Fluoroquinolones for treating tuberculosis

 

Characteristics of included studies [ordered by study ID]

Burman 2006

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Methods	Multicentre randomized controlled trial Generation of allocation sequence: randomized in a factorial design; continent and pulmonary cavitation are stratification factors Allocation concealment: unclear Blinding: unclear Inclusion of all randomized participants in the final analysis: 59/336 (17.6%) excluded from final analysis Mean duration of follow up: 8 weeks
Participants	Number: 336 randomized; 277 evaluated Inclusion criteria: aged 18 years or older with suspected pulmonary tuberculosis and acid-fast bacilli in an expectorated sputum sample Exclusion criteria: history of > 7 days of a fluoroquinolone antibiotic or tuberculosis treatment within the previous 6 months; pregnancy or breastfeeding; initial sputum cultures negative for Mycobacterium tuberculosis or resistance to rifampicin, fluoroquinolones, or pyrazinamide (patients whose isolates were resistant to isoniazid were included)
Interventions	Fluoroquinolone (moxifloxacin) substituted into regimen (replacing ethambutol) for 2 months (8 weeks), initial 2 weeks of daily therapy 1. Moxifloxacin (400 mg daily) orally plus basic regimen (5 days a week or thrice a week for both dosing regimens) for 2 months 2. Ethambutol (0.8 g - 40 to 55 kg; 1.2 g - 56 to 75 kg; 1.6 g - 76 to 90 kg) daily orally 5 days a week OR (1.2 g - 40 to 55 kg; 2 g - 56 to 75 kg; 2.4g - 76 to 90 kg) thrice weekly for 2 months plus basic regimen Basic regimen: Isoniazid (300 mg), rifampicin (450 mg if ≤ 45 kg; 600 mg if > 45 kg), and pyrazinamide (1 g - 40 to 55 kg; 1.5 g - 56 to 75 kg; 2 g - 76 to 90 kg) given orally 5 days a week for 2 months; or Isoniazid (15 mg/kg, max dose 900 mg), rifampicin (450 mg if ≤ 45 kg; 600 mg if > 45 kg), and pyrazinamide (1.5 g - 40 to 55 kg; 2.5 g - 56 to 75 kg; 3 g - 76 to 90 kg) given thrice weekly orally for 2 months
Outcomes	1. Cure (sputum culture negative at 8 weeks) 2. Adverse events 3. Serious adverse events 4. Total number of adverse events (calculated by review authors by summing up reported adverse events)
Notes	Location: Canada, South Africa, Uganda, USA Human immunodeficiency virus (HIV) status: HIV-positive participants (30/169 randomized - study group, 30/167 randomized - control group) Drug-resistance status: isoniazid resistance (15/169 randomized - study group, 10/167 randomized - control group); 11 participants with resistance to rifampicin, fluoroquinolone or pyrazinamide - excluded from analysis

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El-Sadr 1998

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Methods	Multicentre randomized controlled trial Generation of allocation sequence: centrally randomized with stratified permuted block randomization; the research unit is a stratification factor Allocation concealment: unclear Blinding: assessors only Inclusion of all randomized participants in the final analysis: adequate for 8 weeks; 39% lost to follow up in continuation phase Mean duration of follow up: 12 months
Participants	Number: 174 randomized; 101 evaluated Inclusion criteria: suspected human immunodeficiency virus (HIV) and pulmonary tuberculosis; age > 18 years in resistant areas or > 13 years in other areas; aspartate aminotransferase (AST) ≤ 10 times upper limit; serum bilirubin < 2.5 times upper limit; serum creatinine ≤ 3 times upper limit or creatinine clearance rate ≥ 50 mL/min Exclusion criteria: history of multiple-drug-resistant tuberculosis (MDR-TB) or close contact with an MDR-TB patient; > 3 weeks continuous antituberculous treatment immediately prior to enrolment; > 12 weeks antituberculous therapy in the past 2 years; pregnancy; exclusively extrapulmonary tuberculosis
Interventions	Fluoroquinolone (levofloxacin) added to regimen 1. Levofloxacin plus standard regimen 500 mg levofloxacin daily for 2 weeks (induction phase); then 750 mg levofloxacin thrice weekly for 6 weeks; then standard regimen only (continuation phase) 2. Standard regimen Induction phase (2 weeks daily): isoniazid (300 mg), vitamin B6 (50 mg), rifampicin (450 to 600 mg; < 50 to > 50 kg), pyrazinamide (1.5 to 2.0 g; < 50 to > 50 kg), ethambutol (20 mg/kg; rounded to the nearest 400 mg) 6 weeks (thrice weekly): isoniazid (600 to 900 mg; < 50 to > 50 kg), vitamin B6 (50 mg), rifampicin (600 mg), pyrazinamide (2.0 to 2.5 g; < 50 to > 50 kg), ethambutol (30 mg/kg; rounded to the nearest 400 mg) Continuation phase lasting 6 or 9 months (18 or 31 weeks of total therapy) (twice weekly): isoniazid (600 to 900 mg; < 50 to > 50 kg), vitamin B6 (50 mg), rifampicin (600 mg)
Outcomes	1. Cure (sputum culture negative at 8 weeks and at the end of treatment period; at least 2 consecutive negative cultures with no subsequent positive cultures) 2. Treatment failure (sputum smear positive at 8 weeks) 3. Death (from any cause) 4. Death (tuberculosis-related) 5. Clinical or radiological improvement 6. Serious adverse events
Notes	Location: USA HIV status: suspected HIV-positive participants (separate data not provided) Drug-resistance status: resistant areas

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Huang 2000

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Methods	Randomized controlled trial Generation of allocation sequence: unclear Allocation concealment: unclear Blinding: unclear Inclusion of all randomized participants in the final analysis: no losses Mean duration of follow up: 12 months
Participants	Number: 104 randomized and evaluated Inclusion criteria: multiple-drug-resistant tuberculosis (MDR-TB) patients with positive sputum smear after 1 year conventional antituberculous treatment; sputum culture showing growth of mycobacterium with multiple resistance to at least 2 of streptomycin, isoniazid, rifampicin, pyrazinamide, or ethambutol; no history of allergy to fluoroquinolone; age 16 to 75 years Exclusion criteria: heart, liver or kidney dysfunction, and diabetes
Interventions	Comparison of different fluoroquinolones (sparfloxacin versus ofloxacin) added to regimen 1. Sparfloxacin (0.2 twice daily) plus standard regimen 2. Ofloxacin (0.3 twice daily) plus standard regimen Standard regimen: isoniazid (0.3 g), rifampicin (0.45 g), ethambutol (0.75 g), pyrazinamide (1.5 g), streptomycin (0.75 g intramuscularly)
Outcomes	1. Sputum smear or culture conversion 2. Clinical or radiological improvement 3. Total number of adverse events
Notes	Location: China Human immunodeficiency virus (HIV) status: presumed HIV negative Drug-resistance status: MDR-TB

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Ji 2001

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Methods	Randomized controlled trial Generation of allocation sequence: unclear Allocation concealment: unclear Blinding: unclear Inclusion of all randomized participants in the final analysis: no losses to follow up Mean duration of follow up: 12 months
Participants	Number: 69 randomized (2 new cases; 67 retreatment cases); 69 evaluated Inclusion criteria: multiple-drug-resistant tuberculosis (MDR-TB); sputum-positive (not reported if culture or smear) inpatients; age 18 to 70 years; new and retreatment cases Exclusion criteria: not reported
Interventions	Comparison of different fluoroquinolones (sparfloxacin versus ofloxacin) added to regimen 1. Sparfloxacin (200 mg/day orally for 2 months) plus standard regimen 2. Ofloxacin (200 mg/day orally for 2 months) plus standard regimen Standard regimen: isoniazid (0.3 g), pyrazinamide (1.5 g)
Outcomes	1. Treatment failure 2. Clinical or radiological improvement and sputum conversion 3. Total number of adverse events
Notes	Location: China Human immunodeficiency virus (HIV) status: not reported Drug-resistance status: MDR-TB

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Kennedy 1993

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Methods	Randomized controlled trial Generation of allocation sequence: unclear Allocation concealment: unclear Blinding: none Inclusion of all randomized participants in the final analysis: 95.6% included in analysis; 7 (4.4%) excluded Mean duration of follow up: 6 months
Participants	Number: 160 randomized; 153 evaluated Inclusion criteria: "presented with pulmonary TB"; new cases; age > 18 years Exclusion criteria: severe renal, hepatic, or cardiovascular disease
Interventions	Fluoroquinolone (ciprofloxacin) substituted into regimen (replacing pyrazinamide and ethambutol) 1. Ciprofloxacin (750 mg; for the first 4 months) plus basic regimen 2. Pyrazinamide (25 mg/kg; daily for the first 4 months) and ethambutol (15 mg/kg; daily for the first 2 months) plus basic regimen Basic regimen (daily orally for 6 months): isoniazid (300 mg) and rifampicin (600 mg)
Outcomes	1. Treatment failure 2. Serious adverse events 3. Adverse events 4. Total number of adverse events
Notes	Location: Tanzania Human immunodeficiency virus (HIV) status: 37% to 40% HIV-positive Drug-resistance status: presumed sensitive

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Kennedy 1996

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Methods	Randomized controlled trial Generation of allocation sequence: centrally randomized by computer generated allocation sequence in block size of 10 patients Allocation concealment: sealed, opaque envelopes Blinding: only assessors Inclusion of all randomized participants in the final analysis: 6 (9%) lost to follow up Mean duration of follow up: 12 months (6 months after cessation of the 6 months' therapy)
Participants	Number: 200 randomized Inclusion criteria: acid-fast bacilli present in the sputum on direct fluorescent microscopy Exclusion criteria: history of treatment of tuberculosis or other exposures to any of the study drugs; sputum cultures positive for mycobacteria other than Mycobacterium tuberculosis; isolates of M. tuberculosis resistant to any of the study drugs; severe renal, hepatic, or cardiovascular disease; pregnancy or lactation; history of adverse reaction to any of the study drugs; epilepsy, concomitant treatment with theophylline; severe tuberculosis unlikely to survive
Interventions	Fluoroquinolone (ciprofloxacin) substituted into regimen (replacing pyrazinamide and ethambutol) 1. Ciprofloxacin (750 mg; for the first 4 months) plus basic regimen 2. Pyrazinamide (25 mg/kg; daily for the first 4 months) and ethambutol (15 mg/kg; daily for the first 2 months) plus basic regimen Basic regimen (daily for 6 months): isoniazid (300 mg) and rifampicin (600 mg)
Outcomes	1. Treatment failure (clinical at 12 months) 2. Relapse (sputum culture-proven relapse during a 6-month follow-up period after the completion of the 6 months' treatment regimen) 3. Sputum smear conversion (time (months) to first negative results) 4. Sputum culture conversion (time (months) to first negative results) 5. Sputum culture negative at 4 weeks 6. Sputum culture negative at 8 weeks 7. Number of weeks sputum culture negative by the end of trial (8 weeks)
Notes	Location: Tanzania Human immunodeficiency virus (HIV) status: data stratified by HIV status Drug-resistance status: fully drug-sensitive tuberculosis A preliminary report on 20 participants with 8 weeks of follow up (no losses) that provided information on outcomes (5), (6), and (7) was published in 1993

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Kohno 1992

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Methods	Randomized controlled trial Generation of allocation sequence: unclear Allocation concealment: unclear Blinding: unclear Inclusion of all randomized participants in the final analysis: 32 (20% 25%) lost to follow up Mean duration of follow up: 12 months
Participants	Number: 156 randomized; 124 evaluated Inclusion criteria: inpatients previously untreated; sputum smear-positive or culture-positive pulmonary tuberculosis, age > 15 years (range 15 to 81 years) Exclusion criteria: not reported
Interventions	Fluoroquinolone (ofloxacin) substituted into regimen (replacing ethambutol) 1. Ofloxacin (600 mg for the initial 2 months; 300 mg for the following 7 months) plus basic regimen 2. Ethambutol (1 g) plus basic regimen Basic regimen (orally, daily for 9 months): isoniazid (300 mg), rifampicin (600 mg)
Outcomes	1. Relapse (12 months after cessation of therapy) 2. Radiological improvement
Notes	Location: Nagasaki, Japan Human immunodeficiency virus (HIV) and drug-resistance status: not reported

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Lu 2000

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Methods	Randomized controlled trial Generation of allocation sequence: random-number table Allocation concealment: unclear Blinding: participants blinded; unclear if providers and assessors blinded Inclusion of all randomized participants in the final analysis: 6/144 (4.167%) lost to follow up Mean duration of follow up: 6 months
Participants	Number: 144 randomized; 138 evaluated Inclusion criteria: sputum smear positive and x-ray confirmed pulmonary tuberculosis, including newly diagnosed (antituberculous treatment ≤ 1 month) or retreatment pulmonary tuberculosis (treatment failure, or after completion of routine chemotherapy with rifampicin or ethambutol for < 6 months, or pyrazinamide < 3 months; or patients relapsed, but never use of fluoroquinolone-resistant and fluoroquinolone-sensitive cases); age 15 to 70 years; body weight > 40 kg Exclusion criteria: pregnancy; severe heart, liver, or kidney diseases; other severe complications
Interventions	Comparison of different fluoroquinolones (levofloxacin versus ofloxacin) added to regimen 1. Intervention group: isoniazid (0.3 g), ethambutol (0.75 to 1 g), pyrazinamide (1.5 g), thioacetazone (0.6 g), levofloxacin (0.3 g) 2. Control group: isoniazid (0.3 g), ethambutol (0.75 to 1 g), pyrazinamide (1.5 g), thioacetazone (0.6 g), ofloxacin (0.6 g)
Outcomes	1. Cure (sputum smear conversion for 2 consecutive months) 2. Radiological improvement 3. Total number of adverse events
Notes	Location: China Human immunodeficiency virus (HIV) status: presumed HIV negative Drug-resistance status: multiple-drug-resistant tuberculosis (MDR-TB) (presumed 38/73)

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Mohanty 1993

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Methods	Randomized controlled trial Generation of allocation sequence: unclear Allocation concealment: unclear Blinding: providers, participants, and radiograph assessors blinded Inclusion of all randomized participants in the final analysis: 25/60 (42%) lost to follow up Mean duration of follow up: 6 months of therapy, and 12 months after cessation of therapy
Participants	Number: 60 randomized; 53 evaluated at 2 months, and 35 at 6 months Inclusion criteria: age > 15 years (age range 15 to > 45 years (9 participants)), sputum smear positive; not previously taken > 3 weeks antituberculous therapy; willing to stay in hospital for initial 2 months' intensive phase of treatment Exclusion criteria: diabetes; human immunodeficiency virus (HIV) infection; hypertension; other concomitant diseases; pregnant women
Interventions	Fluoroquinolone (ciprofloxacin) substituted into regimen (replacing rifampicin) 1. Ciprofloxacin (750 mg orally daily for 6 months) plus basic regimen 2. Rifampicin (450 mg orally daily for 6 months) plus basic regimen Basic regimen: streptomycin (0.75 g intramuscularly) and pyrazinamide (1.5 g orally) daily for 2 months; isoniazid (400 mg orally daily) for 6 months
Outcomes	1. Sputum smear conversion at 2 and 6 months 2. Treatment failure 3. Relapse 4. Radiological improvement at 2 and 6 months 5. Serious adverse events requiring change of treatment regimen
Notes	Location: India HIV status: all participants HIV-negative Drug-resistance status: no data

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Saigal 2001

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Methods	Randomized controlled trial Generation of allocation sequence: random-number table Allocation concealment: unclear Blinding: none Inclusion of all randomized participants in the final analysis: no losses Mean duration of follow up: 12 months
Participants	Number: 31 randomized and evaluated Inclusion criteria: histological evidence of caseating granulomas; sputum positive for acid-fast bacilli; sputum-culture positive for Mycobacterium tuberculosis; positive polymerase chain reaction (PCR) for M. tuberculosis in tissues; chronic liver disease informed written consent Exclusion criteria: serum bilirubin > 5 mg/dL; baseline alanine aminotransferase/aspartate aminotransferase (ALT/AST) ALT/AST > 200 international units/L (IU/L); serum creatinine > 2.5 mg/dL; increase in ALT/AST > 2-fold baseline levels over 1 week before starting the antituberculous drugs
Interventions	Fluoroquinolone (ofloxacin) and pyrazinamide substituted into regimen (replacing rifampicin). 1. Ofloxacin (400 mg orally) and pyrazinamide (World Health Organization (WHO) dose of 25 mg/kg for initial 2 months) daily for 12 months plus basic regimen 2. Rifampicin (WHO dose of 10 mg/kg orally) daily for 12 months plus basic regimen Basic regimen: (orally, daily for 12 months): isoniazid (WHO dose of 5 mg/kg), ethambutol (WHO dose of 15 mg/kg daily; for the initial 2 months)
Outcomes	1. Serious adverse events (hepatotoxicity requiring interruption and change of treatment)
Notes	Location: India Human immunodeficiency virus (HIV) and drug-resistance status: no data

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Sun 2000

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Methods	Randomized controlled trial Generation of allocation sequence: unclear Allocation concealment: unclear Blinding: unclear Inclusion of all randomized participants in the final analysis: no losses Mean duration of follow up: 9 months
Participants	Number: 80 randomized and evaluated Inclusion criteria: multiple-drug-resistant tuberculosis (MDR-TB) with isoniazid and rifampicin resistance; sputum culture positive after 1 year of treatment with streptomycin, isoniazid, rifampicin, pyrazinamide, and ethambutol; advanced pulmonary inflammatory or cavity enlarged; no prior fluoroquinolone treatment; adults (mean age 45.5±5.5 years; range 20 to 71 years) Exclusion criteria: heart, liver, or kidney dysfunction; diabetes
Interventions	Comparison of different fluoroquinolones (sparfloxacin versus ofloxacin) added to regimen 1. Sparfloxacin (0.1 g) 4 times daily plus basic regimen 2. Ofloxacin (0.2 g thrice daily) plus basic regimen Basic regimen: isoniazid (0.2 g), rifampicin (0.15 g), and protionamide (0.2 g thrice daily) for 6 months
Outcomes	1. Sputum smear or culture conversion 2. Clinical or radiological improvement 3. Total number of adverse events
Notes	Location: China Human immunodeficiency virus (HIV) status: presumed HIV negative Drug-resistance status: all proven MDR-TB

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Characteristics of excluded studies [ordered by study ID]

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Study	Reason for exclusion
Andries 2005	Experimental animal study, plus a small section in healthy human volunteers (tolerability); not a trial report
Anonymous 1997	No randomization or control group
Chambers 1998	The outcome, early bactericidal activity, not in review
Chen 2003	No randomization, and the intervention was a combination of levofloxacin plus capreomycin
Chukanov 2006	Mixed intervention of ciprofloxacin, ofloxacin, or levofloxacin plus kanamycin or amikacin added to the basic regimen in study group versus streptomycin added to the basic regimen in control group
Estebanez 1992	Exclusively urogenital tuberculosis
Gosling 2003	The outcome, early bactericidal activity, not in review
Grishin 1998	No randomization; cohort study
Johnson 2006	The outcome, early bactericidal activity, not in review
Kawahara 1992	No randomization
Kumar 2004	Study in healthy volunteers, not a trial report, in which the outcome was uric acid concentration in urine samples excreted over 0 to 8 h
Marra 2005	Retrospective safety study; not a trial report
O'Brien 1994	Communication to the Editor of Chest; not a trial report
Pletz 2004	The outcome, early bactericidal activity, not in review
Sirgel 1997	The outcome, early bactericidal activity, not in review
Sirgel 2000	The outcome, early bactericidal activity, not in review
Sokolova 1998	No randomization; cohort study
Suo 1996	No randomization; not a controlled study
TRC 2002	No control arm, that is, a group treated without the studied fluoroquinolone (ofloxacin), a different fluoroquinolone, or different dose
Valerio 2003	No randomization and outcomes not reported
Venter 2006	The outcome, indices of adrenocortical function, not in review; none of the included outcomes reported, too small (20 participants)
Wang 2006	Retrospective study; not a trial report
Yoon 2005	Retrospective case-control study; not a trial report
Zhang 1997	The efficacy of bronchofibrescope and catheter intervention with ofloxacin and amikacin studied in comparison with traditional chemotherapy
Zhang 2006	The efficacy of rifabutin versus rifapentine containing antituberculous regimens studied, both regimens included levofloxacin; study question not in review
Zhao 2003	No randomization
Zheng 2004	Mixed intervention of levofloxacin plus pasiniazide plus Mycobacterium vaccae
Zhu 2006	The efficacy of rifabutin versus rifapentine containing antituberculous regimens studied, both regimens included levofloxacin; study question not in review

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Characteristics of studies awaiting assessment [ordered by study ID]

Abdullah 1997

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Methods	—
Participants	—
Interventions	—
Outcomes	—
Notes	—

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Abdullah 1998

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Methods	—
Participants	—
Interventions	—
Outcomes	—
Notes	—

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Characteristics of ongoing studies [ordered by study ID]

ISRCTN07062956

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Trial name or title	A randomised comparison of ciprofloxacin, levofloxacin and gatifloxacin for the treatment of adults with tuberculous meningitis
Methods	—
Participants	Inclusion criteria: aged > 14 years; clinical diagnosis of tuberculous meningitis Exclusion criteria: aged < 15 years; pregnant or breastfeeding; patients in whom the physician believes fluoroquinolones are contraindicated (eg previous adverse reaction); consent of either patient or their relatives not obtained
Interventions	1. Conventional 4-drug antituberculous chemotherapy (ATC) (comprising of isoniazid, rifampicin, pyrazinamide, and ethambutol) 2. Conventional 4-drug ATC plus ciprofloxacin 3. Conventional 4-drug ATC plus levofloxacin 4. Conventional 4-drug ATC plus gatifloxacin
Outcomes	1. Clinical: a. fever clearance, coma clearance, date of discharge, death at 2 months, disability or death at 9 months b. Cerebrospinal fluid pressure, lactate, white cell count, protein, and glucose 2. Microbiological: a. time to cerebrospinal fluid sterility b. time to negative amplified tuberculous meningitis direct test (Mycobacterium Tuberculosis Direct [MTD] test: Gen-probe, California)
Starting date	1 April 2003
Contact information	Dr Guy Thwaites ([e-mail]), Oxford University Clinical Research Unit, Vietnam
Notes	Location: Vietnam Registration number: ISRCTN07062956 Source of funding: The Wellcome Trust (UK)

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ISRCTN13670619

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Trial name or title	A comparative study of the bactericidal and sterilizing activity of three fluoroquinolones: gatifloxacin, moxifloxacin and ofloxacin substituted for ethambutol in the 2 month initial phase of the standard anti-tuberculosis treatment regimen also containing rifampicin, isoniazid and pyrazinamide (South Africa)
Methods	—
Participants	Inclusion criteria: male/female of 18 to 65 years; weight 38 to 80 kg; recently microscopically diagnosed pulmonary tuberculosis; findings in medical history and physical examination not exceeding grade 2; voluntarily signed informed consent; confirmed negative pregnancy test at the screening visit; willing to use effective contraceptive methods during treatment; normal lab values not exceeding grade 2, except haemoglobin < 6.5 g/dL and potassium < 3.0 mEq/L (> grade 1); consent for a pre-screening biological test to exclude possible multi-drug-resistant tuberculosis (MDR-TB) and negative MDR-TB screen test will be a check if pre-screening biological test is done Exclusion criteria: history of tuberculosis within the last 3 years; concomitant infection requiring additional anti-infectious treatment (especially anti-retroviral medication (ARV)); human immunodeficiency virus (HIV)-infected patients at World Health Organization stage 4; diabetes mellitus or non-insulin dependent diabetes mellitus requiring treatment; drug and alcohol abuse; history of drug hypersensitivity and/or active allergic disease; impaired renal, hepatic or gastric function that may interfere with drug absorption, distribution, metabolism, or elimination
Interventions	1. Standard antituberculous treatment (isoniazid, rifampicin, pyrazinamide, and ethambutol) 2. Isoniazid, rifampicin, pyrazinamide, and gatifloxacin 3. Isoniazid, rifampicin, pyrazinamide, and ofloxacin 4. Isoniazid, rifampicin, pyrazinamide, and moxifloxacin
Outcomes	Bactericidal and sterilizing activity
Starting date	25 November 2004
Contact information	Dr T Kanyok ([e-mail]), UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), Switzerland
Notes	Location: South Africa Registration number: ISRCTN13670619 Sources of funding: UNICEF-UNDP-World Bank-WHO Special Programme for Research and Training in Tropical Diseases (TDR)

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ISRCTN44153044

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Trial name or title	An international multicentre controlled clinical trial to evaluate high dose RIFApentine and a QUINolone in the treatment of pulmonary tuberculosis
Methods	—
Participants	Inclusion criteria: newly diagnosed pulmonary tuberculosis; 2 sputum specimens positive for tubercle bacilli on direct smear microscopy; either no previous antituberculous chemotherapy, or < 2 weeks of previous chemotherapy; aged 18 years and over; firm home address that is readily accessible for visiting and be intending to remain there during the entire treatment and follow-up period; willing to agree to participate in the study and to give a sample of blood for HIV testing Exclusion criteria: any condition (except HIV infection) that may prove fatal during the study period; tuberculous meningitis; pre-existing nontuberculous disease likely to prejudice the response to, or assessment of, treatment (eg insulin-dependent diabetes, liver or kidney disease, blood disorders, peripheral neuritis); female and known to be pregnant or breastfeeding; suffering from a condition likely to lead to unco-operative behaviour such as psychiatric illness or alcoholism; contraindications to any medications in the study regimens; requires anti-retroviral treatment (ART) at diagnosis; history of prolonged QTc syndrome or current or planned therapy with quinidine, procainamide, amiodarone, sotalol, disopyramide, ziprasidone, or terfenadine during the intensive phase of antituberculous therapy; haemoglobin < 7g/L; aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 times the upper range; creatinine clearance < 30 mL/min; history of seizures; HIV positive with a CD4 count < 200/mm^3; weight < 35 kg
Interventions	1. 2 months of daily ethambutol (E), moxifloxacin (M), rifampicin (R), and pyrazinamide (Z) followed by 2 months of twice weekly moxifloxacin and rifapentine (2EMRZ/2P2M2). 2. 2 months of daily ethambutol, moxifloxacin, rifampicin, and pyrazinamide followed by 4 months of once weekly moxifloxacin and rifapentine (2EMRZ/4P1M1) 3. 2 months of daily ethambutol (E), isoniazid (H), rifampicin (R), and pyrazinamide (Z) followed by 4 months of daily isoniazid and rifampicin (2EHRZ/4HR)
Outcomes	1. Combined rate of failure at the end of treatment and relapse, measured at 18 months 2. Presence of rifamycin monoresistance (RMR) in relapse cultures of HIV-infected patients, measured at 5, 6, 7, 8, 9, 10, 11, 12, 15, 18 months on the 4-month arm and 7, 8, 9, 10, 11, 12, 15, 18 months on the 6-month arm, plus at any unscheduled visit 3. Occurrence of serious adverse events at any time during chemotherapy, recorded as they present themselves throughout the course of the trial 4. Sputum culture results at 2 months after the initiation of chemotherapy, measured at all visits 5. Rate of completion of chemotherapy according to the protocol, measured at all visits 6. Number of observed doses of chemotherapy ingested, measured at all visits 7. Any adverse events, recorded as they present themselves throughout the course of the trial
Starting date	31 July 2007
Contact information	Dr Amina Jindani ([e-mail]), Centre for Infection Department of Cellular and Molecular Medicine St. George’s University of London, UK
Notes	Location: South Africa, Mozambique, Zimbabwe, Zambia Registration number: ISRCTN44153044 Source of funding: European and Developing Countries Clinical Trials Partnership (EDCTP) (The Netherlands)

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ISRCTN85595810

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Trial name or title	Controlled comparison of two moxifloxacin containing treatment shortening regimens in pulmonary tuberculosis
Methods	—
Participants	Inclusion criteria: signed written consent or witnessed oral consent in the case of illiteracy, before undertaking any trial related activity; 2 sputum specimens positive for tubercle bacilli on direct smear microscopy at the local laboratory; no previous antituberculous chemotherapy; aged 18 years and over; firm home address that is readily accessible for visiting and willingness to inform the study team of any change of address during the treatment and follow-up period; agreement to participate in the study and to give a sample of blood for human immunodeficiency virus (HIV) testing; laboratory parameters performed up to 14 days before enrolment; serum aspartate aminotransferase (AST) activity < 3 times the upper limit of normal (ULN); serum total bilirubin level < 2.5 times ULN; creatinine clearance level > 30 mL/min; haemoglobin level of at least 7.0 g/dL; platelet count of at least 50 x 10^9 cells/L; serum potassium > 3.5 mmol/L; negative pregnancy test (women of childbearing potential); pre-menopausal women must be using a barrier form of contraception or be surgically sterilized or have an intra-uterine contraceptive device in place Exclusion criteria: unable to take oral medication; previously enrolled in this study; received any investigational drug in the past 3 months; received an antibiotic active against Mycobacterium tuberculosis in the last 14 days (fluoroquinolones, macrolides, standard antituberculous drugs); any condition that may prove fatal during the first two months of the study period; tuberculous meningitis or other forms of severe tuberculosis with high risk of a poor outcome; pre-existing non-tuberculosis disease likely to prejudice the response to, or assessment of, treatment (eg insulin-dependent diabetes, liver or kidney disease, blood disorders, peripheral neuritis, chronic diarrhoeal disease); pregnant or breast feeding; suffering from a condition likely to lead to unco-operative behaviour (eg psychiatric illness or alcoholism); contraindications to any medications in the study regimens; known to have congenital or sporadic syndromes of QTc prolongation or receiving concomitant medication reported to increase the QTc interval (eg amiodarone, sotalol, disopyramide, quinidine, procainamide, terfenadine); end stage liver failure (class Child-Pugh C); uncorrected hypokalaemia; weight < 35 kg; known allergy to any fluoroquinolone antibiotic or history of tendinopathy associated with quinolones; HIV infection with CD4 count < 250 x 10^9/L; patients already receiving anti-retroviral therapy; patients whose initial isolate is shown to be multiple drug resistant
Interventions	1. 8 weeks of chemotherapy with ethambutol, isoniazid, rifampicin, and pyrazinamide plus the moxifloxacin placebo, followed by 9 weeks of isoniazid and rifampicin plus the moxifloxacin placebo, followed by 9 weeks of isoniazid and rifampicin only 2. 8 weeks of chemotherapy with moxifloxacin, isoniazid, rifampicin, and pyrazinamide plus the ethambutol placebo, followed by 9 weeks of moxifloxacin, isoniazid and rifampicin, followed by 9 weeks of the isoniazid placebo and the rifampicin placebo 3. 8 weeks of chemotherapy with ethambutol, moxifloxacin, rifampicin, and pyrazinamide plus the isoniazid placebo, followed by 9 weeks of moxifloxacin and rifampicin plus the isoniazid placebo, followed by 9 weeks of the isoniazid placebo and the rifampicin placebo Dosages dependent on patient weight category (all drugs taken orally): 1. Moxifloxacin: 400 mg 2. Rifampicin: ≤ 45 kg - 450 mg; > 45 kg - 600 mg 3. Isoniazid: 300 mg 4. Pyrazinamide: < 40 kg - 25 mg/kg rounded to nearest 500 mg; 40 to 55 kg - 1000 mg; 55 to 75 kg - 1500 mg; > 75 kg - 2000 mg 5. Ethambutol: < 40 kg - 15 mg/kg rounded to nearest 100 mg; 40 to 55 kg - 800 mg; 55 to 75 kg - 1200 mg; > 75 kg - 1600 mg
Outcomes	1. Combined failure of bacteriological cure and relapse within 1 year of completion of therapy 2. Proportion of patients with grade 3 or 4 adverse events according to the World Health Organization grade 3. Proportion of participants culture negative at 8 weeks 4. Time to culture negative sputum 5. Speed of decline of sputum viable count
Starting date	1 June 2007
Contact information	Prof Stephen Gillespie, Centre for Medical Microbiology, Royal Free and University College Medical School, UK
Notes	Location: Kenya, South Africa, Tanzania, Zambia Registration number: ISRCTN85595810 Sources of funding: European and Developing Countries Clinical Trials Partnership (EDCTP) (The Netherlands); TB Alliance (USA); Bayer HealthCare Pharmaceuticals (USA); Sanofi-Aventis (France)

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NCT00144417

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Trial name or title	TBTC Study 28: Evaluation of a moxifloxacin-based, isoniazid-sparing regimen for tuberculosis treatment
Methods	—
Participants	Inclusion criteria: suspected pulmonary tuberculosis with acid-fast bacilli in a stained smear of expectorated or induced sputum. Patients whose sputum cultures do not grow M. tuberculosis and those having an M. tuberculosis isolate resistant to (one or more) isoniazid, rifampin, fluoroquinolones, will be discontinued from the study, but followed for 14 days to detect late toxicities from study therapy. Patients having extra-pulmonary manifestations of tuberculosis, in addition to smear-positive pulmonary disease, are eligible for enrolment. Sputum must be expectorated or induced; smear results from respiratory secretions obtained by bronchoalveolar lavage or bronchial wash may not be used for assessment of study eligibility; willingness to have HIV testing performed, if HIV serostatus is not known or if the last documented negative HIV test was more than 6 months before enrolment. HIV testing does not need to be repeated if there is written documentation of a positive test (positive ELISA and Western Blot or a plasma HIV-RNA level > 5000 copies/mL) at any time in the past; 7 or fewer days of multidrug therapy for tuberculosis disease in the 6 months preceding enrolment; 7 or fewer days of fluoroquinolone therapy in the 3 months preceding enrolment; age > 18 years; Karnofsky score of at least 60 (requires occasional assistance but is able to care for most of his/her needs); signed informed consent; women with child-bearing potential must agree to practice an adequate (barrier) method of birth control or to abstain from heterosexual intercourse during study therapy; serum amino aspartate transferase (AST) activity ≤ 3 times upper limit of normal; serum total bilirubin level ≤ 2.5 times upper limit of normal; serum creatinine level ≤ 2 times upper limit of normal; complete blood count with hemoglobin level of at least 7.0 g/dL; complete blood count with platelet count of at least 50,000/mm ^3 ; serum potassium > 3.5 meq/L; negative pregnancy test (women of childbearing potential) Exclusion criteria: breastfeeding; known intolerance to any of the study drugs; known allergy to any fluoroquinolone antibiotic; concomitant disorders or conditions for which moxifloxacin (MXF), isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), or ethambutol (EMB) are contraindicated (including severe hepatic damage, acute liver disease of any cause, and acute uncontrolled gouty arthritis); current or planned therapy during the intensive phase of therapy using drugs having unacceptable interactions with rifampin (rifabutin can be substituted for rifampin during the continuation phase of therapy); current or planned antiretroviral therapy during intensive phase of therapy; history of prolonged QT syndrome or current or planned therapy with quinidine, procainamide, amiodarone, sotalol, disopyramide, ziprasidone, or terfenadine during the intensive phase of therapy; pulmonary silicosis; central nervous system tuberculosis
Interventions	1. Moxifloxacin (with rifampin, pyrazinamide, and ethambutol) 2. Isoniazid (with rifampin, pyrazinamide, and ethambutol)
Outcomes	1. Culture-conversion rate at the end of the intensive phase of therapy 2. Safety and tolerability 3. Time to culture-conversion using data from 2-, 4-, 6-, and 8-week cultures 4. Proportion of patients with any Grade 3 or 4 adverse reactions 5. Adverse events and 2-month culture conversion rates among HIV-infected patients vs. HIV-uninfected patients 6. Rates of treatment failure 7. Delayed toxicity attributable to moxifloxacin (toxicity that becomes evident after the 8 weeks of moxifloxacin therapy)
Starting date	February 2006
Contact information	Richard E Chaisson (Study Chair), Johns Hopkins University, USA
Notes	Location: Brazil, Canada (Manitoba, Quebec), South Africa, Spain, Uganda, USA (Arkansas, California, Colorado, Washington DC, Georgia, Illinois, Maryland, Massachusetts, New Jersey, New York, North Carolina, Tennessee, Texas, Washington) Registration number: NCT00144417 Sponsors and collaborators: Centers for Disease Control and Prevention; Global Alliance for TB Drug Development; Bayer

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NCT00216385

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Trial name or title	A controlled trial of a 4-month quinolone-containing regimen for the treatment of pulmonary tuberculosis
Methods	—
Participants	Inclusion criteria: male or female; aged 18 to 65 years; currently suffering from recently diagnosed microscopically proven pulmonary tuberculosis and providing informed consent for inclusion in the study Exclusion criteria: history of tuberculosis treatment within the last 3 years; history of diabetes mellitus or noninsulin dependent diabetes mellitus requiring treatment; concomitant infection requiring additional anti-infective treatment (especially anti-retroviral therapy); HIV- infected patients with WHO stage 3 infection - except those presenting with only the "loss of weight>10% body weight" criterion - and all HIV infected patients at WHO stage 4
Interventions	1. 4-month gatifloxacin-containing antituberculous regimen 2. Standard antituberculous regimen
Outcomes	1. Percentage of relapses by 24 months following treatment cure 2. Percentage of adverse events 3. Time to relapse 4. Percentage of smear and culture conversion at 8 weeks 5. Percentage of patient cured at the end 6. of treatment 7. Time to a composite "unsatisfactory" endpoint 8. Distribution of type and grading of adverse events
Starting date	January 2005
Contact information	Christian Lienhardt (Study Director), Institut de Recherche pour le Developpement, France
Notes	Location: Benin, Guinea, Kenya, Senegal, South Africa Registration number: NCT00216385 Sponsors and collaborators: Institut de Recherche pour le Developpement; World Health Organization; European Commission

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NCT00396084

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Trial name or title	Randomized, open label, multiple dose Phase I study of the early bactericidal activity of linezolid, gatifloxacin, levofloxacin, and moxifloxacin in HIV-non-infected adults with Initial episodes of sputum smear-positive pulmonary tuberculosis (DMID 01-553)
Methods	—
Participants	Inclusion criteria: adults, male or female, aged 18 to 65 years; women with child-bearing potential (not surgically sterilized or postmenopausal for < 1 year) must be using or agree to use an adequate method of birth control (condom: intravaginal spermicide (foams, jellies, sponge) and diaphragm: cervical cap or intrauterine device) during study drug treatment; newly diagnosed sputum smear-positive pulmonary tuberculosis as confirmed by sputum AFB smear and chest x-ray findings consistent with pulmonary tuberculosis; willing and able to provide informed consent; reasonably normal hemoglobin (≥ 8 gm/dL), renal function (serum creatinine < 2 mg/dL), hepatic function (serum AST < 1.5 times the upper limit of normal for the testing laboratory and total bilirubin < 1.3 mg/dL), and random blood glucose < 150 mg/dL Exclusion criteria: HIV infection; weight < 75% of ideal body weight; presence of significant hemoptysis; patients who cough up frank blood (more than blood streaked sputum); pregnant or breastfeeding women and those who are not practicing birth control; significant respiratory impairment (respiratory rate > 35/min); clinical suspicion of dissemated tuberculosis or tuberculosis meningitis; presence of serious underlying medical illness (eg such as liver failure, renal failure, diabetes mellitus, chronic alcoholism, decompensated heart failure, haematologic malignancy) or patients receiving myelosuppressive chemotherapy; patients receiving any of monoamine oxidase inhibitors (phenelzine, tranylcypromine), adrenergic/serotonergic agonists such as pseudoephedrine and phenylpropanolamine (frequently found in cold and cough remedies), tricyclic antidepressants (amitriptyline, nortriptyline, protriptyline, doxepin, amoxapine, etc), antipsychotics (eg chlorpromazine and buspirone), serotonin re-uptake inhibitors (fluoxetine, paroxetine, sertaline, etc), buproprion, agents known to prolong the QTc interval [erythromycin, clarithromycin, astemizole, type Ia (quinidine, procainamide, disopyramide) and III (amiodarone, sotalol) anti-arrhythmics, carbamazepine, insulin, sulfonylureas, and meperidine; presence of QTc prolongation (> 450 msec) on baseline EKG; allergy or contraindication to use of study drugs; treatment with antituberculous medications or other antibiotics with known activity against Mycobacterium tuberculosis during the preceding 6 months; inability to provide informed consent; total white blood cell count < 3000/mm^3; platelet count < 150,000/mm^3; patients with suspected drug-resistant tuberculosis (eg contact to source patient with drug-resistant tuberculosis, patients who have relapsed after previous treatment for tuberculosis); patients likely, in the opinion of the local investigator, to be unable to comply with the requirements of the study protocol
Interventions	Participants will be randomized to receive gatifloxacin, levofloxacin, moxifloxacin, or isoniazid (control), and after these arms are enrolled, they will be randomized to receive either linezolid (600 mg once daily) or linezolid (600 mg twice daily) or isoniazid (control). After the initial treatment, all participants will receive 6 months of standard antituberculous treatment outside of the hospital
Outcomes	1. Early bactericidal activity 2. Extended early bactericidal activity 3. Safety evaluations including clinical examination, complete blood counts, and serum total bilirubin, aspartate aminotransferase, and creatinine, and urinalysis will be followed to monitor for drug toxicity
Starting date	February 2004
Contact information	John Johnson ([e-mail])
Notes	Location: University of Espírito Santo, Vitória, Brazil Registration number: NCT00396084 Sponsors: National Institute of Allergy and Infectious Diseases (NIAID)

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Comparison 1. Fluoroquinolone substituted into regimen

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Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

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 1 Cure (sputum culture conversion) at 8 weeks

3

416

Risk Ratio (M-H, Random, 95% CI)

0.98 [0.82, 1.17]

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1.1 Ciprofloxacin vs rifampicin

1

60

Risk Ratio (M-H, Random, 95% CI)

1.08 [0.88, 1.32]

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1.2 Ciprofloxacin vs ethambutol plus pyrazinamide

1

20

Risk Ratio (M-H, Random, 95% CI)

0.68 [0.42, 1.09]

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1.3 Moxifloxacin vs ethambutol

1

336

Risk Ratio (M-H, Random, 95% CI)

1.00 [0.83, 1.19]

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 2 Treatment failure at 12 months

3

388

Risk Ratio (M-H, Fixed, 95% CI)

2.14 [0.71, 6.42]

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2.1 Ciprofloxacin vs rifampicin

1

60

Risk Ratio (M-H, Fixed, 95% CI)

3.0 [0.13, 70.83]

---

2.2 Ciprofloxacin vs ethambutol plus pyrazinamide

2

328

Risk Ratio (M-H, Fixed, 95% CI)

2.03 [0.63, 6.58]

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 3 Relapse

3

384

Risk Ratio (M-H, Fixed, 95% CI)

7.17 [1.33, 38.58]

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3.1 Ciprofloxacin vs ethambutol plus pyrazinamide

1

168

Risk Ratio (M-H, Fixed, 95% CI)

15.72 [0.91, 270.96]

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3.2 Ciprofloxacin vs rifampicin

1

60

Risk Ratio (M-H, Fixed, 95% CI)

3.0 [0.33, 27.23]

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3.3 Ofloxacin vs ethambutol

1

156

Risk Ratio (M-H, Fixed, 95% CI)

Not estimable

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 4 Relapse: by HIV status

1

Risk Ratio (M-H, Fixed, 95% CI)

Totals not selected

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4.1 HIV-positive participants: ciprofloxacin vs ethambutol plus pyrazinamide

1

Risk Ratio (M-H, Fixed, 95% CI)

Not estimable

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4.2 HIV-negative participants: ciprofloxacin vs ethambutol plus pyrazinamide

1

Risk Ratio (M-H, Fixed, 95% CI)

Not estimable

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 5 Time to sputum culture conversion (months)

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

---

5.1 Ciprofloxacin vs ethambutol plus pyrazinamide

1

Mean Difference (IV, Fixed, 95% CI)

Not estimable

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 6 Time to sputum culture conversion (months): by HIV status

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

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6.1 HIV-positive participants: ciprofloxacin vs ethambutol plus pyrazinamide

1

Mean Difference (IV, Random, 95% CI)

Not estimable

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6.2 HIV-negative participants: ciprofloxacin vs ethambutol plus pyrazinamide

1

Mean Difference (IV, Random, 95% CI)

Not estimable

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 7 Clinical or radiological improvement at 8 weeks

2

216

Risk Ratio (M-H, Random, 95% CI)

0.89 [0.49, 1.59]

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7.1 Ciprofloxacin vs rifampicin

1

60

Risk Ratio (M-H, Random, 95% CI)

1.08 [0.88, 1.32]

---

7.2 Ofloxacin vs ethambutol

1

156

Risk Ratio (M-H, Random, 95% CI)

0.69 [0.44, 1.08]

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 8 Serious adverse events

5

743

Risk Ratio (M-H, Fixed, 95% CI)

0.98 [0.56, 1.72]

---

8.1 Ciprofloxacin vs rifampicin

1

60

Risk Ratio (M-H, Fixed, 95% CI)

1.0 [0.07, 15.26]

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8.2 Ofloxacin vs ethambutol

1

156

Risk Ratio (M-H, Fixed, 95% CI)

1.30 [0.47, 3.57]

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8.3 Ciprofloxacin vs ethambutol plus pyrazinamide

1

160

Risk Ratio (M-H, Fixed, 95% CI)

0.98 [0.20, 4.69]

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8.4 Ofloxacin vs rifampicin

1

31

Risk Ratio (M-H, Fixed, 95% CI)

0.10 [0.01, 1.79]

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8.5 Moxifloxacin vs ethambutol

1

336

Risk Ratio (M-H, Fixed, 95% CI)

1.24 [0.50, 3.05]

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 9 Total number of adverse events

4

712

Risk Ratio (M-H, Fixed, 95% CI)

1.17 [0.96, 1.43]

---

9.1 Ciprofloxacin vs rifampicin

1

60

Risk Ratio (M-H, Fixed, 95% CI)

1.0 [0.22, 4.56]

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9.2 Ciprofloxacin vs ethambutol plus pyrazinamide

1

160

Risk Ratio (M-H, Fixed, 95% CI)

0.87 [0.60, 1.24]

---

9.3 Ofloxacin vs ethambutol

1

156

Risk Ratio (M-H, Fixed, 95% CI)

1.95 [0.70, 5.44]

---

9.4 Moxifloxacin vs ethambutol

1

336

Risk Ratio (M-H, Fixed, 95% CI)

1.29 [1.00, 1.66]

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 10 Total number of adverse events, substitutions for ethambutol

2

492

Risk Ratio (M-H, Fixed, 95% CI)

1.34 [1.05, 1.72]

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Comparison 2. Fluoroquinolone added to regimen

---

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

---

 1 Cure (sputum culture conversion) at 8 weeks

1

Risk Ratio (M-H, Fixed, 95% CI)

Totals not selected

---

1.1 Levofloxacin vs no levofloxacin

1

Risk Ratio (M-H, Fixed, 95% CI)

Not estimable

---

 2 Treatment failure at 12 months

1

Risk Ratio (M-H, Fixed, 95% CI)

Totals not selected

---

2.1 Levofloxacin vs no levofloxacin

1

Risk Ratio (M-H, Fixed, 95% CI)

Not estimable

---

 3 Clinical or radiological improvement at 8 weeks

1

Risk Ratio (M-H, Fixed, 95% CI)

Totals not selected

---

3.1 Levofloxacin vs no levofloxacin

1

Risk Ratio (M-H, Fixed, 95% CI)

Not estimable

---

 4 Death from any cause

1

Risk Ratio (M-H, Fixed, 95% CI)

Totals not selected

---

4.1 Levofloxacin vs no levofloxacin

1

Risk Ratio (M-H, Fixed, 95% CI)

Not estimable

---

 5 Tuberculosis-related death

1

Risk Ratio (M-H, Fixed, 95% CI)

Totals not selected

---

5.1 Levofloxacin vs no levofloxacin

1

Risk Ratio (M-H, Fixed, 95% CI)

Not estimable

---

 6 Serious adverse events

1

Risk Ratio (M-H, Fixed, 95% CI)

Totals not selected

---

6.1 Levofloxacin vs no levofloxacin

1

Risk Ratio (M-H, Fixed, 95% CI)

Not estimable

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Comparison 3. Comparison of fluoroquinolones (levofloxacin vs ofloxacin) substituted into regimen

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Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Cure (sputum culture conversion) within 2 to 3 weeks	1		Risk Ratio (M-H, Fixed, 95% CI)	Totals not selected
2 Treatment failure at 12 months	1		Risk Ratio (M-H, Fixed, 95% CI)	Totals not selected
3 Clinical or radiological improvement at 8 weeks	1		Risk Ratio (M-H, Fixed, 95% CI)	Totals not selected
4 Total number of adverse events	1		Risk Ratio (M-H, Fixed, 95% CI)	Totals not selected

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Comparison 4. Comparison of fluoroquinolones (sparfloxacin vs ofloxacin) added to regimens

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Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Cure (sputum culture conversion within 2 to 3 weeks)	2	184	Risk Ratio (M-H, Random, 95% CI)	2.10 [0.77, 5.71]
2 Treatment failure at 12 months	2	149	Risk Ratio (M-H, Fixed, 95% CI)	0.61 [0.26, 1.47]
3 Clinical or radiological improvement at 8 weeks	3	333	Risk Ratio (M-H, Fixed, 95% CI)	1.07 [0.92, 1.24]
4 Total number of adverse events	3	253	Risk Ratio (M-H, Fixed, 95% CI)	0.98 [0.59, 1.64]

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Table 1. Highest multiple-drug-resistant tuberculosis (MDR-TB) rates in 1998^a

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Location	New case	Previously treated case
Estonia	14.1	18.1
Henan Province, China	10.8	15.1
Latvia	9.0	12.0
Ivanovo Oblast, Russian Federation	9.0	12.3
Tomsk Oblast, Russian Federation	6.5	13.7

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 ^aSource: Loddenkemper 2002.

 

Table 2. Risk of bias assessment

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Trial	Allocation sequence generation	Allocation concealment	Blinding	Inclusion^a
Burman 2006	Unclear	Unclear	Unclear	Inadequate
El-Sadr 1998	Adequate	Unclear	Assessors only	Adequate for 8 weeks Inadequate for continuation phase (39% lost)
Huang 2000	Unclear	Unclear	Unclear	Adequate
Ji 2001	Unclear	Unclear	Unclear	Adequate
Kennedy 1993	Unclear	Unclear	None	Adequate
Kennedy 1996	Adequate	Adequate	Assessors only	Adequate
Kohno 1992	Unclear	Unclear	Unclear	Inadequate
Lu 2000	Adequate	Unclear	Participants: yes Providers and assessors: unclear	Adequate
Mohanty 1993	Unclear	Unclear	Providers, participants, and radiograph assessors: yes	Inadequate
Saigal 2001	Adequate	Unclear	None	Adequate
Sun 2000	Unclear	Unclear	Unclear	Adequate

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 ^aInclusion of all randomized participants in the final analysis.