Early Bactericidal Activity of Linezolid, Gatifloxacin, Levofloxacin, Isoniazid (INH) and Moxifloxacin in HIV Negative Adults With Initial Episodes of Sputum Smear-Positive Pulmonary Tuberculosis
Early Bactericidal Activity of Linezolid, Gatifloxacin, Levofloxacin, Isoniazid (INH) and Moxifloxacin in HIV Negative Adults With Initial Episodes of Sputum Smear-Positive Pulmonary Tuberculosis
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.
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.
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.