-TB +INJr MDR-TB +FQr XDR-TB Total MDR-TB cases Cases n 4763 1130 426 405 6724 Resistance First-line drugs Pyrazinamide 1052 (41) 556 (70) 234 (58) 211 (69) 2053 (50) Ethambutol 1524 (51) 845 (76) 296 (74) 295 (81) 2960 (61) Fluoroquinolones# 0 0 426 (100) 405 (100) 831 (12) Injectable drugs Streptomycin 1534 (51) 960 (86) 226 (53) 291 (78) 3011 (61) Amikacin/kanamycin¶ 0 1042 (92) 0 383 (95) 1425 (21) Capreomycin 0 399 (42) 0 104 (38) 503 (16) Amikacin/kanamycin and capreomycin 0 311 (33) 0 82 (30) 393 (13) Amikacin/kanamycin and capreomycin and streptomycin 0 295 (31) 0 68 (25) 363 (12) Group 4 drugs Ethionamide/protionamide 528 (19) 401 (41) 194 (48) 212 (59) 1335 (29) Cycloserine/terizidone 125 (4) 56 (5) 76 (18) 89 (24) 346 (7) p-aminosalicylic acid 391 (14) 281 (31) 125 (31) 127 (43) 924 (21) TB drugs tested+ 7.9±3.0 10.0±1.3 10.2±0.9 9.6±1.7 8.5±2.1 Total number of TB drugs to which strain was resistant§ 2 2259 (47) 0 0 0 2259 (34) 3 947 (20) 15 (1) 19 (4) 0 981 (15) 4 784 (16) 100 (9) 66 (15) 4 (1) 954 (14) 5 513 (11) 331 (29) 101 (24) 32 (8) 977 (15) 6 209 (4) 296 (26) 118 (28) 108 (27) 731 (11) 7 42 (1) 221 (20) 89 (21) 105 (26) 457 (7) 8 9 (0.2) 128 (11) 25 (6) 75 (19) 237 (4) 9 0 37 (3) 8 (2) 46 (11) 91 (1) ≥10 0 2 (0.2) 0 35 (9) 37 (0.3) Data are presented as n, n (%) or mean±sd. Drug-susceptibility test results for Group 5 drugs were available from very few centres and were not analysed. n (%) data are presented for the number of cases whose isolate was tested to that specific drug. All cases were tested for susceptibility to at least one fluoroquinolone (FQ) and one second-line injectable drug, but not all the other drugs. #: Most centres tested only for resistance to ofloxacin. Very few centres also tested for resistance to later-generation FQs (results of these tests are not shown). By definition, two patient groups were susceptible to FQ. ¶: Resistance to amikacin or kanamycin combined. Most centres tested for susceptibility to only one of these two drugs and considered them cross-resistant. +: Includes tests to isoniazid and rifampin, as well as to FQs and second-line injectable drugs (performed in all cases). §: In addition to isoniazid and rifampin, to which all patients were resistant, being MDR-TB. MDR-TB: multidrug-resistant tuberculosis (resistance to at least isoniazid and rifampicin); MDR-TB only: MDR-TB, but susceptible to FQs, amikacin/kanamycin and capreomycin (at least one second-line injectable drug tested); MDR-TB+INJr: MDR-TB plus resistance to amikacin/kanamycin and/or capreomycin, but susceptible to FQs; MDR-TB+FQr: MDR-TB plus resistance to any FQ, but susceptible to amikacin/kanamycin and/or capreomycin (at least one second-line injectable drug tested); XDR-TB: extensively drug-resistant tuberculosis (MDR-TB plus resistance to any FQ and any second-line injectable drug (amikacin/kanamycin and/or capreomycin)).
- Table 3– Treatment outcomes by multidrug-resistant tuberculosis (MDR-TB) patient group
Pooled treatment outcomes# MDR-TB only MDR-TB +INJr MDR-TB +FQr XDR-TB Total Subjects 4763 1130 426 405 6724 Treatment success 64 (57–72) 56 (45–66) 48 (36–60) 40 (27–53) 62 (54–69) Treatment failure or relapse 4 (2–6) 12 (9–15) 18 (14–21) 22 (15–28) 7 (4–9) Died 8 (5–11) 8 (3–14) 11 (3–19) 15 (8–23) 9 (5–12) Defaulted 18 (12–24) 16 (7–24) 12 (1–23) 16 (8–24) 17 (11–22) Data are presented as n or % (95% CI). MDR-TB: multidrug-resistant TB (resistance to at least isoniazid and rifampicin); MDR-TB only: as MDR-TB, but susceptible to fluoroquinolones, amikacin/kanamycin and capreomycin (at least one second-line injectable drug tested); MDR-TB+INJr: MDR-TB plus resistance to amikacin/kanamycin and/or capreomycin, but susceptible to fluoroquinolones; MDR-TB+FQr: MDR-TB plus resistance to any fluoroquinolone, but susceptible to amikacin/kanamycin and/or capreomycin (at least one second-line injectable drug tested); XDR-TB: extensively drug-resistant tuberculosis (MDR-TB plus resistance to any fluoroquinolone and any second-line injectable drug (amikacin/kanamycin and/or capreomycin)). #: from study level meta-analysis; column percentages do not total 100%. See the Methods section and [17] for treatment outcome definitions.
- Table 4– Association of treatment success with patient characteristics and multidrug-resistant tuberculosis (MDR-TB) patient group
Cases Adjusted odds of treatment success versus treatment failure/relapse/death# Male (versus female)¶ 4653 1.0 (0.9–1.1) Older age (per 10-year increment) ¶ 6724 0.8 (0.8–0.9) HIV infected (versus not HIV infected) ¶ 615 0.3 (0.2–0.4) Extensive disease (versus not extensive) ¶ 4792 0.5 (0.4–0.6) Previous TB treatment¶ None 1275 1.0 (Reference) First-line drugs only 4410 0.6 (0.5–0.8) First-line and second-line drugs 618 0.2 (0.15–0.3) MDR-TB patient group+ MDR-TB only 4763 1.0 (Reference) MDR+INJr 1130 0.6 (0.5–0.7) MDR+FQr 426 0.3 (0.2–0.4) XDR-TB 405 0.2 (0.2–0.3) Pulmonary resection surgery performed (versus no pulmonary resection surgery)+ 373 1.5 (0.9–2.6) Experienced a serious adverse event (versus no serious adverse event)+ 1511 1.0 (0.8–1.2) Data are presented as n or adjusted OR (95% CI). TB: tuberculosis; MDR-TB: multidrug-resistant TB (resistance to at least isoniazid and rifampicin); MDR-TB only: MDR-TB, but susceptible to fluoroquinolones, amikacin/kanamycin and capreomycin (at least one second-line injectable drug tested); MDR-TB+INJr: MDR-TB plus resistance to amikacin/kanamycin and/or capreomycin, but susceptible to fluoroquinolones; MDR-TB+FQr: MDR-TB plus resistance to any fluoroquinolone, but susceptible to amikacin/kanamycin and/or capreomycin (at least one second-line injectable drug tested); XDR-TB: extensively drug-resistant tuberculosis (MDR-TB plus resistance to any fluoroquinolone and any second-line injectable drug (amikacin/kanamycin and/or capreomycin)). #: odds ratios of treatment success (cure and completion) versus treatment failure/relapse/death adjusted for age, sex, HIV infection, previous TB treatment, previous MDR treatment (treatment for >1 month with two or more second-line drugs) and extent of disease. See Methods and [17] for treatment outcome definitions. ¶: estimate adjusted for all other covariates (characteristics) shown. +: each of these parameters estimated separately, and adjusted for age, sex, HIV, extent of disease and previous treatment with first- or second-line TB drugs. Statistical significance is represented by bold type.
- Table 5– Association of treatment success with individual drugs used in treatment by multidrug-resistant tuberculosis (MDR-TB) patient group
MDR-TB only MDR-TB+INJr MDR-TB+FQr XDR-TB Cases# n Adjusted OR (95% CI)¶ Cases# n Adjusted OR (95% CI)¶ Cases# n Adjusted OR (95% CI)¶ Cases# n Adjusted OR (95% CI)¶ First-line drugs Pyrazinamide 2480 1.3 (0.8–2.0) 474 1.2 (0.8–1.8) 171 0.8 (0.4–1.5) 174 1.1 (0.6–2.0) Ethambutol 1794 0.7 (0.5–0.9) 271 0.8 (0.6–1.2) 94 0.7 (0.4–1.3) 93 1.8 (0.9–3.5) Injectable drugs+ Amikacin or kanamycin 2250 153 135 85 versus no injectable drug 1.9 (1.1–3.1) 2.0 (0.7–5.4) 0.8 (0.1–5.6) 2.0 (0.5–8.7) versus capreomycin 1.1 (0.6–1.9) 1.8 (0.9–3.6) 1.1 (0.2–5.9) 1.2 (0.3–5.3) versus streptomycin 1.4 (0.9–2.3) 2.4 (1.1–5.0) 1.1 (0.3–4.3) 1.7 (0.3–7.9) Capreomycin only 204 435 34 109 versus no injectable drug 2.2 (1.1–4.2) 0.9 (0.2–4.1) 2.5 (0.9–7.0) versus streptomycin 1.4 (0.6–3.3) 0.8 (0.2–3.9) 1.4 (0.1–14) Fluoroquinolones§ Ofloxacin 2956 787 197 227 versus no fluoroquinolone 2.9 (1.7–4.9) 2.8 (0.9–8.6) 1.1 (0.5–2.4) 0.7 (0.3–1.6) versus ciprofloxacin 1.2 (0.5–3.2) 1.8 (0.1–23) 1.0 (0.1–19) 0.2 (0.1–3.6) Group 4 drugs Ethionamide or protionamide 2973 2.2 (1.5–3.2) 689 1.6 (1.0–2.4) 258 0.8 (0.4–1.7) 253 1.0 (0.5–2.1) Cycloserine or terizidone 2007 1.8 (1.4–2.2) 822 1.7 (0.8–3.9) 292 0.9 (0.3–3.0) 284 1.3 (0.5–3.6) p-aminosalicylic acid 1396 1.0 (0.8–1.3) 614 1.1 (0.7–1.6) 219 1.1 (0.6–2.3) 228 1.3 (0.6–3.1) Group 5 drugsƒ Any one group 5 drug versus none 561 0.8 (0.6–1.2) 323 0.9 (0.5–1.6) 84 0.6 (0.3–1.4) 95 1.1 (0.4–2.9) Two or more group 5 drugs versus one 135 0.5 (0.2–0.9) 111 0.6 (0.3–1.5) 55 0.8 (0.3–1.8) 58 1.2 (0.5–3.3) MDR-TB: multidrug-resistant TB (resistance to at least isoniazid and rifampicin); MDR-TB only: MDR-TB, but susceptible to fluoroquinolones, amikacin/kanamycin and capreomycin (at least one second-line injectable drug tested); MDR-TB+INJr: MDR-TB plus resistance to amikacin/kanamycin and/or capreomycin, but susceptible to fluoroquinolones; MDR-TB+FQr: MDR-TB plus resistance to any fluoroquinolone, but susceptible to amikacin/kanamycin and/or capreomycin (at least one second-line injectable drug tested); XDR-TB: extensively drug-resistant tuberculosis (MDR-TB plus resistance to any fluoroquinolone and any second-line injectable drug (amikacin/kanamycin and/or capreomycin)). #: number of cases that received the drug in question and were included in the specific analysis. ¶: odds ratios of treatment success (cure and completion) versus treatment failure/relapse/death adjusted for age, sex, HIV infection, previous TB treatment, previous MDR treatment (treatment for >1 month with two or more second-line drugs) and extent of disease. If there were <50 observations no estimate was derived. See Methods and [17] for treatment outcome definitions. +: patients receiving two or more injectable drugs were excluded from this analysis. §: patients receiving two or more fluoroquinolones were excluded from this analysis. Insufficient numbers of patients received later-generation fluoroquinolones (including gatifloxacin, levofloxacin, moxifloxacin and sparfloxacin) within the MDR-TB patient groups with additional resistance, so were not analysed. ƒ: insufficient numbers of patients received specific group 5 drugs within the MDR-TB patient groups with additional resistance, so outcomes by individual group 5 drugs were not analysed. Group 5 drugs included amoxicillin/clavulanate, macrolides (azithromycin, clarithromycin and roxithromycin), clofazimine, thiacetazone, imipenem, linezolid, high-dose isoniazid and thioridazine. Statistical significance is represented by bold type.
- Table 6– Association of treatment success with the number of effective drugs used in the intensive and continuation phases of treatment by the multidrug-resistant tuberculosis (MDR-TB) patient group
Number of drugs MDR-TB only MDR-TB+INJr MDR-TB+FQr XDR-TB Cases n Adjusted OR# (95% CI) Cases n Adjusted OR# (95% CI) Cases n Adjusted OR# (95% CI) Cases n Adjusted OR# (95% CI) Intensive phase¶ ≤2 45 1.0 (reference) 29 1.0 (reference) 10 1.0 (reference) 24 1.0 (reference) 3 62 1.1 (0.5–2.3) 27 1.7 (0.5–5.2) 32 1.0 (reference) 47 1.0 (reference) 4 165 1.9 (1.0–3.7) 83 1.3 (0.5–3.1) 49 1.6 (0.7–3.8) 46 1.9 (0.8–4.3) 5 296 1.7 (0.8–3.8) 137 1.2 (0.4–3.4) 35 1.4 (0.3–6.4) 36 1.8 (0.5–6.6) ≥6 380 1.0 (0.5–1.8) 120 1.3 (0.5–3.3) 27 1.1 (0.4–2.9) 20 4.9 (1.4–16.6) Continuation phase+ ≤2 77 1.0 (reference) 46 1.0 (reference) 35 1.0 (reference) 27 1.0 (reference) 3 133 5.9 (3.1–11.0) 33 12.2 (3.4–44) 27 2.5 (0.8–7.4) 32 3.3 (1.3–8.5) 4 239 6.0 (2.8–13.1) 101 3.7 (1.7–8.2) 27 3.1 (0.5–21.1) 28 6.1 (1.4–26.3) ≥5 233 4.7 (2.7–8.1) 100 3.1 (1.7–6.0) 20 2.3 (0.7–7.2) 17 2.3 (0.7–7.6) MDR-TB: multidrug-resistant TB (resistance to at least isoniazid and rifampicin); MDR-TB only: MDR-TB, but susceptible to fluoroquinolones, amikacin/kanamycin and capreomycin (at least one second-line injectable drug tested); MDR-TB+INJr: MDR-TB plus resistance to amikacin/kanamycin and/or capreomycin, but susceptible to fluoroquinolones; MDR-TB+FQr: MDR-TB plus resistance to any fluoroquinolone, but susceptible to amikacin/kanamycin and/or capreomycin (at least one second-line injectable drug tested); XDR-TB: extensively drug-resistant tuberculosis (MDR-TB plus resistance to any fluoroquinolone and any second-line injectable drug (amikacin/kanamycin and/or capreomycin)). #: odds ratios of treatment success (cure and completion) versus treatment failure/relapse/death adjusted for age, sex, HIV infection, previous TB treatment, previous MDR treatment (treatment for >1 month with two or more second-line drugs) and extent of disease. See Methods and [17] for treatment outcome definitions. ¶: the initial part of a course of treatment during which an injectable drug is given. +: the period immediately following the initial phase when no injectable drug is given. Only 18 studies provided information regarding drug susceptibility testing and the number of drugs in the intensive phase, while only 15 of these described the number of drugs in the continuation phase. Statistical significance is represented by bold type.
- Table 7– Association between the duration of treatment and treatment success by multidrug-resistant tuberculosis (MDR-TB) patient group
MDR-TB only MDR-TB+INJr MDR-TB+FQr XDR-TB Cases n Adjusted OR# (95%CI) Cases n Adjusted OR# (95%CI) Cases n Adjusted OR# (95%CI) Cases n Adjusted OR# (95%CI) Duration of intensive phase¶ months 1–4.0 1924 1.0 (reference) 99 1.0 (reference) 33 1.0 (reference) 55 1.0 (reference) 4.1–6.5 274 2.8 (0.8–9.7) 82 3.2 (0.8–13.6) 41 0.9 (0.2–4.5) 41 6.1 (0.6–62) 6.6–9.0 244 3.1 (1.1–8.3) 79 9.8 (1.9–49) 36 0.6 (0.1–4.1) 37 71.0 (5.2–200) 9.1–20.0 347 2.1 (0.9–5.1) 155 4.1 (1.5–11.2) 55 0.4 (0.1–2.0) 77 5.1 (1.2–21) Total duration of treatment months 6.0–15.0 443 1.0 (reference) 279 1.0 (reference) 54 1.0 (reference) 87 1.0 (reference) 15.1–20.0 2171 3.6 (1.7–7.9) 260 3.1 (1.0–9.1) 47 2.4 (0.4–14.3) 79 2.0 (0.3–11.7) 20.1–25.0 484 5.9 (3.0–11.5) 202 7.7 (3.8–15.7) 60 2.1 (0.7–6.5) 61 5.5 (1.7–17.6) 25.1–30.0 147 2.8 (1.2–6.9) 65 6.0 (2.3–15.6) 24 4.1 (0.9–19.4) 21 5.8 (1.3–25.1) 30.1–36.0 61 1.8 (0.6–5.6) 17 2.9 (0.7–12.2) 13 1.1 (0.2–5.2) 10 1.3 (0.2–7.8) MDR-TB: multidrug-resistant TB (resistance to at least isoniazid and rifampicin); MDR-TB only: MDR-TB, but susceptible to fluoroquinolones, amikacin/kanamycin and capreomycin (at least one second-line injectable drug tested); MDR-TB+INJr: MDR-TB plus resistance to amikacin/kanamycin and/or capreomycin, but susceptible to fluoroquinolones; MDR-TB+FQr: MDR-TB plus resistance to any fluoroquinolone, but susceptible to amikacin/kanamycin and/or capreomycin (at least one second-line injectable drug tested); XDR-TB: extensively drug-resistant tuberculosis (MDR-TB plus resistance to any fluoroquinolone and any second-line injectable drug (amikacin/kanamycin and/or capreomycin)). #: Odds ratios of treatment success versus treatment failure or relapse adjusted for age, sex, HIV infection, previous TB treatment, previous MDR treatment (treatment for >1 month with two or more second-line drugs) and extent of disease. See Methods and [17] for treatment outcome definitions. ¶: The initial part of a course of treatment during which an injectable drug is given.
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- Supplementary tables - Tables S1-S3
