Tuberculosis
Conditions
Keywords
Brazil, gatifloxacin, isoniazid, levofloxacin, linezolid, moxifloxacin, tuberculosis
Brief summary
This study will evaluate the ability of 4 antibiotics to kill the bacteria that cause tuberculosis (TB). The antibiotics to be studied are linezolid, gatifloxacin, levofloxacin, and moxifloxacin. All are approved by the Brazilian health authorities to treat infections caused by germs other than TB. Seventy human immunodeficiency virus (HIV)-negative adults, aged 18-65 years, who have been newly diagnosed with pulmonary (lung) TB, will participate in this study. Study volunteers will be given one of the 4 study drugs or a comparison antibiotic, Isoniazid, which has been used around the world as a standard of care treatment for TB. Volunteers will stay in the hospital for 10 days and be given a study antibiotic 7 of those days. Blood and saliva samples will be taken. Six weeks later, volunteers will return for a final health check. All volunteers will receive 6 months of standard tuberculosis treatment.
Detailed description
Multi-drug resistant tuberculosis now affects all regions of the world and is a significant concern for national tuberculosis (TB) control programs. The development and testing of new drugs and new classes of drugs and immunotherapeutic agents are vital elements in the global response to this challenge. The fluoroquinolones and oxazolidinones represent two promising classes of drugs that show activity against Mycobacterium tuberculosis (MTB). This study is a randomized, open label, multiple dose phase I clinical trial to evaluate the early bactericidal activity (EBA) of gatifloxacin, levofloxacin, moxifloxacin, and linezolid compared with an isoniazid (INH) control arm in patients with newly-diagnosed sputum smear-positive pulmonary tuberculosis (TB). Secondary study objectives are to: compare results of sputum MTB messenger ribonucleic acid (mRNA) clearance with results of a standard EBA study \[change in sputum viable counts \[colony forming units (CFU)\]; compare the rate of clearance of sputum cytokine proteins with results of a standard EBA assay CFU; determine the pharmacokinetics (PK) of the study drugs in patients with smear-positive pulmonary TB; and demonstrate that lack of EBA activity is not due to low serum drug concentrations. Seventy human immunodeficiency virus (HIV) negative adults, aged 18-65 years, who have been newly diagnosed with pulmonary TB, will be enrolled and admitted to the Centro de Pesquisa (Clinical Research Ward) at the Hospital Universitario Cassiano Antonio de Moraes of the Universidade Federal do Espírito Santo in Vitória. The subjects will be randomized to receive gatifloxacin, levofloxacin, moxifloxacin, or INH (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 INH (control). During the inpatient stay, study drugs will be given for 7 days following a 2-day drug-free period when baseline sputum bacillary counts will be measured. The 7-day duration of the study drug phase will allow measurement of sputum bactericidal activity both during the first 2 days of study drug administration and between days 2 and 7 of study drug administration to gain additional information on the possible sterilizing activity of the drugs. The extended nature of these EBA studies will allow assessment of this possibility in the study drugs that would be missed if a shorter EBA study was performed. Sputum specimens will be collected for 2 days prior to initiation of study drug in order to establish a baseline quantitative culture result and then specimens will be collected daily thereafter. Sputum specimens will be processed to evaluate changes in mycobacterial mRNA/proteins and cytokine proteins. PK studies will be performed after 5 days of study drug administration (Day 5). Safety evaluations including clinical examination, complete blood counts, and serum total bilirubin, aspartate aminotransferase (AST), creatinine, and urinalysis will be followed to monitor for drug toxicity. Drug susceptibility testing will be performed on an initial sputum isolate and will be repeated after completion of 7 days of study drugs, and on isolates from patients with positive sputum cultures at the day 42 study visit to assess for the development of acquired drug resistance. Isolates will be tested against INH, rifampicin, pyrazinamide, ethambutol and the subject's assigned study drug. Patients who are found to be resistant to their assigned study drug at baseline will not be analyzable. After the initial treatment, all subjects will receive 6 months of standard TB treatment outside of the hospital.
Interventions
DRUGIsoniazid
Isoniazid 300 mg/day x 7 days.
DRUGLevofloxacin
Levofloxacin 1000 mg/day x 7 days.
DRUGLinezolid
Linezolid 600 mg/day x 7 days; Linezolid 600 mg every 12 hours x 7 days.
DRUGMoxifloxacin
Moxifloxacin 400 mg/day x 7 days.
DRUGGatifloxacin
Gatifloxacin 400 mg/day x 7 days.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
-Adults, male or female, age 18 to 65 years. -Women with child-bearing potential (not surgically sterilized or postmenopausal for less than 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 acid fast bacilli (AFB) smear and chest X-ray findings consistent with pulmonary tuberculosis. -Willing and able to provide informed consent. -Reasonably normal hemoglobin (greater than or equal to 8 gm/dL), renal function (serum creatinine less than 2 mg/dL), hepatic function \[serum aspartate aminotransferase (AST) less than 1.5 times the upper limit of normal for the testing laboratory and total bilirubin less than 1.3 mg/dL\], and random blood glucose less than 150 mg/dL.
Exclusion criteria
-Human immunodeficiency virus (HIV) infection. -Weight less than 75 percent of ideal body weight. -Presence of significant hemoptysis. Patients who cough up frank blood (more than blood streaked sputum) will not be eligible for enrollment. -Pregnant or breastfeeding women and those who are not practicing birth control. -Significant respiratory impairment (respiratory rate greater than 35/minute). -Clinical suspicion of disseminated tuberculosis or tuberculosis meningitis. -Presence of serious underlying medical illness, such as liver failure, renal failure, diabetes mellitus, chronic alcoholism, decompensated heart failure, hematologic malignancy or patients receiving myelosuppressive chemotherapy. -Patients receiving any of the following medications - 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 such as chlorpromazine and buspirone, serotonin re-uptake inhibitors (fluoxetine, paroxetine, sertraline, 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 (greater than 450 msec) on baseline electrocardiogram (EKG). -Allergy or contraindication to use of study drugs. -Treatment with antituberculosis medications or other antibiotics with known activity against M. tuberculosis during the preceding 6 months. -Inability to provide informed consent. -Total white blood cell count less than 3000/mm\^3. -Platelet count less than 150,000/mm\^3. -Patients with suspected drug resistant tuberculosis (e.g., 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Study drug administration duration - 7 days monotherapy | The adjusted area under the curve (aAUC) for sputum colony forming units (cfu) for each day on treatment was calculated. The aAUC represents the percentage of the expected AUC given no change in log cfu in response to study drug administration. |
| Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Fluoroquinolones/Isoniazid (INH) Comparison | Day 0 to Day 2 Monotherapy | Early bactericidal activity (EBA 0-2) was calculated as the rate of fall in sputum colony forming units (cfu) (expressed in log10 units) during the first 2 days of monotherapy. |
| Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Fluoroquinolones/Isoniazid (INH) Comparison | Day 2 to Day 7 Monotherapy | The rate of fall in sputum cfu between day 2 and day 7 of monotherapy was estimated by the slope of the linear regression obtained by fitting the 6 sputum cfu values corresponding to Days 2 through 7. |
| Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Linezolid Once Daily/Linezolid Twice Daily/Isoniazid (INH) Comparison | Day 0 to Day 2 Monotherapy | Early bactericidal activity (EBA 0-2) was calculated as the rate of fall in sputum cfu (expressed in log10 units) during the first 2 days of monotherapy. Mean values for the 3 treatment groups were compared. |
| Difference in Sputum Bacillary Loads: Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Linezolid Once Daily/Linezolid Twice Daily/INH Comparison | Day 2 to Day 7 Monotherapy | The rate of fall in sputum cfu between day 2 and day 7 of monotherapy was estimated by the slope of the linear regression obtained by fitting the 6 sputum cfu values corresponding to Days 2 through 7. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic Parameters: Area Under the Curve (AUC) During First 12 and 24 Hours | Day 5 (7 time points) | Area under the curve (AUC), from time 0-12 hours for INH or 0-24 hours for gatifloxacin, levofloxacin, and moxifloxacin. |
| Area Under the Curve During First 12 or 24 Hours / Minimum Inhibitory Concentration (AUC/MIC) | Day 5 (7 time points) | Area Under the Curve (AUC) During First 12 or 24 Hours /Minimum Inhibitory Concentration. AUC reflects total drug (bound and unbound). MIC values were determined using protein-containing media. |
| Pharmacokinetic Parameters: Area Under the Curve During First 12 and 24 Hours | Day 5 (7 time points) | Median pharmacokinetic parameters (range). AUC 0-12 and AUC 0-24 = area under the curve during the first 12 and 24 hours after dosing, respectively |
| Maximum Plasma Drug Concentrations (Cmax), Adjusted for Free Drug Concentration | Day 5 (7 time points) | Cmax adjusted for free drug concentrations after 5 days of monotherapy with study drugs |
| Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC) | Day 5 (7 time points) | — |
| Area Under the Curve (AUC) During First 12 and 24 Hours Adjusted for Free Drug Concentrations | Day 5 (7 time points) | Median pharmacodynamic parameters (range) adjusted for free drug concentrations. AUC 0-12 and AUC 0-24 = area under the curve during the first 12 and 24 hours after dosing, respectively |
| Area Under the Curve (AUC) Adjusted for Free Drug Concentrations/Minimum Inhibitory Concentration (MIC) | Day 5 (7 time points) | Area Under the Curve 0-12 (AUC 0-12) Adjusted for Free Drug Concentrations/Minimum Inhibitory Concentration (MIC) and AUC 0-24/MIC |
| Percent Dosing Interval Above Minimum Inhibitory Concentration (MIC) | Day 5 (7 time points) | Determined by linear extrapolation of concentration-versus-time curve to intersection with MIC. |
| Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC) Adjusted for Free Drug Concentrations | Day 5 (7 time points) | — |
| Sputum mRNA Clearance Rate - Results Are Pending. | Study drug administration duration | — |
| Sputum Cytokine Proteins - Results Are Pending. | Study drug administration duration | — |
| Maximum Plasma Drug Concentration (Cmax) | Day 5 (7 time points) | Maximum plasma concentration, given sampling scheme |
| Time to Maximum Plasma Drug Concentration (Tmax) and Half-life | Day 5 (7 time points) | — |
Countries
Brazil, United States
Participant flow
Recruitment details
Screening for the trial began in February 2004 in Vitória, Brazil. Non-HIV infected adults aged 18-65 years with suspected pulmonary tuberculosis (TB) were recruited at local TB posts and the Hospital Universitario Cassiano Antonio de Moraes of the Universidade Federal do Espírito Santo (UFES) in Vitória. Enrollment was completed in October 2007.
Pre-assignment details
A total of 113 adults with suspected pulmonary TB were evaluated for study participation. Forty-three were excluded because they did not meet the eligibility criteria, leaving a total of 70 patients.
Participants by arm
| Arm | Count |
|---|---|
| Gatifloxacin 400 mg/Day Gatifloxacin 400 mg/day x 7 days | 10 |
| Levofloxacin 1000 mg/Day Levofloxacin 1000 mg/day x 7days | 10 |
| Linezolid 600 mg / Once Daily Linezolid 600 mg/once daily x 7days | 10 |
| Linezolid 600 mg / Twice Daily Linezolid 600 mg twice daily x 7 days | 10 |
| Moxifloxacin 400 mg/Day Moxifloxacin 400 mg/day x 7 days | 10 |
| Isoniazid (INH) 300 mg/Day Isoniazid (INH) 300 mg/day x 7 days | 20 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 1 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Levofloxacin 1000 mg/Day | Linezolid 600 mg / Once Daily | Linezolid 600 mg / Twice Daily | Gatifloxacin 400 mg/Day | Moxifloxacin 400 mg/Day | Isoniazid (INH) 300 mg/Day | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 10 Participants | 10 Participants | 10 Participants | 10 Participants | 20 Participants | 70 Participants |
| Age, Continuous | 43.5 years INTER_QUARTILE_RANGE 6.4 | 33.5 years INTER_QUARTILE_RANGE 13.4 | 45.0 years INTER_QUARTILE_RANGE 12.7 | 34.5 years INTER_QUARTILE_RANGE 10.1 | 35.0 years INTER_QUARTILE_RANGE 8.4 | 33.0 years INTER_QUARTILE_RANGE 11.4 | 35.0 years INTER_QUARTILE_RANGE 11.2 |
| Region of Enrollment Brazil | 10 participants | 10 participants | 10 participants | 10 participants | 10 participants | 20 participants | 70 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 2 Participants | 1 Participants | 1 Participants | 3 Participants | 11 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 8 Participants | 9 Participants | 9 Participants | 17 Participants | 59 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 10 | 7 / 10 | 8 / 10 | 5 / 10 | 7 / 10 | 7 / 20 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 20 |
Outcome results
Primary
Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Fluoroquinolones/Isoniazid (INH) Comparison
Early bactericidal activity (EBA 0-2) was calculated as the rate of fall in sputum colony forming units (cfu) (expressed in log10 units) during the first 2 days of monotherapy.
Time frame: Day 0 to Day 2 Monotherapy
Population: Early bactericidal activity (EBA 0-2) was calculated for 10 subjects per treatment arm (n=40).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Gatifloxacin 400 mg/Day | Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Fluoroquinolones/Isoniazid (INH) Comparison | 0.35 log10 cfu/ml/day | Standard Deviation 0.27 |
| Levofloxacin 1000 mg/Day | Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Fluoroquinolones/Isoniazid (INH) Comparison | 0.45 log10 cfu/ml/day | Standard Deviation 0.35 |
| Moxifloxacin 400 mg/Day | Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Fluoroquinolones/Isoniazid (INH) Comparison | 0.33 log10 cfu/ml/day | Standard Deviation 0.39 |
| Isoniazid (INH) 300 mg/Day | Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Fluoroquinolones/Isoniazid (INH) Comparison | 0.67 log10 cfu/ml/day | Standard Deviation 0.17 |
Comparison: Mean values of EBA Days 0 to 2 for the 4 treatment groups were compared.p-value: 0.05ANOVA
Comparison: Two way comparison of INH against gatifloxacin using a simultaneous non-parametric procedure.p-value: 0.01Wilcoxon (Mann-Whitney)
Comparison: Two way comparison of INH against moxifloxacin using a simultaneous non-parametric procedure.p-value: 0.02Wilcoxon (Mann-Whitney)
Comparison: Two way comparison of INH against levofloxacin using a simultaneous non-parametric procedure.p-value: 0.14Wilcoxon (Mann-Whitney)
Primary
Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Linezolid Once Daily/Linezolid Twice Daily/Isoniazid (INH) Comparison
Early bactericidal activity (EBA 0-2) was calculated as the rate of fall in sputum cfu (expressed in log10 units) during the first 2 days of monotherapy. Mean values for the 3 treatment groups were compared.
Time frame: Day 0 to Day 2 Monotherapy
Population: EBA 0-2 comparisons across groups were done for 29 patients. One patient in the linezolid twice daily arm withdrew from the study after randomization before receiving any doses of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Gatifloxacin 400 mg/Day | Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Linezolid Once Daily/Linezolid Twice Daily/Isoniazid (INH) Comparison | 0.67 log10 cfu/ml/day | Standard Deviation 0.35 |
| Levofloxacin 1000 mg/Day | Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Linezolid Once Daily/Linezolid Twice Daily/Isoniazid (INH) Comparison | 0.18 log10 cfu/ml/day | Standard Deviation 0.27 |
| Moxifloxacin 400 mg/Day | Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Linezolid Once Daily/Linezolid Twice Daily/Isoniazid (INH) Comparison | 0.26 log10 cfu/ml/day | Standard Deviation 0.42 |
Comparison: Mean values of EBA Days 0 to 2 for the 3 treatments groups were compared.p-value: <0.01ANOVA
Comparison: Two way comparison of INH against Linezolid once daily using a simultaneous non-parametric procedure.p-value: <0.01Wilcoxon (Mann-Whitney)
Comparison: Mean EBA 0-2 of INH was compared to pooled Linezolid once daily and Linezolid twice daily results.p-value: <0.01Wilcoxon (Mann-Whitney)
Primary
Difference in Sputum Bacillary Loads: Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Linezolid Once Daily/Linezolid Twice Daily/INH Comparison
The rate of fall in sputum cfu between day 2 and day 7 of monotherapy was estimated by the slope of the linear regression obtained by fitting the 6 sputum cfu values corresponding to Days 2 through 7.
Time frame: Day 2 to Day 7 Monotherapy
Population: One patient in the INH arm discontinued the study drug after 5 days. Days 3 and 7 cultures for another patient in the INH arm were contaminated and cfu data are not available for this patient. One patient in the linezolid twice daily arm withdrew from the study after randomization before receiving any doses of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Gatifloxacin 400 mg/Day | Difference in Sputum Bacillary Loads: Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Linezolid Once Daily/Linezolid Twice Daily/INH Comparison | 0.16 log10 cfu/ml | Standard Deviation 0.11 |
| Levofloxacin 1000 mg/Day | Difference in Sputum Bacillary Loads: Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Linezolid Once Daily/Linezolid Twice Daily/INH Comparison | 0.09 log10 cfu/ml | Standard Deviation 0.17 |
| Moxifloxacin 400 mg/Day | Difference in Sputum Bacillary Loads: Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Linezolid Once Daily/Linezolid Twice Daily/INH Comparison | 0.04 log10 cfu/ml | Standard Deviation 0.11 |
Comparison: Mean values EBA Days 2-7 for the 3 treatment groups were compared.p-value: 0.25ANOVA
Comparison: The rate of fall in sputum cfu for the 3 treatment groups between day 2 and day 7 of monotherapy was estimated by the slope of the linear regression obtained from fitting the 6 sputum cfu values corresponding to days 2 through 7.p-value: 0.42ANOVA
Comparison: EBA Days 2-7 for INH was compared to that of the pooled linezolid arms.p-value: 0.14Wilcoxon (Mann-Whitney)
Primary
Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Fluoroquinolones/Isoniazid (INH) Comparison
The rate of fall in sputum cfu between day 2 and day 7 of monotherapy was estimated by the slope of the linear regression obtained by fitting the 6 sputum cfu values corresponding to Days 2 through 7.
Time frame: Day 2 to Day 7 Monotherapy
Population: A total of 38 patients were analyzed for Early Bactericidal Activity (EBA) Days 2-7. One patient in the moxifloxacin arm discontinued the study drug after 4 days. One patient in the INH arm discontinued the study drug after 6 days.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Gatifloxacin 400 mg/Day | Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Fluoroquinolones/Isoniazid (INH) Comparison | 0.17 log10 cfu/ml/day | Standard Deviation 0.13 |
| Levofloxacin 1000 mg/Day | Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Fluoroquinolones/Isoniazid (INH) Comparison | 0.18 log10 cfu/ml/day | Standard Deviation 0.13 |
| Moxifloxacin 400 mg/Day | Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Fluoroquinolones/Isoniazid (INH) Comparison | 0.17 log10 cfu/ml/day | Standard Deviation 0.09 |
| Isoniazid (INH) 300 mg/Day | Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Fluoroquinolones/Isoniazid (INH) Comparison | 0.08 log10 cfu/ml/day | Standard Deviation 0.09 |
Comparison: Mean values of EBA Days 2 to 7 for the 4 treatment groups were compared.p-value: 0.51ANOVA
Comparison: The rate of fall in sputum cfu for the 4 treatment groups between day 2 and day 7 of monotherapy was estimated by the slope of the linear regression obtained from fitting the 6 sputum cfu values corresponding to days 2 through 7.p-value: 0.16ANOVA
Comparison: EBA Days 2-7 for patients in the 3 fluoroquinolone groups were pooled and compared to bactericidal activity of patients in the INH arm.p-value: 0.036Wilcoxon (Mann-Whitney)
Primary
Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC)
The adjusted area under the curve (aAUC) for sputum colony forming units (cfu) for each day on treatment was calculated. The aAUC represents the percentage of the expected AUC given no change in log cfu in response to study drug administration.
Time frame: Study drug administration duration - 7 days monotherapy
Population: The aAUC was calculated for 10 subjects per treatment arm (n=40).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gatifloxacin 400 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 1 | 0.98 Percentage | Standard Deviation 0.03 |
| Gatifloxacin 400 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 6 | 0.85 Percentage | Standard Deviation 0.08 |
| Gatifloxacin 400 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 5 | 0.87 Percentage | Standard Deviation 0.08 |
| Gatifloxacin 400 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 2 | 0.96 Percentage | Standard Deviation 0.03 |
| Gatifloxacin 400 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 7 | 0.82 Percentage | Standard Deviation 0.09 |
| Gatifloxacin 400 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 3 | 0.92 Percentage | Standard Deviation 0.05 |
| Gatifloxacin 400 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 4 | 0.89 Percentage | Standard Deviation 0.07 |
| Levofloxacin 1000 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 6 | 0.83 Percentage | Standard Deviation 0.1 |
| Levofloxacin 1000 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 4 | 0.88 Percentage | Standard Deviation 0.08 |
| Levofloxacin 1000 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 3 | 0.91 Percentage | Standard Deviation 0.07 |
| Levofloxacin 1000 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 5 | 0.85 Percentage | Standard Deviation 0.09 |
| Levofloxacin 1000 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 7 | 0.81 Percentage | Standard Deviation 0.1 |
| Levofloxacin 1000 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 2 | 0.95 Percentage | Standard Deviation 0.05 |
| Levofloxacin 1000 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 1 | 0.98 Percentage | Standard Deviation 0.03 |
| Moxifloxacin 400 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 4 | 0.89 Percentage | Standard Deviation 0.09 |
| Moxifloxacin 400 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 1 | 0.96 Percentage | Standard Deviation 0.04 |
| Moxifloxacin 400 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 2 | 0.94 Percentage | Standard Deviation 0.06 |
| Moxifloxacin 400 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 3 | 0.91 Percentage | Standard Deviation 0.08 |
| Moxifloxacin 400 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 5 | 0.87 Percentage | Standard Deviation 0.1 |
| Moxifloxacin 400 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 6 | 0.85 Percentage | Standard Deviation 0.1 |
| Moxifloxacin 400 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 7 | 0.83 Percentage | Standard Deviation 0.1 |
| Isoniazid (INH) 300 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 3 | 0.87 Percentage | Standard Deviation 0.04 |
| Isoniazid (INH) 300 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 7 | 0.80 Percentage | Standard Deviation 0.06 |
| Isoniazid (INH) 300 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 6 | 0.80 Percentage | Standard Deviation 0.06 |
| Isoniazid (INH) 300 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 2 | 0.90 Percentage | Standard Deviation 0.04 |
| Isoniazid (INH) 300 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 1 | 0.95 Percentage | Standard Deviation 0.03 |
| Isoniazid (INH) 300 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 5 | 0.81 Percentage | Standard Deviation 0.05 |
| Isoniazid (INH) 300 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 4 | 0.84 Percentage | Standard Deviation 0.04 |
Comparison: Mean adjusted aAUC for all 4 treatment groups over the 7 days of study drug administrationp-value: <0.001ANOVA
Comparison: Day 1. Pooled sputum bacillary load data for patients in the 3 fluoroquinolones arms were combined and compared to that of patients in the INH arm.p-value: 0.041Wilcoxon (Mann-Whitney)
Comparison: Day 2. Pooled sputum bacillary load data for patients in the 3 fluoroquinolones arms were combined and compared to that of patients in the INH arm.p-value: 0.008Wilcoxon (Mann-Whitney)
Comparison: Day 3. Pooled sputum bacillary load data for patients in the 3 fluoroquinolones arms were combined and compared to that of patients in the INH arm.p-value: 0.012Wilcoxon (Mann-Whitney)
Comparison: Day 4. Pooled sputum bacillary load data for patients in the 3 fluoroquinolones arms were combined and compared to that of patients in the INH arm.p-value: 0.01Wilcoxon (Mann-Whitney)
Comparison: Day 5. Pooled sputum bacillary load data for patients in the 3 fluoroquinolones arms were combined and compared to that of patients in the INH arm.p-value: 0.03Wilcoxon (Mann-Whitney)
Comparison: Day 6. Pooled sputum bacillary load data for patients in the 3 fluoroquinolones arms were combined and compared to that of patients in the INH arm.p-value: 0.091Wilcoxon (Mann-Whitney)
Comparison: Day 7. Pooled sputum bacillary load data for patients in the 3 fluoroquinolones arms were combined and compared to that of patients in the INH arm.p-value: 0.354Wilcoxon (Mann-Whitney)
Primary
Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC)
The adjusted area under the curve (aAUC) for sputum colony forming unit (cfu) for each day on treatment was calculated for patients in the INH arm and those in the Linezolid once daily and Linezolid twice daily arms. The aAUC represents the percentage of the expected AUC given no change in log cfu in response to study drug administration.
Time frame: Study drug administration duration - 7 days monotherapy
Population: The aAUC was calculated for 29 patients. One patient in the linezolid twice daily arm withdrew after randomization before receiving any doses of study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gatifloxacin 400 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 2 | 0.89 Percentage | Standard Deviation 0.08 |
| Gatifloxacin 400 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 5 | 0.83 Percentage | Standard Deviation 0.1 |
| Gatifloxacin 400 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 4 | 0.85 Percentage | Standard Deviation 0.09 |
| Gatifloxacin 400 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 1 | 0.94 Percentage | Standard Deviation 0.06 |
| Gatifloxacin 400 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 7 | 0.83 Percentage | Standard Deviation 0.07 |
| Gatifloxacin 400 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 6 | 0.81 Percentage | Standard Deviation 0.12 |
| Gatifloxacin 400 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 3 | 0.89 Percentage | Standard Deviation 0.03 |
| Levofloxacin 1000 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 4 | 0.96 Percentage | Standard Deviation 0.07 |
| Levofloxacin 1000 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 1 | 0.98 Percentage | Standard Deviation 0.04 |
| Levofloxacin 1000 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 2 | 0.97 Percentage | Standard Deviation 0.07 |
| Levofloxacin 1000 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 3 | 0.96 Percentage | Standard Deviation 0.07 |
| Levofloxacin 1000 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 5 | 0.95 Percentage | Standard Deviation 0.07 |
| Levofloxacin 1000 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 6 | 0.95 Percentage | Standard Deviation 0.07 |
| Levofloxacin 1000 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 7 | 0.95 Percentage | Standard Deviation 0.07 |
| Moxifloxacin 400 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 5 | 0.94 Percentage | Standard Deviation 0.08 |
| Moxifloxacin 400 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 2 | 0.96 Percentage | Standard Deviation 0.07 |
| Moxifloxacin 400 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 7 | 0.93 Percentage | Standard Deviation 0.07 |
| Moxifloxacin 400 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 6 | 0.93 Percentage | Standard Deviation 0.07 |
| Moxifloxacin 400 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 4 | 0.94 Percentage | Standard Deviation 0.08 |
| Moxifloxacin 400 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 3 | 0.95 Percentage | Standard Deviation 0.08 |
| Moxifloxacin 400 mg/Day | Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) | Day 1 | 0.98 Percentage | Standard Deviation 0.04 |
Comparison: Mean adjusted aAUC for all 3 treatment groups over the 7 days of study drug administrationp-value: <0.001ANOVA
Comparison: Day 1. Pooled sputum bacillary load data for patients in the linezolid arms were combined and compared to that of patients in the INH arm.p-value: 0.023Wilcoxon (Mann-Whitney)
Comparison: Day 2. Pooled sputum bacillary load data for patients in the linezolid arms were combined and compared to that of patients in the INH arm.p-value: 0.018Wilcoxon (Mann-Whitney)
Comparison: Day 3. Pooled sputum bacillary load data for patients in the linezolid arms were combined and compared to that of patients in the INH arm.p-value: 0.03Wilcoxon (Mann-Whitney)
Comparison: Day 4. Pooled sputum bacillary load data for patients in the linezolid arms were combined and compared to that of patients in the INH arm.p-value: 0.012Wilcoxon (Mann-Whitney)
Comparison: Day 5. Pooled sputum bacillary load data for patients in the linezolid arms were combined and compared to that of patients in the INH arm.p-value: 0.003Wilcoxon (Mann-Whitney)
Comparison: Day 6. Pooled sputum bacillary load data for patients in the linezolid arms were combined and compared to that of patients in the INH arm.p-value: 0.003Wilcoxon (Mann-Whitney)
Comparison: Day 7. Pooled sputum bacillary load data for patients in the linezolid arms were combined and compared to that of patients in the INH arm.p-value: 0.004Wilcoxon (Mann-Whitney)
Secondary
Area Under the Curve (AUC) Adjusted for Free Drug Concentrations/Minimum Inhibitory Concentration (MIC)
Area Under the Curve 0-12 (AUC 0-12) Adjusted for Free Drug Concentrations/Minimum Inhibitory Concentration (MIC) and AUC 0-24/MIC
Time frame: Day 5 (7 time points)
Population: Twenty-nine patients underwent pharmacodynamic (PD) sampling after receiving 5 daily doses of study drug. One subject in the linezolid twice daily arm withdrew from the study after randomization before receiving any doses of study drug.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gatifloxacin 400 mg/Day | Area Under the Curve (AUC) Adjusted for Free Drug Concentrations/Minimum Inhibitory Concentration (MIC) | AUC 0-12/MIC | 306.7 ug/h/ml |
| Gatifloxacin 400 mg/Day | Area Under the Curve (AUC) Adjusted for Free Drug Concentrations/Minimum Inhibitory Concentration (MIC) | AUC 0-24/MIC | 344.6 ug/h/ml |
| Levofloxacin 1000 mg/Day | Area Under the Curve (AUC) Adjusted for Free Drug Concentrations/Minimum Inhibitory Concentration (MIC) | AUC 0-12/MIC | 107.8 ug/h/ml |
| Levofloxacin 1000 mg/Day | Area Under the Curve (AUC) Adjusted for Free Drug Concentrations/Minimum Inhibitory Concentration (MIC) | AUC 0-24/MIC | 116.2 ug/h/ml |
| Moxifloxacin 400 mg/Day | Area Under the Curve (AUC) Adjusted for Free Drug Concentrations/Minimum Inhibitory Concentration (MIC) | AUC 0-12/MIC | 121.6 ug/h/ml |
| Moxifloxacin 400 mg/Day | Area Under the Curve (AUC) Adjusted for Free Drug Concentrations/Minimum Inhibitory Concentration (MIC) | AUC 0-24/MIC | 243.2 ug/h/ml |
Secondary
Area Under the Curve (AUC) During First 12 and 24 Hours Adjusted for Free Drug Concentrations
Median pharmacodynamic parameters (range) adjusted for free drug concentrations. AUC 0-12 and AUC 0-24 = area under the curve during the first 12 and 24 hours after dosing, respectively
Time frame: Day 5 (7 time points)
Population: Twenty-nine patients underwent pharmacodynamic (PD) sampling after receiving 5 daily doses of study drug. One subject in the linezolid twice daily arm withdrew from the study after randomization before receiving any doses of study drug.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gatifloxacin 400 mg/Day | Area Under the Curve (AUC) During First 12 and 24 Hours Adjusted for Free Drug Concentrations | AUC 0-12 | 15.3 ug/h/ml |
| Gatifloxacin 400 mg/Day | Area Under the Curve (AUC) During First 12 and 24 Hours Adjusted for Free Drug Concentrations | AUC 0-24 | 17.2 ug/h/ml |
| Levofloxacin 1000 mg/Day | Area Under the Curve (AUC) During First 12 and 24 Hours Adjusted for Free Drug Concentrations | AUC 0-12 | 60.1 ug/h/ml |
| Levofloxacin 1000 mg/Day | Area Under the Curve (AUC) During First 12 and 24 Hours Adjusted for Free Drug Concentrations | AUC 0-24 | 66.8 ug/h/ml |
| Moxifloxacin 400 mg/Day | Area Under the Curve (AUC) During First 12 and 24 Hours Adjusted for Free Drug Concentrations | AUC 0-12 | 80.3 ug/h/ml |
| Moxifloxacin 400 mg/Day | Area Under the Curve (AUC) During First 12 and 24 Hours Adjusted for Free Drug Concentrations | AUC 0-24 | 160.7 ug/h/ml |
Secondary
Area Under the Curve During First 12 or 24 Hours / Minimum Inhibitory Concentration (AUC/MIC)
Area Under the Curve (AUC) During First 12 or 24 Hours /Minimum Inhibitory Concentration. AUC reflects total drug (bound and unbound). MIC values were determined using protein-containing media.
Time frame: Day 5 (7 time points)
Population: Thirty-nine patients underwent pharmacokinetic (PK) sampling after receiving 5 daily doses of study drug. One subject in the moxifloxacin arm was discontinued from the study before day 5 and did not undergo PK sampling
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gatifloxacin 400 mg/Day | Area Under the Curve During First 12 or 24 Hours / Minimum Inhibitory Concentration (AUC/MIC) | 85.6 ug/ml |
| Levofloxacin 1000 mg/Day | Area Under the Curve During First 12 or 24 Hours / Minimum Inhibitory Concentration (AUC/MIC) | 129.1 ug/ml |
| Moxifloxacin 400 mg/Day | Area Under the Curve During First 12 or 24 Hours / Minimum Inhibitory Concentration (AUC/MIC) | 110.5 ug/ml |
| Isoniazid (INH) 300 mg/Day | Area Under the Curve During First 12 or 24 Hours / Minimum Inhibitory Concentration (AUC/MIC) | 215.2 ug/ml |
Secondary
Maximum Plasma Drug Concentration (Cmax)
Maximum Plasma Drug Concentration (Cmax), given sampling scheme
Time frame: Day 5 (7 time points)
Population: Twenty-nine patients underwent pharmacokinetic (PK) sampling after receiving 5 daily doses of study drug. One subject in the linezolid twice daily arm withdrew from the study after randomization before receiving any doses of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gatifloxacin 400 mg/Day | Maximum Plasma Drug Concentration (Cmax) | 3.3 ug/ml |
| Levofloxacin 1000 mg/Day | Maximum Plasma Drug Concentration (Cmax) | 15.0 ug/ml |
| Moxifloxacin 400 mg/Day | Maximum Plasma Drug Concentration (Cmax) | 19.4 ug/ml |
Secondary
Maximum Plasma Drug Concentration (Cmax)
Maximum plasma concentration, given sampling scheme
Time frame: Day 5 (7 time points)
Population: Thirty-nine patients underwent pharmacokinetic (PK) sampling after receiving 5 daily doses of study drug. Plasma samples were collected at 7 time points on the 5th day after beginning study drug monotherapy. One subject in the moxifloxacin arm was discontinued from the study before day 5 and did not undergo PK sampling.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gatifloxacin 400 mg/Day | Maximum Plasma Drug Concentration (Cmax) | 4.8 ug/ml |
| Levofloxacin 1000 mg/Day | Maximum Plasma Drug Concentration (Cmax) | 15.6 ug/ml |
| Moxifloxacin 400 mg/Day | Maximum Plasma Drug Concentration (Cmax) | 6.1 ug/ml |
| Isoniazid (INH) 300 mg/Day | Maximum Plasma Drug Concentration (Cmax) | 3.6 ug/ml |
Secondary
Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC)
Time frame: Day 5 (7 time points)
Population: Thirty-nine patients underwent pharmacokinetic (PK) sampling after receiving 5 daily doses of study drug. One subject in the moxifloxacin arm was discontinued from the study before day 5 and did not undergo PK sampling.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gatifloxacin 400 mg/Day | Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC) | 9.5 ug/ml |
| Levofloxacin 1000 mg/Day | Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC) | 15.6 ug/ml |
| Moxifloxacin 400 mg/Day | Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC) | 12.3 ug/ml |
| Isoniazid (INH) 300 mg/Day | Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC) | 70.6 ug/ml |
Secondary
Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC) Adjusted for Free Drug Concentrations
Time frame: Day 5 (7 time points)
Population: Twenty-nine patients underwent pharmacodynamic sampling after receiving 5 daily doses of study drug. One subject in the linezolid twice daily arm withdrew from the study after randomization before receiving any doses of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gatifloxacin 400 mg/Day | Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC) Adjusted for Free Drug Concentrations | 62.7 ug/ml |
| Levofloxacin 1000 mg/Day | Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC) Adjusted for Free Drug Concentrations | 20.0 ug/ml |
| Moxifloxacin 400 mg/Day | Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC) Adjusted for Free Drug Concentrations | 16.2 ug/ml |
Secondary
Maximum Plasma Drug Concentrations (Cmax), Adjusted for Free Drug Concentration
Cmax adjusted for free drug concentrations after 5 days of monotherapy with study drugs
Time frame: Day 5 (7 time points)
Population: Twenty-nine patients underwent pharmacokinetic (PK) sampling after receiving 5 daily doses of study drug. One subject in the linezolid twice daily arm withdrew from the study after randomization before receiving any doses of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gatifloxacin 400 mg/Day | Maximum Plasma Drug Concentrations (Cmax), Adjusted for Free Drug Concentration | 3.1 ug/ml |
| Levofloxacin 1000 mg/Day | Maximum Plasma Drug Concentrations (Cmax), Adjusted for Free Drug Concentration | 10.3 ug/ml |
| Moxifloxacin 400 mg/Day | Maximum Plasma Drug Concentrations (Cmax), Adjusted for Free Drug Concentration | 13.4 ug/ml |
Secondary
Percent Dosing Interval Above Minimum Inhibitory Concentration (MIC)
Determined by linear extrapolation of concentration-versus-time curve to intersection with MIC.
Time frame: Day 5 (7 time points)
Population: Twenty-nine patients underwent pharmacodynamic (PD) sampling after receiving 5 daily doses of study drug. One subject in the linezolid twice daily arm withdrew from the study after randomization before receiving any doses of study drug.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Gatifloxacin 400 mg/Day | Percent Dosing Interval Above Minimum Inhibitory Concentration (MIC) | 95.5 Percentage |
| Levofloxacin 1000 mg/Day | Percent Dosing Interval Above Minimum Inhibitory Concentration (MIC) | 62.8 Percentage |
| Moxifloxacin 400 mg/Day | Percent Dosing Interval Above Minimum Inhibitory Concentration (MIC) | 100.0 Percentage |
Secondary
Pharmacokinetic Parameters: Area Under the Curve (AUC) During First 12 and 24 Hours
Area under the curve (AUC), from time 0-12 hours for INH or 0-24 hours for gatifloxacin, levofloxacin, and moxifloxacin.
Time frame: Day 5 (7 time points)
Population: Thirty-nine patients underwent pharmacokinetic (PK) sampling after receiving 5 daily doses of study drug. Plasma samples were collected at 7 time points on the 5th day after beginning study drug monotherapy. One subject in the moxifloxacin arm was discontinued from the study before day 5 and did not undergo PK sampling.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gatifloxacin 400 mg/Day | Pharmacokinetic Parameters: Area Under the Curve (AUC) During First 12 and 24 Hours | 42.8 ug/h/ml |
| Levofloxacin 1000 mg/Day | Pharmacokinetic Parameters: Area Under the Curve (AUC) During First 12 and 24 Hours | 129.1 ug/h/ml |
| Moxifloxacin 400 mg/Day | Pharmacokinetic Parameters: Area Under the Curve (AUC) During First 12 and 24 Hours | 55.3 ug/h/ml |
| Isoniazid (INH) 300 mg/Day | Pharmacokinetic Parameters: Area Under the Curve (AUC) During First 12 and 24 Hours | 11.9 ug/h/ml |
Secondary
Pharmacokinetic Parameters: Area Under the Curve During First 12 and 24 Hours
Median pharmacokinetic parameters (range). AUC 0-12 and AUC 0-24 = area under the curve during the first 12 and 24 hours after dosing, respectively
Time frame: Day 5 (7 time points)
Population: Twenty-nine patients underwent pharmacokinetic (PK) sampling after receiving 5 daily doses of study drug. One subject in the linezolid twice daily arm withdrew from the study after randomization before receiving any doses of study drug.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gatifloxacin 400 mg/Day | Pharmacokinetic Parameters: Area Under the Curve During First 12 and 24 Hours | AUC 0-12 (ug/h/ml) | 17.0 ug/h/ml |
| Gatifloxacin 400 mg/Day | Pharmacokinetic Parameters: Area Under the Curve During First 12 and 24 Hours | AUC 0-24 (ug/h/ml) | 19.2 ug/h/ml |
| Levofloxacin 1000 mg/Day | Pharmacokinetic Parameters: Area Under the Curve During First 12 and 24 Hours | AUC 0-12 (ug/h/ml) | 87.0 ug/h/ml |
| Levofloxacin 1000 mg/Day | Pharmacokinetic Parameters: Area Under the Curve During First 12 and 24 Hours | AUC 0-24 (ug/h/ml) | 96.9 ug/h/ml |
| Moxifloxacin 400 mg/Day | Pharmacokinetic Parameters: Area Under the Curve During First 12 and 24 Hours | AUC 0-12 (ug/h/ml) | 116.4 ug/h/ml |
| Moxifloxacin 400 mg/Day | Pharmacokinetic Parameters: Area Under the Curve During First 12 and 24 Hours | AUC 0-24 (ug/h/ml) | 232.9 ug/h/ml |
Secondary
Sputum Cytokine Proteins - Results Are Pending.
Time frame: Study drug administration duration
Secondary
Sputum mRNA Clearance Rate - Results Are Pending.
Time frame: Study drug administration duration
Secondary
Time to Maximum Plasma Drug Concentration (Tmax) and Half-life
Time frame: Day 5 (7 time points)
Population: Twenty-nine patients underwent pharmacokinetic (PK) sampling after receiving 5 daily doses of study drug. One subject in the linezolid twice daily arm withdrew from the study after randomization before receiving any doses of study drug.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gatifloxacin 400 mg/Day | Time to Maximum Plasma Drug Concentration (Tmax) and Half-life | Tmax in h (apparent time of max plasma conc.) | 1.0 hours |
| Gatifloxacin 400 mg/Day | Time to Maximum Plasma Drug Concentration (Tmax) and Half-life | Half-life | 3.6 hours |
| Levofloxacin 1000 mg/Day | Time to Maximum Plasma Drug Concentration (Tmax) and Half-life | Tmax in h (apparent time of max plasma conc.) | 1.5 hours |
| Levofloxacin 1000 mg/Day | Time to Maximum Plasma Drug Concentration (Tmax) and Half-life | Half-life | 3.20 hours |
| Moxifloxacin 400 mg/Day | Time to Maximum Plasma Drug Concentration (Tmax) and Half-life | Tmax in h (apparent time of max plasma conc.) | 1.0 hours |
| Moxifloxacin 400 mg/Day | Time to Maximum Plasma Drug Concentration (Tmax) and Half-life | Half-life | 4.56 hours |
Secondary
Time to Maximum Plasma Drug Concentration (Tmax) and Half-life
Time frame: Day 5 (7 time points)
Population: Thirty-nine patients underwent pharmacokinetic (PK) sampling after receiving 5 daily doses of study drug. One subject in the moxifloxacin arm was discontinued from the study before day 5 and did not undergo PK sampling.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gatifloxacin 400 mg/Day | Time to Maximum Plasma Drug Concentration (Tmax) and Half-life | Tmax | 1.5 hours |
| Gatifloxacin 400 mg/Day | Time to Maximum Plasma Drug Concentration (Tmax) and Half-life | Half-life | 6.0 hours |
| Levofloxacin 1000 mg/Day | Time to Maximum Plasma Drug Concentration (Tmax) and Half-life | Half-life | 7.6 hours |
| Levofloxacin 1000 mg/Day | Time to Maximum Plasma Drug Concentration (Tmax) and Half-life | Tmax | 1.0 hours |
| Moxifloxacin 400 mg/Day | Time to Maximum Plasma Drug Concentration (Tmax) and Half-life | Tmax | 1.0 hours |
| Moxifloxacin 400 mg/Day | Time to Maximum Plasma Drug Concentration (Tmax) and Half-life | Half-life | 8.1 hours |
| Isoniazid (INH) 300 mg/Day | Time to Maximum Plasma Drug Concentration (Tmax) and Half-life | Tmax | 1 hours |
| Isoniazid (INH) 300 mg/Day | Time to Maximum Plasma Drug Concentration (Tmax) and Half-life | Half-life | 2.5 hours |